“Sri Lanka gives gov workers Fridays off so they can farm to ease a food shortage.”
UN Food Chief Halved Refugee Meal Rations As Global Hunger Crisis Worsens
Food riot risks continue to soar worldwide as the head of the food-aid branch of the United Nations halved meal rations for refugees.
On Monday, David Beasley, director of the UN World Food Programme (WFP), released a statement detailing “the heartbreaking decision to cut food rations for refugees who rely on us for their survival.”
“As global hunger soars way beyond the resources available to feed all the families who desperately need WFP’s help, we are being forced to make the heartbreaking decision to cut food rations for refugees who rely on us for their survival,” Beasley said.
Beasley pointed out that WFP already “significantly reduced” rations across its operating areas, indicating cuts up to 50% are affecting 75% of all refugees supported by WFP in Eastern Africa, including Ethiopia, Kenya, South Sudan, and Uganda.
He said “severe funding constraints” has forced WFP to “significantly reduce rations for refugees living in Burkina Faso, Cameroon, Chad, Mali, Mauritania, and Niger.”
“Despite generous support from donors, resourcing remains insufficient to meet the very basic needs of refugee households and imminent disruptions are expected in Angola, Malawi, Mozambique, Republic of Congo, Tanzania, and Zimbabwe,” the statement read.
“Without urgent new funds to support refugees – one of the world’s most vulnerable and forgotten groups of people – many facing starvation will be forced to pay with their lives,” Beasley warned.
Beasley’s statement shouldn’t surprise readers because we’ve detailed in length that this would happen as many vulnerable countries were already on the brink of food shortages.
WFP warned in April about the toxic combination of food disruptions due to the Ukraine conflict and soaring food inflation that has created an unprecedented global food crisis that is only worsening.
“This, coupled with devastating conflict and climate extremes, is hitting refugees the hardest,” WFP said.
Bloomberg Economics recently outlined Nigeria, India, Colombia, the Philippines, and Turkey are countries to monitor for food riots. Peru and Sri Lanka have already been two countries undergoing social instability. Notice global food prices are above 2010/11 Arab Spring levels.
The shortage of essential food staples putting millions of lives in jeopardy and risk destabilizing couentries will be a top threat through at least 2023 as the 2022 Northern Hemisphere planting season could be underwhelm in terms of the harvest due to the Ukraine conflict and resulting Western sanctions on Russia, soaring energy and fertilizer costs, and climate woes plaguing agriculturally rich areas.
As a reminder, Rockefeller Foundation President Rajiv Shah initiated the six-month countdown to a “massive, immediate food crisis” in April.
Iranian institutions facing food shortages as prices skyrocket
low-income Iranians line up to receive food supplies in southern Tehran, 03 Feb, 2014. (AFP)
Local media in Iran say public institutions such as hospitals, prisons, and child-care centres are facing possible food shortages due to skyrocketing prices.
The Tehran-based Etemad newspaper reported on June 15 that the impending “problem” could hit in “the coming weeks” and that “food supplies will be disrupted not only in hospitals but also in other government facilities such as barracks, prisons, nursing homes, and even student dormitories.”
Etemad quoted the head of a private hospital as saying that a sharp rise in food prices has affected the quality of hospital food to such an extent that freshly made items are likely to be eliminated in public and private hospitals, with packaged foods being used instead.
The head of the hospital, who asked not to be identified, added: “In the coming weeks, it will be impossible for many public or private medical centres to provide hot meals, especially protein-rich foods, to hospitalized patients because this increase in food prices was not seen in any hospital budget.”
“Since last year, the head of the hospital has cut off food for staff and nurses, and for those nurses who have 12-hour daily shifts, a sum of 150,000 Iranian rials ($0.40) per shift is paid instead of meals,” a nurse at a public hospital in Tehran said.
Iran’s economy has been devastated by years of harsh sanctions imposed by Washington since the United States pulled out of an accord with global superpowers aimed at curbing Tehran’s nuclear program.
The perceived mismanagement of the economy and anger about rising prices has prompted many Iranians to protest in recent months over the government’s inability to help their lives.
A government decree this year raised the amount of money given to public hospitals by 19.5 percent and by 24 percent for private hospitals. Food costs, however, have increased by up to 30 per cent in public hospitals and by up to 40 per cent in private hospitals.
A May survey by the Statistics Center of Iran on changes in the prices of high-consumption items showed that the prices of 53 food items increased significantly over the same month in 2021.
“Patients admitted to 60 intensive-care units in the country’s hospitals receive less than 62 per cent of their calories and about 54 per cent of their protein needs,” Abdolreza Norouzi, secretary of the National Working Group on Nutrition Science Development, recently warned.
“The situation in the intensive-care units for children and infants is much worse. Premature babies who have no nutritional reserve receive an average of about 48 per cent of the calories and energy they need,” he added.
As Po dries up, Italy’s food and energy supplies are at risk
And here it is, the water shortage that was told to me 3 years ago and said it would coincide with the food shortages. I thought, how can they do this with all the damns etc.
But it’s happening and I doubt my mate predicted the weather.
Water is so low in large stretches of Italy’s largest river that local residents are walking through the middle of the expanse of sand and shipwrecks are resurfacing.
Authorities fear that if it doesn’t rain soon, there’ll be a serious shortage of water for drinking and irrigation for farmers and local populations across the whole of northern Italy.
In a park near the central northern village of Gualtieri, cyclists and hikers stop in curiosity to observe the Zibello, a 50-meter long (164 feet) barge that transported wood during the second world war but sank in 1943. It is normally covered by the Po’s waters.
“It’s the first time that we can see this barge,” said amateur cyclist Raffaele Vezzali as he got off the pedals to stare at the rusted ship. Vezzali was only partially surprised, though, as he knew that the lack of winter rain caused the river to reach record low levels.
But the curiosities of a resurfaced wartime boat and wide sandy beaches do little to mask the disruption this will cause for residents and farmers.
The drying up of the Po, which runs 652 kilometers (405 miles) from the northwestern city of Turin to Venice, is jeopardizing drinking water in Italy’s densely populated and highly industrialized districts and threatening irrigation in the most intensively farmed part of the country, known as the Italianfood valley.
Northern Italy hasn’t seen rainfall for more than 110 days and this year’s snowfall is down by 70%. Aquifers, which hold groundwater, are depleted. Temperatures of 2 degrees Celsius (3.6 degrees Fahrenheit) above season average are melting the tiny snowfields and glaciers that were left on the top of the surrounding Alps, leaving the Po basin without its summer water reservoirs.
All these factors are triggering the worst drought in 70 years, according to the Po River Basin Authority.
“We are in a situation where the river flow is approximately 300 cubic meters (80,000 gallons) per second here in (the riverside village of) Boretto, while normally in this area we have almost 1800 (cubic meters, 476,000 gallons),” explained Meuccio Berselli, secretary-general of the Po River Basin Authority.
The authority is constantly monitoring the river flow but there is very little hope that weather will help. The little rainfall that occurred in June was extreme and localized downpours that weren’t absorbed by the land and didn’t reach the Po and its aquifers.
Berselli is frantically working at a resiliency plan to guarantee drinking and irrigation water to millions of households and to the Po valley farmers, who produce 40% of Italian food. Parmesan cheese, wheat, high-quality tomatoes, rice and renowned grapes grow in huge quantities in the area.
The resilience plan includes higher draining from Alpine lakes, less water for hydroelectric plants and rationing of water in the upstream regions.
The Po drought comes at a time when farmers are already pushing both irrigation and watering systems to their maximum to counter the effect of high temperatures and hot winds.
Martina Codeluppi, a 27-year-old farmer from the tiny rural town of Guastalla, says her fields are entirely irrigated with the water coming from the Po and are already suffering due to the lack of winter and spring rain. She said she’s expecting a “disastrous year.”
“With such high temperatures… with no rain, and it seems that there won’t be rain in the coming days, the situation is catastrophic,” said Codeluppi, as she walked through her family’s fields. She’s proudly growing pumpkins, watermelons, wheat, and grapes on farmland passed down through the family, but she’s extremely concerned about what this year’s harvests will yield.
“We believe that there will be a drop in this wheat productivity by at least 20% or more due to the lack of rain and irrigation,” she said. The Italian farmers confederation estimates that wheat yields could drop by 20% to 40% this year. Wheat is a particular concern for farmers as it’s completely reliant on rain and does not get irritated.
The irrigation system is also at risk. Usually, river water is lifted with diesel fueled electric pumps to upper basins and then flows down in the vast fields of the valley through hundreds of waterways. But now, pumps are at risk of failing to draw water and excavators are frantically working to constantly dredge dedicated waterways to ensure the water necessary for irrigation.
The water shortage won’t just hamper food production, but energy generation, too. If the Po dries up, numerous hydroelectric power plants will be brought to a halt, at a time when the war in Ukraine has already hiked up energy prices across Europe.
According to a state-owned energy service system operator, 55% of the renewable energy coming from hydroelectric plants in Italy comes from the Po and its tributaries. Experts fear that a lack of hydroelectric power will contribute to increased carbon dioxide emissions, as more electricity will have to be produced with natural gas.
“On the top of the critical situation we are creating an additional damaging situation,” said the Po river authority’s Berselli about the likely surge of greenhouse gas emissions.
Swimming chiefs limit transgender participation
Fina also intends to establish a new ‘open’ category for swimmers whose gender identity differs from their birth sex
Swimming’s world governing body, Fina, has voted to ban all transgender athletes that have gone through any part of male puberty from taking part in elite women’s races.
Fina’s new policy, which passed with 71% of votes from 152 Fina members, has been described as “only a first step towards full inclusion” for transgender athletes and was made at an extraordinary general congress at the World Championships currently ongoing in Budapest.
Furthermore, Fina also aims to establish an ‘open’ category at its competitions for swimmers whose gender identities differ from their birth sex.
The new policy will require that transgender competitors must have completed their transition by the time they are 12 years old to take part in women’s competitions.
Before casting their votes, Fina members heard a report from a transgender task force containing leading figures in the worlds of sport, medicine, and law.
Speaking after news of the vote broke, Fina’s executive director Brent Nowicki said that the governing body had “emphasized competitive fairness” in its approach to drafting the policy, which was comprehensive, science-based and inclusive.
Elsewhere, Fina president Husain Al-Musallam claimed that the global authority was trying to “protect the rights of our athletes to compete” in addition to “protecting competitive fairness”.
“Fina will always welcome every athlete,”Al-Musallam insisted. “The creation of an open category will mean that everybody has the opportunity to compete at an elite level.”
“This has not been done before, so Fina will need to lead the way. I want all athletes to feel included in being able to develop ideas during this process,” he added.
Sharron Davies, an ex-Great Britain swimmer who has continually argued against transgender participation in women’s swimming, tweeted that she was “proud” of Fina and her sport for “doing the science, asking the athletes/coaches and standing up for fair sport for females”.
“Swimming will always welcome everyone no matter how you identify but fairness is the cornerstone of sport,” she stressed.
But LGBT advocacy group ‘Athlete Ally’ branded the new policy“discriminatory, harmful, unscientific and not in line with the 2021 IOC principles”.
“If we truly want to protect women’s sports, we must include all women,”said a tweet from the group, which has backed former UPenn college swimmer Lia Thomas in the past.
Fina’s new policy comes at a time when transgender participation in women’s competitions is one of the most debated topics in sport and has only intensified with Thomas’ success.
In March, Thomas, who swam on the UPenn men’s team before undergoing hormone replacement treatment in 2019, won the highest national college title in the US when taking part in the women’s 500-yard freestyle, and she also broke several records at her former Ivy League college.
In cycling, there has also been a furore over whether British cyclist Emily Bridges is allowed to take part in elite women’s events or not.
Moves from Fina’s counterpart in the sport the UCI this week mean that she will have to wait until 2023 for this given that the body has doubled the period before a rider who has transitioned from male to female can take part in women’s events to two years.
Do you see what they’re doing with their propaganda?
They want you dependent on their toxic food system. Period.
6 million chickens were culled in the U.S. And 97 food processing plants have were destroyed, hundreds of thousands of tonnes of fertilizer were destroyed in TWO separate trains that both left the tracks. One in Canada and the United States.
DO YOU SEE WHAT THEY ARE DOING?
Australia has an apparent Swine Flu and is culling pigs. America also has a foot and mouth problem and is killing cows and deer.
The UK has had a few food processing plants catch fire too. Just happened to be CHICKEN plants..
So why? Well, I’ve mentioned this before. The UN has a protein alternative set up. And yes it’s true. You can find it on the UN website.
In case of an emergency of hunger or famine, the UN has a stockpile of protein alternatives. These include crushed-up insects like grasshoppers, mealworms and cockroaches.
Less hard work and cost. No real farming, Someone in the WEF has most definitely started up this supply chain waiting to go.
Deutsche Bank now expects ‘an earlier and somewhat more severe recession’
The first economist on Wall Street to predict a U.S. recession in 2023 is moving up his timeline for an economic contraction.
“More than two months ago we forecasted that the U.S. economy would tip into a recession by end-2023,” Deutsche Bank Chief U.S. economist Matt Luzzetti wrote in a note to clients on Friday. “Since that time, the Fed has undertaken a more aggressive hiking path, financial conditions have tightened sharply and economic data are beginning to show clear signs of slowing. In response to these developments, we now expect an earlier and somewhat more severe recession.”
Luzzetti now sees U.S. gross domestic product (GDP) growth coming in at “sub-1%” in the first half of 2023, followed by a -3.1% contraction in the third quarter of 2023 — one quarter earlier than Luzzetti previously estimated. In the fourth quarter of 2023, Luzzetti expects growth to contract by another -0.4%.
Source: Deutsche Bank
“The upshot is that the economy is likely to contract next year by about 0.5%,” the note stated. “A more severe downturn leads to a higher unemployment rate, which peaks near 5.5%. The weaker labour market helps to guide inflation closer to target by 2024, though we still anticipate a nearly half per cent overshoot at that point.”
Luzzetti and team also see the Consumer Price Index (CPI) peaking at 9% in the third quarter of 2022. CPI, a closely watched measure of what Americans pay for goods and services, was up 8.6% year-over-year as of May — the most since 1981.
Storm clouds loom over an American flag in Convent, Louisiana, U.S., June 11, 2018. REUTERS/Jonathan Bachman
Recession fears are picking up across Wall Street and the C-Suite as the Federal Reserve embarks on an aggressive pace of rate hiking. On Wednesday, the Fed lifted rates by 75 basis points as the central bank took a harder tone on stomping out inflation.
On Friday, the Fed reiterated his hawkish stance on policy by noting in a report to Congress that the monetary body is “acutely” focused on bringing down inflation. The commentary weighed on stocks yet again despite the S&P 500 and Nasdaq Composite already being in a bear market.
“A more severe tightening of financial conditions could easily pull forward recession risks to around the turn of the year, which could short-circuit the Fed’s tightening cycle,” added Luzzetti. “That said, higher inflation during that period would likely constrain the Fed’s ability to cut rates to counteract the downturn. On the other side, a more resilient economy in the near-term with more persistent inflation pressures would spell upside risk to our Fed view.”
NEW – Powell: “Rapid changes are taking place in the global monetary system
A US central bank digital currency is being examined to “help the US dollar’s international standing.”
“Due to de-dollarization, we will now need a digital dollar Central Bank Digital Currency”
— what an amazing statement! 3 years ago when all this was being said by myself and others, people wanted us to die of covid.
NEW – Powell: "Rapid changes are taking place in the global monetary system that may affect the international role of the dollar."
A US central bank digital currency is being examined to "help the US dollar's international standing." pic.twitter.com/htP6r1brNz
Marching towards starvation’: UN warns of hell on earth if Ukraine war goes on
This is a joke. Russia is being blamed for everything. All because he would not go ahead with Dr Evils’ ( Klaus Schwab ) plan and started exposing the WEFs whole agenda.
But they censored Russia and started blaming him for everything. Even meddling with the U.S elections. 🙈
This war will carry on for another year. If you read my blogs you will know this.
So Putin must be responsible for the 97 food plants that were destroyed? Because if anything is going to cause a food shortage, I think that may be it.
Dozens of countries risk protests, riots and political violence this year as food prices surge around the world, the head of the food-aid branch of the United Nations has warned.
Speaking in Ethiopia’s capital, Addis Ababa, on Thursday, David Beasley, director of the UN World Food Programme (WFP), said the world faced “frightening” shortages that could destabilise countries that depend on wheat exports from Ukraine and Russia.ÿ
“Even before the Ukraine crisis, we were facing an unprecedented global food crisis because of Covid and fuel price increases,” said Beasley. “Then, we thought it couldn’t get any worse, but this war has been devastating.”
Ukraine grows enough food every year to feed 400 million people. It produces 42% of the world’s sunflower oil, 16% of its maize and 9% of its wheat. Somalia relies on Ukraine and Russia for all of its wheat imports, while Egypt gets 80% of its grain from the two countries.
The WFP sources 40% of the wheat for its emergency food-relief programmes from Ukraine and, after its operating costs rose by $70m (£58m) a month, it has been forced to halve rations in several countries.
Citing increases in the price of shipping, fertiliser and fuel as key factors – due to Covid-19, the climate crisis and the Ukraine war – Beasley said the number of people suffering from “chronic hunger” had risen from 650 million to 810 million in the past five years.
Beasley added that the number of people experiencing “shock hunger” had increased from 80 million to 325 million over the same period. They are classified as living in crisis levels of food insecurity, a term he described as “marching towards starvation and you don’t know where your next meal is coming from”.
Beasley said that after the economic crash of 2007-09, riots and other unrest erupted in 48 countries around the world as commodity prices and inflation rose.
SO, if you have been listening, or if you do not believe what I say? Then this is why I kept the best story last.
World’s Largest Cricket protein ‘factory’ completed in Ontario — “you really will eat ze bugs”:
Aspire’s the new plant will reportedly produce 9000 metric tons of crickets every year for human and pet consumption. — about two billion insects are distributed annually across Canada and throughout the United States.
Aspire also reports that it already has orders for the next two years.
Crickets are currently being explored as a protein-rich superfood. They contain fibre and are already found in grocery stores and restaurants, and have a smaller environmental footprint than traditional protein sources.
On May 26th, Aspire Food Groupannounced that it has completed construction of its alternative protein manufacturing facility. London, Ontario is now home to the world’s largest cricket production facility.
Aspire’s the new plant will reportedly produce 9000 metric tons of crickets every year for human and pet consumption. That’s about two billion insects to be distributed annually across Canada and throughout the United States.
Aspire also reports that it already has orders for the next two years.
Crickets are currently being explored as a protein-rich superfood. They contain fibre and are already found in grocery stores and restaurants, and have a smaller environmental footprint than traditional protein sources.
The construction was led by EllisDon, and the new London facility, which will be fully operational in the fall, reportedly showcases four first-of-a-kind newly developed technologies; an automated storage retrieval system (ASRS), a new type of HVAC system, a 5G IoT network and an AI solution that’s been recognized by UNESCO.
AUS: Fruit and vegetable costs to skyrocket in coming weeks
Aussies are being warned the price of all fruit and vegetables will spike in the coming weeks as farmers face labour shortages and growing production costs.
Tyson Cattle, from the national industry representative AusVeg, told Today the issues were critical and “impacting grower confidence to plant more crops”.
“They’re unable to access the pickers and packers needed to get crops off the ground and onto supermarket shelves,” Tyson told Today.
The plan for creating a food shortage is set at high speed. I have told people to prep but they don’t listen. So please stock now before it’s too late for you to find food.
Here’s something I have posted before. Google can not edit books.
Monkeypox can only be a serious problem for humans if it has been meddled with. For instance, GOF, ( gain of function )
The National Institute of Allergy and Infectious Diseases, directed by Dr. Anthony Fauci, last year paid $9.8 million to government researchers to test a monkeypox treatment. Some called the timing “curious” given the recent outbreak of the virus.
The National Institute of Allergy and Infectious Diseases (NIAID), directed by Dr. Anthony Fauci, last year paid $9.8 million to government researchers to test a monkeypox treatment, the National Pulse reported.
According to the National Institutes for Health (NIH), which oversees the NIAID, the research began Sept. 28, 2020 and will conclude Sept. 27, 2025. Its goal is to carry out a “randomized, placebo-controlled trial of the safety and efficacy of tecovirimat for the treatment of patients with monkeypox virus disease.” It is unclear if the grant provided for any payments in 2020.
The NIAID awarded the grant to the Frederick National Laboratory for Cancer Research, a federally funded research and development center in Frederick, Maryland, supported by the National Cancer Institute.
According to the grant abstract:
“The similarity between monkeypox and the variola [smallpox] virus, coupled with concerns about the potential of the variola virus as a potential bioterrorism agent, have placed monkeypox treatments at the forefront of public health and scientific research agendas in many countries.”
On May 25, SIGA Technologies Inc.announced that it received approval from the U.S. Food and Drug Administration (FDA) for an intravenous formulation of the antiviral tecovirimat (called TPOXX) for the treatment of smallpox.
Although smallpox was eradicated in 1980, the treatment was developed in the event smallpox were to be used as a bioweapon.
The U.S., Canada and Europe have approved an oral formulation of TPOXX for treating smallpox, and Europe also approved it for treating monkeypox and cowpox.
As of May 30, the NIH project had not generated any publicly available studies, papers or patents, according to The National Pulse.
The National Pulse called the timing of the grant “curious,” as it comes while pharmaceutical giants including Pfizer and Johson & Johnson are making record-level profits due to the COVID-19 pandemic.
Dr. Lori Dodd, a mathematical statistician in the biostatistics research branch of NIAID, is the project’s principal investigator.
On a recent segment of The Hill’s “Rising,” co-hosts Briahna Joy Gray and Kim Iversen reminded viewers that Dodd was “exposed for her involvement in the agency’s reported data altering of remdesivir trials to make [remdesivir] seem more effective against COVID.”
Iversen and Gray also found the timing of the funding suspicious.
“It could just be coincidental,” said Iversen, “ … but I will say that there is something very suspect about the fact that they started working on identifying treatments for monkeypox in September of 2020. This has been a virus that’s been around since 1970.”
However, Gray said, “in a world where everyone’s certainly concerned about viruses because of COVID-19, maybe the money simply started to flow in the fall of 2020.”
“What’s odd,” responded Iversen, “is that there’s now suddenly an outbreak [of monekypox] and that outbreak is making headlines and it’s spreading all around the world.”
Iversen implied the NIH may be hoping to develop a new treatment for monkeypox as public fear of the disease grows.
As The Defender has reported, others also questioned how unexpected the monkeypox outbreak was after learning about a March 2021 tabletop simulationof a hypothetical deadly outbreak of monkeypox predicted to occur in May 2022.
The National Pulse reported that a February 2022 peer-reviewed studyrevealed scientists performed a monkeypox-related gain-of-function research project at the Wuhan Institute of Virology in August 2021.
EVIDENCE OF MILLIONS OF DEATHS AND HUNDREDS OF MILLIONS OF SERIOUS ADVERSE EVENTS RESULTING FROM THE EXPERIMENTAL COVID INJECTIONS
The Vaccine Death Report shows all the scientific evidence that millions of innocent people lost their lives and hundreds of millions are suffering crippling side effects, after being injected with the experimental covid injections. The report exposes the strategic methods used by governments and health agencies to hide 99% of all vaccine injuries and deaths. You will also learn who is really behind all of this, and what their true agenda is.
The report also shows horrifying lab results from microscopic investigation of some vaccine vials: living creatures with tentacles, as well as self-assembling nanorobots. See pictures:
These creatures and self-assembling and self-replicating nanobots are present in some of the vaccines!
The Vaccine Death Report contains a tremendous amount of critical information, that you will find nowhere else in such a comprehensive and well organized format. It ends with a strong message of hope, that will greatly empower you.
This report is a critical alarm call to the world. Download it now, and distribute it far and wide.
Now if you have been paying attention to my blogs, you will already see what is happening here. These scientists ( if they exist ) are well paid to say whatever they are told to say.
The vaccines ( Kill shots ) have been causing almost every blood disorder on the planet. Although some are not reported because the doctors think it’s just normal cancer of the blood because of the backlog.
But none can deny that Myocarditis is a direct result of the vaccine ( kill shot )
Once a rare disorder in those under 24 years of age and even more rare in those under 14 years of age has become a vivid scene for undertaken. But more than that it has become a sad and devastating reality for thousands of parents and sisters and brothers and families of those who have died. Over a thousand professional sports players have collapsed or died in the middle of a game.
I lost 9 very good friends last year and many acquaintances. This year already I have lost one family member and 4 acquaintances. That’s 14 people. One young girl who was a friend of my daughter’s age 23, died 7 days after her vaccine of a brain haemorrhage. One very close friend died of cancer a short time after his vaccine. His vaccine brought back his cancer so quickly and aggressively that it killed him within a week. I was outside his hospital door unable to go in a few hours before he died. He was 55 years old.
Anyway back to myocarditis. Monkeypox is being made out to be a small matter at the moment. But I can assure you that it will be a pandemic. They are building up to it slowly because covid is dying out in people’s minds because of the work people called conspiracy theorists do.
So because myocarditis is proven to be the cause of vaccine damage and there’s no informed consent, the government are being held reliable. And we all know that the government do not like to give the people the money that they are entitled to.
Even the emergency use authorisation ( EUA ) should not still be active because the pandemic is over. But still, even though they know that the kill shots are causing millions of deaths and millions of injuries, they have used an illegal EUA to allow untested kill shots knowing that thousands of you will die. But of course, it’s all to do with your health.
Lockdown and all the other restrictions were killers that didn’t work too. Or Lockstep I like to call it. Did you know that 192 countries all scrapped their decades-old pandemic mandates at the same time and mysteriously all followed the same New rules set out by the 192 countries WITHOUT supposedly contacting any of the other leaders etc?
Every country is the same. Except for China! They had the lab leak and there were videos of people falling dead in the street. 🙄
But now look at them. They did their bit and didn’t have to pretend anymore.
There is no smallpox in the world!
The approved drug causes heart damage, myocarditis, and pericarditis, but the DOD, in its quest to decimate the American military allowed it in 2018.
The US government has millions of doses, even though there aren’t confirmed smallpox cases.
And the UK just ordered tens of thousands of the monkeypox kill shots as planned but, Don’t work. They will cause the deaths that are mentioned and just like Covid, only the vaccinated will get so-called monkeypox, become unwell or die. But this won’t target the elderly, this will target anyone who has no critical thinking and is clouded by the media telling them they are conspiracy theories.
here’s a paragraph from a book on viruses. The good thing about books is Google and Wikipedia can not edit them. Have a read on monkeypox
Does not appear to be highly infectious and is not thought to be a great risk to humans
There is a video here you can watch by Dr Jane Ruby.
The link below for a video if you would like to hear a video from a professional.
Today you will hear Dr Jane Ruby Show, where she speaks about the latest combination of Smallpox/Monkeypox vaccines, approved four years ago!
Thank you for reading.
Please share this with everyone. I’m not after the followers so they don’t have to sign up and like them. I’m doing my bit by researching everything I have sent to myself, watching government websites worldwide and the CDC, WHO, WEF, NIH, CHAN ZUCKERBERG and many more websites.
Remember that the Americans are blaming Russia for everything. You name it and it will be Russian disinformation.
Well if you look at my blog “ what’s happening really in Ukraine “ you will see firsthand footage of the citizens speaking out, and plenty of other Russian Ukraine war and other updates.
Please remember to share and stop this fake monkeypox kill shot from being put into every one. Save lives, don’t let them take the shot.
An Inquest, Likely due to the family not expecting an ‘unexplained’ death and pushing for answers, is further proof of the dangers of the Pfizer Vaccine. Another healthy young woman, daughter, mother and wife has lost her life from being coerced by our lying governments, global ‘health agencies’ and big Pharma.
She leaves behind her year old son… How many more will we lose, how many children?
‘A post-mortem examination on the body of Dawn Wooldridge had previously proved inconclusive but an inquest heard on Thursday that the unexpected death, which happened 11 days after Dawn’s first Covid jab, was likely caused as a result of the vaccination.
The 36-year-old was found dead in her home by her brother in June last year, after she failed to collect her five-year-old son from school that day.
In a statement to the Berkshire coroner by Dawn’s husband, Ashley, he said: “We met on holiday in Turkey and we have been married for seven years this year.’
t.me/FionaRoseDiamond
Davos Man, his World Economic Forum, and his Servants
The purpose of this essay and the accompanying spreadsheet is to provide you with information and transparency about who these people are, where they come from, what their ethics and policy positions are, where they work, what sectors they work in, and when they were trained to do the bidding of the World Economic Forum (“WEF”).
These people have been trained to believe in and support a globalist form of unelected government, in which business is at the centre of the management and decision-making process. They are fundamentally anti-democratic, and their views are both fundamentally corporatist and globalist, which is another way of saying that they are for totalitarian fascism – the fusion of the interests of business with the power of the state – on a global scale.
The Malone Institute, in collaboration with the Pharos Foundation and Pharos Media Productions in Sweden, has invested months of time and hundreds of labour hours to mine existing and historic publicly available data sources to develop a detailed summary of graduates from two WEF training programs; Global Leaders of Tomorrow (a one-year program that ran from 1993 to 2003) and Young Global Leaders (a five-year program started 2004/2005 and still running).
The current 100 WEF full members (“Strategic Partners”) are drawn from the largest corporations in the world, together with their owners and managers (referred to as “Davos Man”). The list of corporations, owners and managers who control the WEF is not disclosed and membership can only be inferred indirectly. However, the WEF members do not act alone, but have developed various groups of globally distributed trainees who generally act in accordance with the detailed policies and positions developed and distributed by WEF leadership. These training programs have been operating for over three decades, resulting in placement, distribution and rapid advancement of many thousands of WEF-trained operatives throughout the world. WEF chairman Klaus Schwab has famously claimed that these operatives have been strategically inserted into key positions in various governments, as well as influential spots in key industries such as media, finance, and technology.
“Davos Man” is a term coined by former Harvard University Director of the Centre for International Affairs Professor Dr. Samuel Huntington (1927-2008) to define an emerging group of economic elites who are members of a social caste which has “little need for national loyalty, view national boundaries as obstacles that are thankfully vanishing, and see national governments as residues from the past whose only useful function is to facilitate the elite’s global operations.” The title of his prescient 2004 article published in The National Interest is telling: “Dead Souls: The Denationalisation of the American Elite”.
In a 2005 article published in The Guardian titled “Davos man’s death wish”, Timothy Garton Ash described Davos Man and the World Economic Forum:
“Davos Man is mainly white, middle-aged and European or Anglo-Saxon. Of course, some of the participants at this year’s five-day meeting of the World Economic Forum in the Swiss mountain resort were Indian, Chinese, African or/and women. But they continue to be a minority. The dominant culture of Davos remains that of white western man
“Davos man has a troublesome pre-history of combining brilliance and stupidity, of being blinded by national and ideological prejudice to his own long-term interest and destroying with one hand what he has built with the other.”
Wikipedia defines “megalomania” as “an obsession with power and wealth, and a passion for grand schemes.” It also relates this term to the following psychological terms: Narcissistic personality disorder, Grandiose delusions, and Omnipotence (psychoanalysis), a stage of child development. Davos Man fits the definition of megalomania and has acquired what he believes are the financial and political resources to try to force his obsession and grand schemes on the world, and to force you, your family, and the world to comply with his vision.
Regarding the WEF, Andrew Marshall developed a brief introductory summary which I strongly recommend reading, published in a 2015 article entitled “World Economic Forum: a history and analysis”. The membership of the WEF is divided into three categories: Regional Partners, Industry Partner Groups, and the most esteemed, the Strategic Partners. Membership fees from corporations and industry groups finance the Forum and provide the member company with extra access and to set the agenda. A full list of current Strategic Partners can be found HERE.
“Why should you care?”
The WEF is the organisation which has masterminded the globally harmonised planning, development and implementation of the lockdowns, mandates, authoritarian vaccine campaigns, suppression of early treatment options, global targeting of dissenting physicians, censorship, propaganda, information and thought control programs which we have all experienced since late 2019. This is the organisational structure used by the ones who have sought to control and manage the world to advance the economic and political interests of their members through the ongoing “Great Reset” (as named and described by their chairman Klaus Schwab) by exploiting and exacerbating the social and economic disruption which they have artificially and intentionally crafted since SARS-CoV-19 began spreading across the world.
The musings and plans of this trade organisation read and sound like the implausible sinister plot of an international spy novel concocted by a second-rate version of Ian Fleming, John Le Carre, or Robert Ludlum. Unfortunately, they are backed by the financial resources of many of the wealthiest people in the world. For examples of the muddled thinking and pseudo-science which these self-appointed masters of the universe proudly publish, I recommend that you do your best to read COVID-19: The Great Reset, The Great Narrative for a better future (both by Klaus Schwab and Thierry Malleret), and How to Prevent the Next Pandemic (by Bill Gates). A detailed interactive summary of their policy positions and the interrelationships of those policies (“transformation map”) can be found HERE and for COVID-19, HERE.
“What can you do about it?”
After all you have seen and experienced since September 2019, please look in the mirror and ask yourself these two questions:
“Are these people I can trust with my future and that of my children?”
“Do they represent my interests, values, and what I believe in?”
If you decide that you cannot trust them, or that they do not share your interests and values, then it is high time to act to prevent them from taking control of all aspects of your life. Otherwise, the WEF seeks to take away everything you own, and to completely control all aspects of your life. One of the key predictions of their “Global Future Councils” is that by 2030, you (or your children) will own nothing, and will be happy. Here is a LINK to other aspects of their vision of tomorrow.
Whatever your answer, you deserve to know who these people are that wish to control the world, your daily life, what information you can access, what you are allowed to think, and what you are allowed to own. You deserve to know who they represent, and what are their names. The purpose of this essay and the accompanying spreadsheet is to provide you with information and transparency about who these people are, where they come from, what their ethics and policy positions are, where they work, what sectors they work in, and when they were trained to do the bidding of the WEF (there are often close bonds between members of the same class year).
These people have been trained to believe in and support a globalist form of unelected government, in which business is at the centre of the management and decision-making process. They have been trained to advance the interests of a global transnational government which represents a public-private partnership in which the business interests of the WEF members take precedence over the constitution of the United States. The WEF believes that the concept of independent nation-states is obsolete and must be replaced with a global government which controls all. They are fundamentally anti-democratic, and their views are both fundamentally corporatist and globalist, which is another way of saying that they are for totalitarian fascism – the fusion of the interests of business with the power of the state – on a global scale. These people do not represent the interests of the nation-state in which they reside, work, and may hold political office, but rather their allegiance appears to be to the WEF vision of a dominant world government which has dominion over nations and their constitutions. In my opinion, in the case of those trainees and WEF members who are in politics, and particularly those who have been used to “penetrate the global cabinets of countries”, these persons should be forced to register as foreign agents within their host countries.
Davos Man’s Servants are Foreign Agents. The full title of the US Foreign Principal Registration Act of 1938 (FARA) is “An Act to require the registration of certain persons employed by agencies to disseminate propaganda in the United States and for other purposes.” Citing Wikipedia,
“The Foreign Agents Registration Act (FARA) (2 U.S.C. § 611 et seq.) is a United States law requiring persons engaged in domestic political or advocacy work on behalf of foreign interests to register with the Department of Justice and disclose their relationship, activities, and related financial compensation. Its purpose is to allow the government and general public to be informed of the identities of individuals representing the interests of foreign governments or entities. The law is administered and enforced (or not…) by the FARA Unit of the Counterintelligence and Export Control Section (CES) in the National Security Division (NSD).”
The List of WEF Trainees
The Malone Institute (primarily Dr. Jill Glasspool-Malone and Anita Hasbury-Snogles), in collaboration with the Pharos Foundation and Pharos Media Productions in Sweden, has invested months of time and hundreds of labour hours to mine existing and historic publicly available data sources to develop a detailed summary of graduates from two WEF training programs; the World Economic Forum’s Global Leaders of Tomorrow (a one-year program that ran from 1993 to 2003) and Young Global Leaders (a five-year program started 2004/2005 and still running). Pharos foundations’ summary can be found here. These people have been intentionally and internationally deployed as foreign agents representing the interests of the WEF members to “penetrate the global cabinets of countries” as well as a wide range of key business sectors including banking/finance, other business sectors (including health and biotechnology), academia and health, media, technology, logistics, arts and culture, sports, politics and government, think tanks, telecommunications, real estate, financial investment/holding companies, a variety of non-governmental organisations, energy, aerospace and military, food and agriculture.
This list can be found and downloaded at the following link:
The list contains a summary of the graduates of the World Economic Forum’s Global Leaders of Tomorrow (a one-year program that ran from 1993 to 2003) as well as the Young Global Leaders (a five-year program started 2004/2005 and still running).
To create this list, the Malone Institute and the Pharos Foundation have used World Economic Forum search engines and cross-checked published lists, Wayback Machine archives, Wikispooks, and other complementary sources. It may not be 100% accurate, but we have done our best to make it as correct and updated as possible. Some people have been removed from the WEF website, and some were never listed but have been identified by Klaus Schwab himself as members of his young global agents of change. We have done extensive manual research in order to identify and verify those for whom very little information has been provided. When missing, there has been an attempt to find and add relevant countries, positions etc. When identified, links have been provided to existing biographies, primarily those included in World Economic Forum webpages, or else Wikipedia, LinkedIn, company pages, or articles. In some cases (when available) we have also provided links to organisations they have worked at. When possible, positions and organisations in many cases have been updated to the most recent identifiable.
The Sector designations chosen by WEF have changed over the years, so the spreadsheet uses the most descriptive term for their updated sector and position, but in some cases we have added our own – especially in the Business sector where we have added Sub-sectors for more detailed information. The Region designations used by WEF have also changed over the years, so we have used simpler geographical regions. We have added extra columns in the spreadsheet for Sex, Political position, Health connection, and finally Notes for additional or relevant information.
This list is open to corrections and additions, should anyone spot an error or have more information. Please write to us at info@MaloneInstitute.org if you have additional information, details, or corrections.
So that you can cross-check for yourself, below are provided hyperlinked sources for this summary, which includes only the listed groups (GLT = Global Leaders of Tomorrow, YGL = Young Global Leaders). There are additional WEF trainee groups including “Young Scientists”, and these will be the focus of future similar summary spreadsheets. The lists below do not contain the full documentation of the members found on our master list above.
According to economist Richard Werner, who was selected for the GLT program in 2003, the Global Leaders of Tomorrow program (GLT) was closed down and rebooted as a more controllable group called the “Young Global Leaders” (YGL) because too many people were asking difficult questions in the forum (see “Last American Vagabond” podcast titled “COVID Measures And The Central Controls Over The Economy” here). Many of the more recently graduate classes are explicitly identified as revolutionaries who are “Driving the Fourth Industrial Revolution” on behalf of the WEF.
There are hundreds of references at the end of this paper and it’s in plain sight on the NIH website 4/5/2022
Mingyang Tang, Xiaodong Hu, […], and Qiang Fang
Graphical abstract
Ivermectin has powerful antitumor effects, including the inhibition of proliferation, metastasis, and angiogenic activity, in a variety of cancer cells. This may be related to the regulation of multiple signaling pathways by ivermectin through PAK1 kinase. On the other hand, ivermectin promotes programmed cancer cell death, including apoptosis, autophagy and pyroptosis. Ivermectin induces apoptosis and autophagy is mutually regulated. Interestingly, ivermectin can also inhibit tumor stem cells and reverse multidrug resistance and exerts the optimal effect when used in combination with other chemotherapy drugs.
Abbreviations: ASC, Apoptosis-associated speck-like protein containing a CARD; ALCAR, acetyl-L-carnitine; CSCs, Cancer stem cells; DAMP, Damage-associated molecular pattern; EGFR, Epidermal growth factor receptor; EBV, Epstein-Barr virus; EMT, Epithelial mesenchymal-transition; GABA, Gamma-aminobutyric acid; GSDMD, Gasdermin D; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HER2, Human epidermal growth factor receptor 2; HMGB1, High mobility group box-1 protein; HSP27, Heat shock protein 27; LD50, median lethal dose; LDH, Lactate dehydrogenase; IVM, Ivermectin; MDR, Multidrug resistance; NAC, N-acetyl-L-cysteine; OCT-4, Octamer-binding protein 4; PAK1, P-21-activated kinases 1; PAMP, Pathogen-associated molecular pattern; PARP, poly (ADP- ribose) polymerase; P-gp, P-glycoprotein; PRR, pattern recognition receptor; ROS, Reactive oxygen species; STAT3, Signal transducer and activator of transcription 3; SID, SIN3-interaction domain; siRNA, small interfering RNA; SOX-2, SRY-box 2; TNBC, Triple-negative breast cancer; YAP1, Yes-associated protein 1
Chemical compounds reviewed in this article: ivermectin(PubChem CID:6321424), avermectin(PubChem CID:6434889), selamectin(PubChem CID:9578507), doramectin(PubChem CID:9832750), moxidectin(PubChem CID:9832912)
Keywords: ivermectin, cancer, drug repositioning
Abstract
Ivermectin is a macrolide antiparasitic drug with a 16-membered ring that is widely used for the treatment of many parasitic diseases such as river blindness, elephantiasis and scabies. Satoshi ōmura and William C. Campbell won the 2015 Nobel Prize in Physiology or Medicine for the discovery of the excellent efficacy of ivermectin against parasitic diseases. Recently, ivermectin has been reported to inhibit the proliferation of several tumor cells by regulating multiple signaling pathways. This suggests that ivermectin may be an anticancer drug with great potential. Here, we reviewed the related mechanisms by which ivermectin inhibited the development of different cancers and promoted programmed cell death and discussed the prospects for the clinical application of ivermectin as an anticancer drug for neoplasm therapy.
1. Introduction
Ivermectin(IVM) is a macrolide antiparasitic drug with a 16-membered ring derived from avermectin that is composed of 80% 22,23-dihydroavermectin-B1a and 20% 22,23-dihydroavermectin-B1b [1]. In addition to IVM, the current avermectin family members include selamectin, doramectin and moxidectin [[2], [3], [4], [5]] (Fig. 1 ). IVM is currently the most successful avermectin family drug and was approved by the FDA for use in humans in 1978 [6]. It has a good effect on the treatment of parasitic diseases such as river blindness, elephantiasis, and scabies. The discoverers of IVM, Japanese scientist Satoshi ōmura and Irish scientist William C. Campbell, won the Nobel Prize in Physiology or Medicine in 2015 [7,8]. IVM activates glutamate-gated chloride channels in the parasite, causing a large amount of chloride ion influx and neuronal hyperpolarization, thereby leading to the release of gamma-aminobutyric acid (GABA) to destroy nerves, and the nerve transmission of muscle cells induces the paralysis of somatic muscles to kill parasites [9,10]. IVM has also shown beneficial effects against other parasitic diseases, such as malaria [11,12], trypanosomiasis [13], schistosomiasis [14], trichinosis [15] and leishmaniasis [16].
The chemical structures of ivermectin and other avermectin family compounds in this review.
IVM not only has strong effects on parasites but also has potential antiviral effects. IVM can inhibit the replication of flavivirus by targeting the NS3 helicase [17]; it also blocks the nuclear transport of viral proteins by acting on α/β-mediated nuclear transport and exerts antiviral activity against the HIV-1 and dengue viruses [18]. Recent studies have also pointed out that it has a promising inhibitory effect on the SARS-CoV-2 virus, which has caused a global outbreak in 2020 [19]. In addition, IVM shows potential for clinical application in asthma [20] and neurological diseases [21]. Recently scientists have discovered that IVM has a strong anticancer effect.
Since the first report that IVM could reverse tumor multidrug resistance (MDR) in 1996 [22], a few relevant studies have emphasized the potential use of IVM as a new cancer
treatment [[23], [24], [25], [26], [27]]. Despite the large number of related studies, there are still some key issues that have not been resolved. First of all, the specific mechanism of IVM-mediated cytotoxicity in tumor cells is unclear; it may be related to the effect of IVM on various signaling pathways, but it is not very clear overall. Second, IVM seems to induce mixed cell death in tumor cells, which is also a controversial issue. Therefore, this review summarized the latest findings on the anticancer effect of IVM and discussed the mechanism of the inhibition of tumor proliferation and the way that IVM induces tumor programmed cell death to provide a theoretical basis for the use of IVM as a potential anticancer drug. As the cost of the research and development of new anticancer drugs continues to increase, drug repositioning has become increasingly important. Drug repositioning refers to the development of new drug indications that have been approved for clinical use [28]. For some older drugs that are widely used for their original indications and have clinical data and safety information, drug repositioning allows them to be developed via a cheaper and faster cycle and to be used more effectively in clinical use clinically [29]. Here, we systematically summarized the anticancer effect and mechanism of IVM, which is of great significance for the repositioning of IVM for cancer treatment.
2. The role of IVM in different cancers
2.1. Breast cancer
Breast cancer is a malignant tumor produced by gene mutation in breast epithelial cells caused by multiple carcinogens. The incidence of breast cancer has increased each year, and it has become one of the female malignant tumors with the highest incidence in globally. On average, a new case is diagnosed every 18 seconds worldwide [30,31]. After treatment with IVM, the proliferation of multiple breast cancer cell lines including MCF-7, MDA-MB-231 and MCF-10 was significantly reduced. The mechanism involved the inhibition by IVM of the Akt/mTOR pathway to induce autophagy and p-21-activated kinase 1(PAK1)was the target of IVM for breast cancer [32]. Furthermore, Diao’s study showed that IVM could inhibit the proliferation of the canine breast tumor cell lines CMT7364 and CIPp by blocking the cell cycle without increasing apoptosis, and the mechanism of IVM may be related to the inhibition of the Wnt pathway [33].
Triple-negative breast cancer (TNBC) refers to cancer that is negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2(HER2) and is the most aggressive subtype of breast cancer with the worst prognosis. In addition, there is also no clinically applicable therapeutic drug currently [34,35]. A drug screening study of TNBC showed that IVM could be used as a SIN3-interaction domain (SID) mimic to selectively block the interaction between SID and paired a-helix2. In addition, IVM regulated the expression of the epithelial mesenchymal-transition (EMT) related gene E-cadherin to restore the sensitivity of TNBC cells to tamoxifen, which implies the possibility that IVM functions as an epigenetic regulator in the treatment of cancer[36].
Recent studies have also found that IVM could promote the death of tumor cells by regulating the tumor microenvironment in breast cancer. Under the stimulation of a tumor microenvironment with a high level of adenosine triphosphate (ATP) outside tumor cells, IVM could enhance the P2 × 4/ P2 × 7/Pannexin-1 mediated release of high mobility group box-1 protein (HMGB1) [37]. However, the release of a large amount of HMGB1 into the extracellular environment will promote immune cell-mediated immunogenic death and inflammatory reactions, which will have an inhibitory effect on the growth of tumor cells. Therefore, we believe that the anticancer effect of IVM is not limited to cytotoxicity, but also involves the regulation of the tumor microenvironment. IVM regulates the tumor microenvironment and mediates immunogenic cell death, which may be a new direction for research exploring anticancer mechanisms in the future.
2.2. Digestive system cancer
Gastric cancer is one of the most common malignant tumors worldwide. In the past year, more than one million patients with gastric cancer have been diagnosed worldwide [38]. Nambara’s study showed that IVM could significantly inhibit the proliferation of gastric cancer cells in vivo and in vitro and that the inhibitory effect of IVM depended on the expression of Yes-associated protein 1(YAP1)[39]. The gastric cancer cell lines MKN1 and SH-10-TC have higher YAP1 expression than MKN7 and MKN28 cells, so MKN1 and SH-10-TC cells are sensitive to IVM, while MKN7 and MKN28 are not sensitive to IVM.YAP1 plays an oncogenic role in tumorigenesis, indicating the possibility of the use of IVM as a YAP1 inhibitor for cancer treatment [40].
In a study that screened Wnt pathway inhibitors, IVM inhibited the proliferation of multiple cancers, including the colorectal cancer cell lines CC14, CC36, DLD1, and Ls174 T, and promoted apoptosis by blocking the Wnt pathway [41]. After intervention with IVM, the expression of caspase-3 in DLD1 and Ls174 T cells increased, indicating that IVM has an apoptosis-inducing effect and inhibits the expression of the downstream genes AXIN2, LGR5, and ASCL2 in the Wnt/β-catenin pathway. However, the exact molecular target of IVM that affects the Wnt/β-catenin pathway remains to be explored.
Hepatocellular carcinoma is the fourth leading cause of cancer death worldwide. Approximately 80% of cases of liver cancer are caused by hepatitis B virus (HBV) and hepatitis C virus (HCV) infection [42]. IVM could inhibit the development of hepatocellular carcinoma by blocking YAP1 activity in spontaneous liver cancer Mob1b-/-mice [43].Cholangiocarcinoma is a malignant tumor that originates in the bile duct inside and outside the liver. Intuyod’s experiment found that IVM inhibited the proliferation of KKU214 cholangiocarcinoma cells in a dose- and time-dependent manner [44]. IVM halted the cell cycle in S phase and promoted apoptosis. Surprisingly, gemcitabine-resistant KKU214 cells showed high sensitivity to IVM, which suggested that IVM shows potential for the treatment of tumors that are resistant to conventional chemotherapy drugs.
2.3. Urinary system cancer
Renal cell carcinoma is a fatal malignant tumor of the urinary system derived from renal tubular epithelial cells. Its morbidity has increased by an average of 2% annually worldwide and the clinical treatment effect is not satisfactory [[45], [46], [47]]. Experiments confirmed that IVM could significantly inhibit the proliferation of five renal cell carcinoma cell lines without affecting the proliferation of normal kidney cells, and its mechanism may be related to the induction of mitochondrial dysfunction [48]. IVM could significantly reduce the mitochondrial membrane potential and inhibit mitochondrial respiration and ATP production. The presence of the mitochondrial fuel acetyl-L-carnitine (ALCAR), and the antioxidant N-acetyl-L-cysteine (NAC), could reverse IVM-induced inhibition. In animal experiments, the immunohistochemical results for IVM-treated tumor tissues showed that the expression of the mitochondrial stress marker HEL was significantly increased, and the results were consistent with those of the cell experiments.
Prostate cancer is a malignant tumor derived from prostate epithelial cells, and its morbidity is second only to that of lung cancer among men in Western countries [49]. In Nappi’s experiment, it was found that IVM could enhance the drug activity of the anti-androgen drug enzalutamide in the prostate cancer cell line LNCaP and reverse the resistance of the prostate cancer cell line PC3 to docetaxel [50]. Interestingly, IVM also restored the sensitivity of the triple-negative breast cancer to the anti-estrogen drug tamoxifen [36], which also implies the potential for IVM to be used in endocrine therapy. Moreover, IVM was also found to have a good inhibitory effect on the prostate cancer cell line DU145 [51].
2.4. Hematological cancer
Leukemia is a type of malignant clonal disease caused by abnormal hematopoietic stem cells [52]. In an experiment designed to screen potential drugs for the treatment of leukemia, IVM preferentially killed leukemia cells at low concentrations without affecting normal hematopoietic cells [51]. The mechanism was related to the increase in the influx of chloride ions into the cell by IVM, resulting in hyperpolarization of the plasma membrane and induction of reactive oxygen species (ROS) production. It was also proven that IVM has a synergistic effect with cytarabine and daunorubicin on the treatment of leukemia. Wang’s experiment found that IVM could selectively induce mitochondrial dysfunction and oxidative stress, causing chronic myeloid leukemia K562 cells to undergo increased caspase-dependent apoptosis compared with normal bone marrow cells [53]. It was also confirmed that IVM inhibited tumor growth in a dose-dependent manner, and dasatinib had improved efficacy.
2.5. Reproductive system cancer
Cervical cancer is one of the most common gynecological malignancies, resulting in approximately 530,000 new cases and 270,000 deaths worldwide each year. The majority of cervical cancers are caused by human papillomavirus (HPV) infection [54,55]. IVM has been proven to significantly inhibit the proliferation and migration of HeLa cells and promote apoptosis [56]. After intervention with IVM, the cell cycle of HeLa cells was blocked at the G1/S phase, and the cells showed typical morphological changes related to apoptosis.
Ovarian cancer is a malignant cancer that lacks early clinical symptoms and has a poor therapeutic response. The 5-year survival rate after diagnosis is approximately 47% [27,57]. In a study by Hashimoto, it found that IVM inhibited the proliferation of various ovarian cancer cell lines, and the mechanism was related to the inhibition of PAK1 kinase [58]. In research to screen potential targets for the treatment of ovarian cancer through the use of an shRNA library and a CRISPR/Cas9 library, the oncogene KPNB1 was detected. IVM could block the cell cycle and induce cell apoptosis through a KPNB1-dependent mechanism in ovarian cancer [59]. Interestingly, IVM and paclitaxel have a synergistic effect on ovarian cancer, and combined treatment in in vivo experiments almost completely inhibited tumor growth. Furthermore, according to a report by Zhang, IVM can enhance the efficacy of cisplatin to improve the treatment of epithelial ovarian cancer, and the mechanism is related to the inhibition of the Akt/mTOR pathway [60].
2.6. Brain glioma
Glioma is the most common cerebral tumor and approximately 100,000 people worldwide are diagnosed with glioma every year. Glioblastoma is the deadliest glioma, with a median survival time of only 14-17 months [61,62]. Experiments showed that IVM inhibited the proliferation of human glioblastoma U87 and T98 G cells in a dose-dependent manner and induced apoptosis in a caspase-dependent manner [63]. This was related to the induction of mitochondrial dysfunction and oxidative stress. Moreover, IVM could induce apoptosis of human brain microvascular endothelial cells and significantly inhibit angiogenesis. These results showed that IVM had the potential to resist tumor angiogenesis and tumor metastasis. In another study, IVM inhibited the proliferation of U251 and C6 glioma cells by inhibiting the Akt/mTOR pathway [64].
In gliomas, miR-21 can regulate the Ras/MAPK signaling pathway and enhance its effects on proliferation and invasion [65]. The DDX23 helicase activity affects the expression of miR-12 [66]. IVM could inhibit the DDX23/miR-12 signaling pathway by affecting the activity of DDX23 helicase, thereby inhibiting malignant biological behaviors. This indicated that IVM may be a potential RNA helicase inhibitor and a new agent for of tumor treatment. However, here, we must emphasize that because IVM cannot effectively pass the blood-brain barrier [67], the prospect of the use of IVM in the treatment of gliomas is not optimistic.
2.7. Respiratory system cancer
Nasopharyngeal carcinoma is a malignant tumor derived from epithelial cells of the nasopharyngeal mucosa. The incidence is obviously regional and familial, and Epstein-Barr virus (EBV) infection is closely related [68]. In a study that screened drugs for the treatment of nasopharyngeal cancer, IVM significantly inhibited the development of nasopharyngeal carcinoma in nude mice at doses that were not toxic to normal thymocytes [69]. In addition, IVM also had a cytotoxic effect on a variety of nasopharyngeal cancer cells in vitro, and the mechanism is related to the reduction of PAK1 kinase activity to inhibit the MAPK pathway.
Lung cancer has the highest morbidity and mortality among cancers [70]. Nishio found that IVM could significantly inhibit the proliferation of H1299 lung cancer cells by inhibiting YAP1 activity [43]. Nappi’s experiment also proved that IVM combined with erlotinib to achieved a synergistic killing effect by regulating EGFR activity and in HCC827 lung cancer cells [50]. In addition, IVM could reduce the metastasis of lung cancer cells by inhibiting EMT.
2.8. Melanoma
Melanoma is the most common malignant skin tumor with a high mortality rate. Drugs targeting BRAF mutations such as vemurafenib, dabrafenib and PD-1 monoclonal antibodies, including pembrolizumab and nivolumab have greatly improved the prognosis of melanoma [71,72]. Gallardo treated melanoma cells with IVM and found that it could effectively inhibit melanoma activity [73]. Interestingly, IVM could also show activity against BRAF wild-type melanoma cells, and its combination with dapafinib could significantly increase antitumor activity. Additionally, it has been confirmed that PAK1 is the key target of IVM that mediates its anti-melanoma activity, and IVM can also significantly reduce the lung metastasis of melanoma in animal experiments. Deng found that IVM could activate the nuclear translocation of TFE3 and induce autophagy-dependent cell death by dephosphorylation of TFE3 (Ser321) in SK-MEL-28 melanoma cells [74]. However, NAC reversed the effect of IVM, which indicated that IVM increased TFE3-dependent autophagy through the ROS signaling pathway.
3. IVM-induced programmed cell death in tumor cells and related mechanisms
3.1. Apoptosis
IVM induces different programmed cell death patterns in different tumor cells (Table 1). As shown in Table 1, the main form of IVM induced programmed cell death is apoptosis. Apoptosis is a programmed cell death that is regulated by genes to maintain cell stability. It can be triggered by two activation pathways: the endogenous endoplasmic reticulum stress/mitochondrial pathway and the exogenous death receptor pathway [75,76]. The decrease in the mitochondrial membrane potential and the cytochrome c is released from mitochondria into the cytoplasm was detected after the intervention of IVM in Hela cells [56].Therefore, we infer that IVM induces apoptosis mainly through the mitochondrial pathway. In addition, morphological changed caused by apoptosis, including chromatin condensation, nuclear fragmentation, DNA fragmentation and apoptotic body formation were observed. Finally, IVM changed the balance between apoptosis-related proteins by upregulating the protein Bax and downregulating anti-apoptotic protein Bcl-2, thereby activating caspase-9/-3 to induce apoptosis [48,53,63] (Fig. 2 ).
Mechanisms of IVM-induced mitochondria-mediated apoptosis.
3.2. Autophagy
Autophagy is a lysosomal-dependent form of programmed cell death. It utilizes lysosomes to eliminate superfluous or damaged organelles in the cytoplasm to maintain homeostasis. It is characterized by double-layered or multilayered vacuolar structures containing cytoplasmic components, which are known as autophagosomes [77]. In recent years, many studies have shown that autophagy is a double-edged sword in tumor development. On the one hand, autophagy can help tumors adapt to the nutritional deficiency of the tumor microenvironment, and to a certain extent, protect tumor cells from chemotherapy- or radiotherapy- induced injury. On the other hand, some autophagy activators can increase the sensitivity of tumors to radiotherapy and chemotherapy by inducing autophagy, and excessive activation of autophagy can also lead to tumor cell death [[78], [79], [80], [81]]. Overall, the specific environment of tumor cells will determine whether autophagy enhances or inhibits tumor development and improving autophagy activity has also become a new approach in cancer therapy. Programmed cell death mediated by autophagy after IVM intervention and the enhancement of the anticancer efficacy of IVM by regulating autophagy are interesting topics. Intervention with IVM in the breast cancer cell lines MCF-7 and MDA-MB-231 significantly increased intracellular autophagic flux and the expression of key autophagy proteins such as LC3, Bclin1, Atg5, and the formation of autophagosomes can be observed [32]. However, after using the autophagy inhibitors chloroquine and wortmannin or knocking down Bclin1 and Atg5 by siRNA to inhibit autophagy, the anticancer activity of IVM significantly decreased. This proves that IVM mainly exerts an antitumor effect through the autophagy pathway. In addition, researchers also used the Akt activator CA-Akt to prove that IVM mainly induces autophagy by inhibiting the phosphorylation of Akt and mTOR (Fig. 3). The phenomenon of IVM-induced autophagy has also been reported in glioma and melanoma [ 64,74]. All of the above findings indicate the potential of IVM as an autophagy activator to induce autophagy-dependent death in tumor cells.
Mechanisms of IVM-induced PAK1/Akt/mTOR-mediated autophagy.
3.3. Cross talk between IVM-induced apoptosis and autophagy
The relationship between apoptosis and autophagy is very complicated, and the cross talk between the two plays a vital role in the development of cancer [82]. Obviously, the existing results suggest that IVM-induced apoptosis and autophagy also exhibit cross talk. For example, it was found in SK-MEL-28 melanoma cells that IVM can promote apoptosis as well as autophagy [74]. After using the autophagy inhibitor bafilomycin A1 or siRNA to downregulate Beclin1, IVM-induced apoptosis was significantly enhanced, which suggested that enhanced autophagy will reduce IVM-induced apoptosis and that IVM-induced autophagy can protect tumor cells from apoptosis. However, in breast cancer cell experiments, it was also found that IVM could induce autophagy, and enhanced autophagy could increase the anticancer activity of IVM [37]. The latest research shows that in normal circumstances autophagy will prevent the induction of apoptosis and apoptosis-related caspase enzyme activation will inhibit autophagy. However, in special circumstances, autophagy may also help to induce apoptosis or necrosis [83]. In short, the relationship between IVM-induced apoptosis and autophagy involves a complex regulatory mechanism, and the specific molecular mechanism needs further study. We believe that deeper exploration of the mechanism can further guide the use of IVM in the treatment of cancer.
3.4. Pyroptosis
Pyroptosis is a type of inflammatory cell death induced by inflammasomes. The inflammasome is a multimolecular complex containing pattern recognition receptor (PRR), apoptosis-associated speck-like protein containing a CARD (ASC), and pro-caspase-1. PRR can identify pathogen-associated molecular patterns (PAMPs) that are structurally stable and evolutionarily conserved on the surface of pathogenic microorganisms and damage-associated molecular patterns (DAMPs) produced by damaged cells [84,85]. Inflammasomes initiate the conversion of pro-caspase-1 via self-shearing into activated caspase-1. Activated caspase-1 can cause pro-IL-1β and pro-IL-18 to mature and to be secreted. Gasdermin D(GSDMD)is a substrate for activated caspase-1 and is considered to be a key protein in the execution of pyroptosis [86,87]. In an experiment by Draganov, it was found that the release of lactate dehydrogenase (LDH) and activated caspase-1 was significantly increased in breast cancer cells after IVM intervention [37]. In addition, characteristic pyroptosis phenomena such as cell swelling and rupturing were observed. The authors speculated that IVM may mediate the occurrence of pyroptosis via the P2 × 4/P2 × 7/NLRP3 pathway (Fig. 4), but there is no specific evidence to prove this speculation. Interestingly, in ischemia-reperfusion experiments, IVM aggravated renal ischemia via the P2 × 7/NLRP3 pathway and increased the release of proinflammatory cytokines in human proximal tubular cells [88]. Although there is currently little evidences showing that IVM induces pyroptosis, it is important to investigate the role of IVM in inducing pyroptosis in other cancers in future studies and realize that IVM may induce different types of programmed cell death in different types of cancer.
Mechanisms of IVM-induced P2 × 4/P2 × 7/NLRP3-mediated pyroptosis.
4. Anticancer effect of IVM through other pathways
4.1. Cancer stem cells
Cancer stem cells (CSCs) are a cell population similar to stem cells with characteristics of self-renewal and differentiation potential in tumor tissue [89,90]. Although CSCs are similar to stem cells in terms of function, because of the lack of a negative feedback regulation mechanism for stem cell self-renewal, their powerful proliferation and multidirectional differentiation abilities are unrestricted, which allows CSCs to maintain certain activities during chemotherapy and radiotherapy [[90], [91], [92]]. When the external environment is suitable, CSCs will rapidly proliferate to reactivate the formation and growth of tumors. Therefore, CSCs have been widely recognized as the main cause of recurrence after treatment [93,94]. Guadalupe evaluated the effect of IVM on CSCs in the breast cancer cell line MDA-MB-231 [95]. The experimental results showed that IVM would preferentially targeted and inhibited CSCs-rich cell populations compared with other cell populations in MDA-MB-231 cells. Moreover, the expression of the homeobox protein NANOG, octamer-binding protein 4 (OCT-4) and SRY-box 2 (SOX-2), which are closely related to the self-renewal and differentiation ability of stem cells in CSCs, were also significantly inhibited by IVM. This suggests that IVM may be used as a potential CSCs inhibitor for cancer therapy. Further studies showed that IVM could inhibit CSCs by regulating the PAK1-STAT3 axis [96].
4.2. Reversal of tumor multidrug resistance
MDR of tumor cells is the main cause of relapses and deaths after chemotherapy [97]. ATP binding transport family-mediated drug efflux and overexpression of P-glycoprotein (P-gp) are widely considered to be the main causes of tumor MDR [[98], [99], [100]]. Several studies have confirmed that IVM could reverse drug resistance by inhibiting P-gp and MDR-associated proteins [[101], [102], [103]]. In Didier’s experiments testing the effect of IVM on lymphocytic leukemia, IVM could be used as an inhibitor of P-gp to affect MDR [22]. In Jiang’s experiment, IVM reversed the drug resistance of the vincristine-resistant colorectal cancer cell line HCT-8, doxorubicin-resistant breast cancer cell line MCF-7 and the chronic myelogenous leukemia cell line K562 [104]. IVM inhibited the activation of EGFR and the downstream ERK/Akt/NF-kappa B signaling pathway to downregulate the expression of P-gp. Earlier, we mentioned the role of IVM in docetaxel-resistant prostate cancer [50] and gemcitabine-resistant cholangiocarcinoma [44]. These results indicated the significance of applying IVM for the treatment of chemotherapy patients with MDR.
4.3. Enhanced targeted therapy and combined treatment
Targeted treatment of key mutated genes in cancer, such as EGFR in lung cancer and HER2 in breast cancer, can achieve powerful clinical effects [105,106]. HSP27 is a molecular chaperone protein that is highly expressed in many cancers and associated with drug resistance and poor prognosis. It is considered as a new target for cancer therapy [107]. Recent studies have found that IVM could be used as an inhibitor of HSP27 phosphorylation to enhance the activity of anti-EGFR drugs in EGFR/HER2- driven tumors. An experiment found that IVM could significantly enhance the inhibitory effects of erlotinib and cetuximab on lung cancer and colorectal cancer [50]. Earlier, we mentioned that IVM combined with conventional chemotherapeutic drugs such as cisplatin [60], paclitaxel [59], daunorubicin and cytarabine [51], or with targeted drugs such as dasatinib [53] and dapafenib [73] shows great potential for cancer treatment. The combination of drugs can effectively increase efficacy, reduce toxicity or delay drug resistance. Therefore, combination therapy is the most common method of chemotherapy. IVM has a variety of different mechanisms of action in different cancers, and its potential for synergistic effects and enhanced efficacy in combination therapy was of particular interest to us. Not only does IVM not overlap with other therapies in term of its mechanism of action, but the fact that of IVM has multiple targets suggests that it is not easy to produce IVM resistance. Therefore, continued study and testing of safe and effective combination drug therapies is essential to maximize the anticancer effects of IVM.
5. Molecular targets and signaling pathways involved in the anticancer potential of IVM
As mentioned above, the anticancer mechanism of IVM involves a wide range of signaling pathways such as Wnt/β-catenin, Akt/mTOR, MAPK and other possible targets such as PAK1 and HSP27, as well as other mechanisms of action (Table 2 ). We found that IVM inhibits tumor cell development in a PAK1-dependent manner in most cancers. Consequently, we have concentrated on discussing the role of PAK1 kinase and cross-talk between various pathways and PAK1 to provide new perspectives on the mechanism of IVM function.
As a member of the PAK family of serine/threonine kinases, PAK1 has a multitude of biological functions such as regulating cell proliferation and apoptosis, cell movement, cytoskeletal dynamics and transformation [108]. Previous studies have indicated that PAK1 is located at the intersection of multiple signaling pathways related to tumorigenesis and is a key regulator of cancer signaling networks (Fig. 5). The excessive activation of PAK1 is involved in the formation, development, and invasion of various cancers [ 109,110]. Targeting PAK1 is a novel and promising method for cancer treatment, and the development of PAK1 inhibitors has attracted widespread attention [111]. IVM is a PAK1 inhibitor in a variety of tumors, and it has good safety compared to that of other PAK1 inhibitors such as IPA-3. In melanoma and nasopharyngeal carcinoma, IVM inhibited cell proliferation activity by inhibiting PAK1 to downregulate the expression of MEK 1/2 and ERK1/2 [69,73]. After IVM intervention in breast cancer, the expression of PAK1 was also significantly inhibited, and the use of siRNA to downregulate the expression of PAK1 in tumor cells significantly reduced the anticancer activity of IVM. Interestingly, IVM could inhibit the expression of PAK1 protein but did not affect the expression of PAK1 mRNA [32].The proteasome inhibitor MG132 reversed the suppressive effect of IVM, which indicated that IVM mainly degraded PAK1 via the proteasome ubiquitination pathway. We have already mentioned that IVM plays an anticancer role in various tumors by regulating pathways closely related to cancer development. PAK1 is at the junction of these pathways. Overall, we speculate that IVM can regulate the Akt/mTOR, MAPK and other pathways that are essential for tumor cell proliferation by inhibiting PAK1 expression, which plays an anticancer role in most cancers.
Malignant tumors are one of the most serious diseases that threaten human health and social development today, and chemotherapy is one of the most important methods for the treatment of malignant tumors. In recent years, many new chemotherapeutic drugs have entered the clinic, but tumor cells are prone to drug resistance and obvious adverse reactions to these drugs. Therefore, the development of new drugs that can overcome resistance, improve anticancer activity, and reduce side effects is an urgent problem to be solved in chemotherapy. Drug repositioning is a shortcut to accelerate the development of anticancer drugs.
As mentioned above, the broad-spectrum antiparasitic drug IVM, which is widely used in the field of parasitic control, has many advantages that suggest that it is worth developing as a potential new anticancer drug. IVM selectively inhibits the proliferation of tumors at a dose that is not toxic to normal cells and can reverse the MDR of tumors. Importantly, IVM is an established drug used for the treatment of parasitic diseases such as river blindness and elephantiasis. It has been widely used in humans for many years, and its various pharmacological properties, including long- and short-term toxicological effects and drug metabolism characteristics are very clear. In healthy volunteers, the dose was increased to 2 mg/Kg, and no serious adverse reactions were found, while tests in animals such as mice, rats, and rabbits found that the median lethal dose (LD50) of IVM was 10-50 mg/Kg [112] In addition, IVM has also been proven to show good permeability in tumor tissues [50]. Unfortunately, there have been no reports of clinical trials of IVM as an anticancer drug. There are still some problems that need to be studied and resolved before IVM is used in the clinic.
(1) Although a large number of research results indicate that IVM affects multiple signaling pathways in tumor cells and inhibits proliferation, IVM may cause antitumor activity in tumor cells through specific targets. However, to date, no exact target for IVM action has been found. (2) IVM regulates the tumor microenvironment, inhibits the activity of tumor stem cells and reduces tumor angiogenesis and tumor metastasis. However, there is no systematic and clear conclusion regarding the related molecular mechanism. Therefore, in future research, it is necessary to continue to explore the specific mechanism of IVM involved in regulating the tumor microenvironment, angiogenesis and EMT. (3) It has become increasingly clear that IVM can induce a mixed cell death mode involving apoptosis, autophagy and pyroptosis depending on the cell conditions and cancer type. Identifying the predominant or most important contributor to cell death in each cancer type and environment will be crucial in determining the effectiveness of IVM-based treatments. (4) IVM can enhance the sensitivity of chemotherapeutic drugs and reduce the production of resistance. Therefore, IVM should be used in combination with other drugs to achieve the best effect, while the specific medication plan used to combine IVM with other drugs remains to be explored.
Most of the anticancer research performed on the avermectin family has been focused on avermectin and IVM until now. Avermectin family drugs such as selamectin [36,41,113], and doramectin [114] also have anticancer effects, as previously reported. With the development of derivatives of the avermectin family that are more efficient and less toxic, relevant research on the anticancer mechanism of the derivatives still has great value. Existing research is sufficient to demonstrate the great potential of IVM and its prospects as a novel promising anticancer drug after additional research. We believe that IVM can be further developed and introduced clinically as part of new cancer treatments in the near future.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
This work was supported by the Science Research Innovation Team Project of Anhui Colleges and Universities (2016-40), the Bengbu City Natural Science Foundation (2019-12), the Key Projects of Science Research of Bengbu Medical College (BYKY2019009ZD) and National University Students’ Innovation and Entrepreneurship Training Program (201910367001).
Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company’s public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre – including this research content – immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
This article has been cited by other articles in PMC.
References
1. Campbell W.C., Fisher M.H., Stapley E.O., Albers-Schonberg G., Jacob T.A. Ivermectin: a potent new antiparasitic agent. Science. 1983;221(4613):823–828. doi: 10.1126/science.6308762. [PubMed] [CrossRef] [Google Scholar]
2. Prichard R.K., Geary T.G. Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance. Int J Parasitol Drugs Drug Resist. 2019;10:69–83. doi: 10.1016/j.ijpddr.2019.06.002.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
3. Ashour D.S. Ivermectin: From theory to clinical application. Int J Antimicrob Agents. 2019;54(2):134–142. doi: 10.1016/j.ijantimicag.2019.05.003.[PubMed] [CrossRef] [Google Scholar]
5. Bishop B.F., Bruce C.I., Evans N.A., Goudie A.C., Gration K.A., Gibson S.P., Pacey M.S., Perry D.A., Walshe N.D., Witty M.J. Selamectin: a novel broad-spectrum endectocide for dogs and cats. Vet Parasitol. 2000;91(3-4):163–176. doi: 10.1016/s0304-4017(00)00289-2. [PubMed] [CrossRef] [Google Scholar]
6. Laing R., Gillan V., Devaney E. Ivermectin – Old Drug, New Tricks? Trends Parasitol. 2017;33(6):463–472. doi: 10.1016/j.pt.2017.02.004.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
7. Crump A. Ivermectin: enigmatic multifaceted’ wonder’ drug continues to surprise and exceed expectations. J Antibiot (Tokyo) 2017;70(5):495–505. doi: 10.1038/ja.2017.11. [PubMed] [CrossRef] [Google Scholar]
8. McKerrow J.H. Recognition of the role of Natural Products as drugs to treat neglected tropical diseases by the 2015 Nobel prize in physiology or medicine. Nat Prod Rep. 2015;32(12):1610–1611. doi: 10.1039/c5np90043c. [PubMed] [CrossRef] [Google Scholar]
9. Kane N.S., Hirschberg B., Qian S., Hunt D., Thomas B., Brochu R., Ludmerer S.W., Zheng Y., Smith M., Arena J.P., Cohen C.J., Schmatz D., Warmke J., Cully D.F. Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin. Proc Natl Acad Sci U S A. 2000;97(25):13949–13954. doi: 10.1073/pnas.240464697.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
10. Fritz L.C., Wang C.C., Gorio A. Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. Proc Natl Acad Sci U S A. 1979;76(4):2062–2066. doi: 10.1073/pnas.76.4.2062. [PMC free article][PubMed] [CrossRef] [Google Scholar]
11. Smit M.R., Ochomo E.O., Aljayyoussi G., Kwambai T.K., Abong’o B.O., Chen T., Bousema T., Slater H.C., Waterhouse D., Bayoh N.M., Gimnig J.E., Samuels A.M., Desai M.R., Phillips-Howard P.A., Kariuki S.K., Wang D., Ward S.A., Ter Kuile F.O. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018;18(6):615–626. doi: 10.1016/s1473-3099(18)30163-4. [PubMed] [CrossRef] [Google Scholar]
12. Foy B.D., Alout H., Seaman J.A., Rao S., Magalhaes T., Wade M., Parikh S., Soma D.D., Sagna A.B., Fournet F., Slater H.C., Bougma R., Drabo F., Diabate A., Coulidiaty A.G.V., Rouamba N., Dabire R.K. Efficacy and risk of harms of repeat ivermectin mass drug administrations for control of malaria (RIMDAMAL): a cluster-randomised trial. Lancet. 2019;393(10180):1517–1526. doi: 10.1016/s0140-6736(18)32321-3.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
13. Udensi U.K., Fagbenro-Beyioku A.F. Effect of ivermectin on Trypanosoma brucei brucei in experimentally infected mice. J Vector Borne Dis. 2012;49(3):143–150.[PubMed] [Google Scholar]
14. Katz N., Araujo N., Coelho P.M.Z., Morel C.M., Linde-Arias A.R., Yamada T., Horimatsu Y., Suzuki K., Sunazuka T., Omura S. Ivermectin efficacy against Biomphalaria, intermediate host snail vectors of Schistosomiasis. J Antibiot (Tokyo) 2017;70(5):680–684. doi: 10.1038/ja.2017.31.[PubMed] [CrossRef] [Google Scholar]
15. B. MM, E.-S. AA Therapeutic potential of myrrh and ivermectin against experimental Trichinella spiralis infection in mice. The Korean journal of parasitology. 2013;51(3):297–304. doi: 10.3347/kjp.2013.51.3.297.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
16. Hanafi H.A., Szumlas D.E., Fryauff D.J., El-Hossary S.S., Singer G.A., Osman S.G., Watany N., Furman B.D., Hoel D.F. Effects of ivermectin on blood-feeding Phlebotomus papatasi, and the promastigote stage of Leishmania major. Vector Borne Zoonotic Dis. 2011;11(1):43–52. doi: 10.1089/vbz.2009.0030. [PubMed] [CrossRef] [Google Scholar]
17. Mastrangelo E., Pezzullo M., De Burghgraeve T., Kaptein S., Pastorino B., Dallmeier K., de Lamballerie X., Neyts J., Hanson A.M., Frick D.N., Bolognesi M., Milani M. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimicrob Chemother. 2012;67(8):1884–1894. doi: 10.1093/jac/dks147. [PMC free article][PubMed] [CrossRef] [Google Scholar]
18. Wagstaff K.M., Sivakumaran H., Heaton S.M., Harrich D., Jans D.A. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443(3):851–856. doi: 10.1042/bj20120150. [PMC free article][PubMed] [CrossRef] [Google Scholar]
19. Caly L., Druce J.D., Catton M.G., Jans D.A., Wagstaff K.M. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020:104787. doi: 10.1016/j.antiviral.2020.104787.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
20. Yan S., Ci X., Chen N., Chen C., Li X., Chu X., Li J., Deng X. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma. Inflamm Res. 2011;60(6):589–596. doi: 10.1007/s00011-011-0307-8.[PubMed] [CrossRef] [Google Scholar]
21. Franklin K.M., Asatryan L., Jakowec M.W., Trudell J.R., Bell R.L., Davies D.L. P2X4 receptors (P2X4Rs) represent a novel target for the development of drugs to prevent and/or treat alcohol use disorders. Front Neurosci. 2014;8:176. doi: 10.3389/fnins.2014.00176.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Didier A., Loor F. The abamectin derivative ivermectin is a potent p-glycoprotein inhibitor. Anticancer Drugs. 1996;7(7):745–751. doi: 10.1097/00001813-199609000-00005. [PubMed] [CrossRef] [Google Scholar]
23. Markowska A., Kaysiewicz J., Markowska J., Huczynski A. Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs. Bioorg Med Chem Lett. 2019;29(13):1549–1554. doi: 10.1016/j.bmcl.2019.04.045. [PubMed] [CrossRef] [Google Scholar]
24. Juarez M., Schcolnik-Cabrera A., Duenas-Gonzalez A. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am J Cancer Res. 2018;8(2):317–331. [PMC free article][PubMed] [Google Scholar]
25. Liu J., Zhang K., Cheng L., Zhu H., Xu T. Progress in Understanding the Molecular Mechanisms Underlying the Antitumour Effects of Ivermectin. Drug Des Devel Ther. 2020;14:285–296. doi: 10.2147/dddt.S237393.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
26. Antoszczak M., Markowska A., Markowska J., Huczynski A. Old wine in new bottles: Drug repurposing in oncology. Eur J Pharmacol. 2020;866:172784. doi: 10.1016/j.ejphar.2019.172784. [PubMed] [CrossRef] [Google Scholar]
27. Kobayashi Y., Banno K., Kunitomi H., Tominaga E., Aoki D. Current state and outlook for drug repositioning anticipated in the field of ovarian cancer. J Gynecol Oncol. 2019;30(1):e10. doi: 10.3802/jgo.2019.30.e10.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
28. Yoshida G.J. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment. J Hematol Oncol. 2017;10(1):67. doi: 10.1186/s13045-017-0436-9.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
29. Wurth R., Thellung S., Bajetto A., Mazzanti M., Florio T., Barbieri F. Drug-repositioning opportunities for cancer therapy: novel molecular targets for known compounds. Drug Discov Today. 2016;21(1):190–199. doi: 10.1016/j.drudis.2015.09.017. [PubMed] [CrossRef] [Google Scholar]
30. Harbeck N., Penault-Llorca F., Cortes J., Gnant M., Houssami N., Poortmans P., Ruddy K., Tsang J., Cardoso F. Breast cancer. Nat Rev Dis Primers. 2019;5(1):66. doi: 10.1038/s41572-019-0111-2. [PubMed] [CrossRef] [Google Scholar]
31. Ginsburg O., Bray F., Coleman M.P., Vanderpuye V., Eniu A., Kotha S.R., Sarker M., Huong T.T., Allemani C., Dvaladze A., Gralow J., Yeates K., Taylor C., Oomman N., Krishnan S., Sullivan R., Kombe D., Blas M.M., Parham G., Kassami N., Conteh L. The global burden of women’s cancers: a grand challenge in global health. Lancet. 2017;389(10071):847–860. doi: 10.1016/s0140-6736(16)31392-7.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
32. Dou Q., Chen H.N., Wang K., Yuan K., Lei Y., Li K., Lan J., Chen Y., Huang Z., Xie N., Zhang L., Xiang R., Nice E.C., Wei Y., Huang C. Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer. Cancer Res. 2016;76(15):4457–4469. doi: 10.1158/0008-5472.CAN-15-2887.[PubMed] [CrossRef] [Google Scholar]
33. Diao H., Cheng N., Zhao Y., Xu H., Dong H., Thamm D.H., Zhang D., Lin D. Ivermectin inhibits canine mammary tumor growth by regulating cell cycle progression and WNT signaling. BMC Vet Res. 2019;15(1):276. doi: 10.1186/s12917-019-2026-2.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
34. Diana A., Carlino F., Franzese E., Oikonomidou O., Criscitiello C., De Vita F., Ciardiello F., Orditura M. Early Triple Negative Breast Cancer: Conventional Treatment and Emerging Therapeutic Landscapes. Cancers (Basel) 2020;12(4) doi: 10.3390/cancers12040819.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
35. Deepak K.G.K., Vempati R., Nagaraju G.P., Dasari V.R., N. S, Rao D.N., Malla R.R. Tumor microenvironment: Challenges and opportunities in targeting metastasis of triple negative breast cancer. Pharmacol Res. 2020;153:104683. doi: 10.1016/j.phrs.2020.104683. [PubMed] [CrossRef] [Google Scholar]
36. Kwon Y.J., Petrie K., Leibovitch B.A., Zeng L., Mezei M., Howell L., Gil V., Christova R., Bansal N., Yang S., Sharma R., Ariztia E.V., Frankum J., Brough R., Sbirkov Y., Ashworth A., Lord C.J., Zelent A., Farias E., Zhou M.M., Waxman S. Selective Inhibition of SIN3 Corepressor with Avermectins as a Novel Therapeutic Strategy in Triple-Negative Breast Cancer. Mol Cancer Ther. 2015;14(8):1824–1836. doi: 10.1158/1535-7163.MCT-14-0980-T.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
37. Draganov D., Gopalakrishna-Pillai S., Chen Y.R., Zuckerman N., Moeller S., Wang C., Ann D., Lee P.P. Modulation of P2X4/P2X7/Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death. Sci Rep. 2015;5:16222. doi: 10.1038/srep16222. [PMC free article][PubMed] [CrossRef] [Google Scholar]
38. Thanh Huong P., Gurshaney S., Thanh Binh N., Gia Pham A., Hoang Nguyen H., Thanh Nguyen X., Pham-The H., Tran P.T., Truong Vu K., Xuan Duong N., Pelucchi C., La Vecchia C., Boffetta P., Nguyen H.D., Luu H.N. Emerging Role of Circulating Tumor Cells in Gastric Cancer. Cancers (Basel) 2020;12(3) doi: 10.3390/cancers12030695.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
39. Nambara S., Masuda T., Nishio M., Kuramitsu S., Tobo T., Ogawa Y., Hu Q., Iguchi T., Kuroda Y., Ito S., Eguchi H., Sugimachi K., Saeki H., Oki E., Maehara Y., Suzuki A., Mimori K. Antitumor effects of the antiparasitic agent ivermectin via inhibition of Yes-associated protein 1 expression in gastric cancer. Oncotarget. 2017;8(64):107666–107677. doi: 10.18632/oncotarget.22587.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
40. Zanconato F., Cordenonsi M., Piccolo S. YAP and TAZ: a signalling hub of the tumour microenvironment. Nat Rev Cancer. 2019;19(8):454–464. doi: 10.1038/s41568-019-0168-y. [PubMed] [CrossRef] [Google Scholar]
41. Melotti A., Mas C., Kuciak M., Lorente-Trigos A., Borges I., Ruiz i Altaba A. The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. EMBO Mol Med. 2014;6(10):1263–1278. doi: 10.15252/emmm.201404084.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
42. Yang J.D., Hainaut P., Gores G.J., Amadou A., Plymoth A., Roberts L.R. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589–604. doi: 10.1038/s41575-019-0186-y.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
43. Nishio M., Sugimachi K., Goto H., Wang J., Morikawa T., Miyachi Y., Takano Y., Hikasa H., Itoh T., Suzuki S.O., Kurihara H., Aishima S., Leask A., Sasaki T., Nakano T., Nishina H., Nishikawa Y., Sekido Y., Nakao K., Shin-Ya K., Mimori K., Suzuki A. Dysregulated YAP1/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice. Proc Natl Acad Sci U S A. 2016;113(1):71–80. doi: 10.1073/pnas.1517188113.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
44. Intuyod K., Hahnvajanawong C., Pinlaor P., Pinlaor S. Anti-parasitic Drug Ivermectin Exhibits Potent Anticancer Activity Against Gemcitabine-resistant Cholangiocarcinoma In Vitro. Anticancer Res. 2019;39(9):4837–4843. doi: 10.21873/anticanres.13669. [PubMed] [CrossRef] [Google Scholar]
45. Wang Y., Su J., Wang Y., Fu D., Ideozu J.E., Geng H., Cui Q., Wang C., Chen R., Yu Y., Niu Y., Yue D. The interaction of YBX1 with G3BP1 promotes renal cell carcinoma cell metastasis via YBX1/G3BP1-SPP1- NF-kappaB signaling axis. J Exp Clin Cancer Res. 2019;38(1):386. doi: 10.1186/s13046-019-1347-0. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
46. Xu W.H., Shi S.N., Xu Y., Wang J., Wang H.K., Cao D.L., Shi G.H., Qu Y.Y., Zhang H.L., Ye D.W. Prognostic implications of Aquaporin 9 expression in clear cell renal cell carcinoma. J Transl Med. 2019;17(1):363. doi: 10.1186/s12967-019-2113-y.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
47. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34. doi: 10.3322/caac.21551.[PubMed] [CrossRef] [Google Scholar]
48. Zhu M., Li Y., Zhou Z. Antibiotic ivermectin preferentially targets renal cancer through inducing mitochondrial dysfunction and oxidative damage. Biochemical and Biophysical Research Communications. 2017;492(3):373–378. doi: 10.1016/j.bbrc.2017.08.097. [PubMed] [CrossRef] [Google Scholar]
49. Arcangeli S., Pinzi V., Arcangeli G. Epidemiology of prostate cancer and treatment remarks. World J Radiol. 2012;4(6):241–246. doi: 10.4329/wjr.v4.i6.241. [PMC free article][PubMed] [CrossRef] [Google Scholar]
50. Nappi L., Aguda A.H., Nakouzi N.A., Lelj-Garolla B., Beraldi E., Lallous N., Thi M., Moore S., Fazli L., Battsogt D., Stief S., Ban F., Nguyen N.T., Saxena N., Dueva E., Zhang F., Yamazaki T., Zoubeidi A., Cherkasov A., Brayer G.D., Gleave M. Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models. J Clin Invest. 2020;130(2):699–714. doi: 10.1172/jci130819.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
51. Sharmeen S., Skrtic M., Sukhai M.A., Hurren R., Gronda M., Wang X., Fonseca S.B., Sun H., Wood T.E., Ward R., Minden M.D., Batey R.A., Datti A., Wrana J., Kelley S.O., Schimmer A.D. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood. 2010;116(18):3593–3603. doi: 10.1182/blood-2010-01-262675.[PubMed] [CrossRef] [Google Scholar]
53. Wang J., Xu Y., Wan H., Hu J. Antibiotic ivermectin selectively induces apoptosis in chronic myeloid leukemia through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2018;497(1):241–247. doi: 10.1016/j.bbrc.2018.02.063. [PubMed] [CrossRef] [Google Scholar]
54. Dong Z., Yu C., Rezhiya K., Gulijiahan A., Wang X. Downregulation of miR-146a promotes tumorigenesis of cervical cancer stem cells via VEGF/CDC42/PAK1 signaling pathway. Artif Cells Nanomed Biotechnol. 2019;47(1):3711–3719. doi: 10.1080/21691401.2019.1664560.[PubMed] [CrossRef] [Google Scholar]
55. Carneiro S.R., da Silva Lima A.A., de Fatima Silva Santos G., de Oliveira C.S.B., Almeida M.C.V., da Conceicao Nascimento Pinheiro M. Relationship between Oxidative Stress and Physical Activity in Women with Squamous Intraepithelial Lesions in a Cervical Cancer Control Program in the Brazilian Amazon. Oxid Med Cell Longev. 2019;2019doi: 10.1155/2019/8909852. [PMC free article][PubMed] [CrossRef] [Google Scholar]
56. Zhang P., Zhang Y., Liu K., Liu B., Xu W., Gao J., Ding L., Tao L. Ivermectin induces cell cycle arrest and apoptosis of HeLa cells via mitochondrial pathway. Cell Prolif. 2019;52(2):e12543. doi: 10.1111/cpr.12543.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
57. Moufarrij S., Dandapani M., Arthofer E., Gomez S., Srivastava A., Lopez-Acevedo M., Villagra A., Chiappinelli K.B. Epigenetic therapy for ovarian cancer: promise and progress. Clin Epigenetics. 2019;11(1):7. doi: 10.1186/s13148-018-0602-0.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
58. Hashimoto H., Messerli S.M., Sudo T., Maruta H. Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther. 2009;3(6):243–246.[PubMed] [Google Scholar]
59. Kodama M., Kodama T., Newberg J.Y., Katayama H., Kobayashi M., Hanash S.M., Yoshihara K., Wei Z., Tien J.C., Rangel R., Hashimoto K., Mabuchi S., Sawada K., Kimura T., Copeland N.G., Jenkins N.A. In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. Proc Natl Acad Sci U S A. 2017;114(35):E7301–E7310. doi: 10.1073/pnas.1705441114.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
60. Zhang X., Qin T., Zhu Z., Hong F., Xu Y., Zhang X., Xu X., Ma A. Ivermectin Augments the In Vitro and In Vivo Efficacy of Cisplatin in Epithelial Ovarian Cancer by Suppressing Akt/mTOR Signaling. Am J Med Sci. 2020;359(2):123–129. doi: 10.1016/j.amjms.2019.11.001. [PubMed] [CrossRef] [Google Scholar]
61. Molinaro A.M., Taylor J.W., Wiencke J.K., Wrensch M.R. Genetic and molecular epidemiology of adult diffuse glioma. Nat Rev Neurol. 2019;15(7):405–417. doi: 10.1038/s41582-019-0220-2.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
62. Wen P.Y., Kesari S. Malignant gliomas in adults. N Engl J Med. 2008;359(5):492–507. doi: 10.1056/NEJMra0708126. [PubMed] [CrossRef] [Google Scholar]
63. Liu Y., Fang S., Sun Q., Liu B. Anthelmintic drug ivermectin inhibits angiogenesis, growth and survival of glioblastoma through inducing mitochondrial dysfunction and oxidative stress. Biochem Biophys Res Commun. 2016;480(3):415–421. doi: 10.1016/j.bbrc.2016.10.064. [PubMed] [CrossRef] [Google Scholar]
64. Liu J., Liang H., Chen C., Wang X., Qu F., Wang H., Yang K., Wang Q., Zhao N., Meng J., Gao A. Ivermectin induces autophagy-mediated cell death through the AKT/mTOR signaling pathway in glioma cells. Biosci Rep. 2019;39(12) doi: 10.1042/bsr20192489.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
65. Kwak H.J., Kim Y.J., Chun K.R., Woo Y.M., Park S.J., Jeong J.A., Jo S.H., Kim T.H., Min H.S., Chae J.S., Choi E.J., Kim G., Shin S.H., Gwak H.S., Kim S.K., Hong E.K., Lee G.K., Choi K.H., Kim J.H., Yoo H., Park J.B., Lee S.H. Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas. Oncogene. 2011;30(21):2433–2442. doi: 10.1038/onc.2010.620. [PubMed] [CrossRef] [Google Scholar]
66. Yin J., Park G., Lee J.E., Choi E.Y., Park J.Y., Kim T.H., Park N., Jin X., Jung J.E., Shin D., Hong J.H., Kim H., Yoo H., Lee S.H., Kim Y.J., Park J.B., Kim J.H. DEAD-box RNA helicase DDX23 modulates glioma malignancy via elevating miR-21 biogenesis. Brain. 2015;138(Pt 9):2553–2570. doi: 10.1093/brain/awv167. [PubMed] [CrossRef] [Google Scholar]
67. Kircik L.H., Del Rosso J.Q., Layton A.M., Schauber J. Over 25 Years of Clinical Experience With Ivermectin: An Overview of Safety for an Increasing Number of Indications. J Drugs Dermatol. 2016;15(3):325–332. [PubMed] [Google Scholar]
68. Chen Y.P., Chan A.T.C., Le Q.T., Blanchard P., Sun Y., Ma J. Nasopharyngeal carcinoma. Lancet. 2019;394(10192):64–80. doi: 10.1016/s0140-6736(19)30956-0.[PubMed] [CrossRef] [Google Scholar]
69. Gallardo F., Mariamé B., Gence R., Tilkin-Mariamé A.-F. Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth. Drug Design, Development and Therapy. 2018;12:2805–2814. doi: 10.2147/dddt.S172538. [PMC free article][PubMed] [CrossRef] [Google Scholar]
70. Thawani R., McLane M., Beig N., Ghose S., Prasanna P., Velcheti V., Madabhushi A. Radiomics and radiogenomics in lung cancer: A review for the clinician. Lung Cancer. 2018;115:34–41. doi: 10.1016/j.lungcan.2017.10.015. [PubMed] [CrossRef] [Google Scholar]
71. Patel H., Yacoub N., Mishra R., White A., Long Y., Alanazi S., Garrett J.T. Current Advances in the Treatment of BRAF-Mutant Melanoma. Cancers (Basel) 2020;12(2) doi: 10.3390/cancers12020482.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
72. Franken M.G., Leeneman B., Gheorghe M., Uyl-de Groot C.A., Haanen J., van Baal P.H.M. A systematic literature review and network meta-analysis of effectiveness and safety outcomes in advanced melanoma. Eur J Cancer. 2019;123:58–71. doi: 10.1016/j.ejca.2019.08.032. [PubMed] [CrossRef] [Google Scholar]
73. Gallardo F., Teiti I., Rochaix P., Demilly E., Jullien D., Mariamé B., Tilkin-Mariamé A.-F. Macrocyclic Lactones Block Melanoma Growth, Metastases Development and Potentiate Activity of Anti– BRAF V600 Inhibitors. Clinical Skin Cancer. 2016;1(1):4–14. doi: 10.1016/j.clsc.2016.05.001. e3. [CrossRef] [Google Scholar]
74. Deng F., Xu Q., Long J., Xie H. Suppressing ROS‐TFE3‐dependent autophagy enhances ivermectin‐induced apoptosis in human melanoma cells. Journal of Cellular Biochemistry. 2018;120(2):1702–1715. doi: 10.1002/jcb.27490. [PubMed] [CrossRef] [Google Scholar]
75. Nagata S. Apoptosis and Clearance of Apoptotic Cells. Annu Rev Immunol. 2018;36:489–517. doi: 10.1146/annurev-immunol-042617-053010. [PubMed] [CrossRef] [Google Scholar]
76. Degterev A., Yuan J. Expansion and evolution of cell death programmes. Nat Rev Mol Cell Biol. 2008;9(5):378–390. doi: 10.1038/nrm2393. [PubMed] [CrossRef] [Google Scholar]
77. Galluzzi L., Green D.R. Autophagy-Independent Functions of the Autophagy Machinery. Cell. 2019;177(7):1682–1699. doi: 10.1016/j.cell.2019.05.026.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
78. Levy J.M.M., Towers C.G., Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017;17(9):528–542. doi: 10.1038/nrc.2017.53. [PMC free article][PubMed] [CrossRef] [Google Scholar]
79. Gewirtz D.A. The four faces of autophagy: implications for cancer therapy. Cancer Res. 2014;74(3):647–651. doi: 10.1158/0008-5472.Can-13-2966. [PubMed] [CrossRef] [Google Scholar]
80. Galluzzi L., Pietrocola F., Bravo-San Pedro J.M., Amaravadi R.K., Baehrecke E.H., Cecconi F., Codogno P., Debnath J., Gewirtz D.A., Karantza V., Kimmelman A., Kumar S., Levine B., Maiuri M.C., Martin S.J., Penninger J., Piacentini M., Rubinsztein D.C., Simon H.U., Simonsen A., Thorburn A.M., Velasco G., Ryan K.M., Kroemer G. Autophagy in malignant transformation and cancer progression. Embo j. 2015;34(7):856–880. doi: 10.15252/embj.201490784.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
81. Galluzzi L., Bravo-San Pedro J.M., Demaria S., Formenti S.C., Kroemer G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat Rev Clin Oncol. 2017;14(4):247–258. doi: 10.1038/nrclinonc.2016.183.[PubMed] [CrossRef] [Google Scholar]
82. Ravegnini G., Sammarini G., Nannini M., Pantaleo M.A., Biasco G., Hrelia P., Angelini S. Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis. Autophagy. 2017;13(3):452–463. doi: 10.1080/15548627.2016.1256522.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
83. Marino G., Niso-Santano M., Baehrecke E.H., Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014;15(2):81–94. doi: 10.1038/nrm3735. [PMC free article][PubMed] [CrossRef] [Google Scholar]
84. Fang Y., Tian S., Pan Y., Li W., Wang Q., Tang Y., Yu T., Wu X., Shi Y., Ma P., Shu Y. Pyroptosis: A new frontier in cancer. Biomed Pharmacother. 2020;121:109595. doi: 10.1016/j.biopha.2019.109595. [PubMed] [CrossRef] [Google Scholar]
85. Gong T., Liu L., Jiang W., Zhou R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol. 2020;20(2):95–112. doi: 10.1038/s41577-019-0215-7. [PubMed] [CrossRef] [Google Scholar]
86. Liu X., Zhang Z., Ruan J., Pan Y., Magupalli V.G., Wu H., Lieberman J. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535(7610):153–158. doi: 10.1038/nature18629. [PMC free article][PubMed] [CrossRef] [Google Scholar]
87. Zheng Z., Li G. Mechanisms and Therapeutic Regulation of Pyroptosis in Inflammatory Diseases and Cancer. Int J Mol Sci. 2020;21(4) doi: 10.3390/ijms21041456.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
88. Han S.J., Lovaszi M., Kim M., D’Agati V., Hasko G., Lee H.T. P2X4 receptor exacerbates ischemic AKI and induces renal proximal tubular NLRP3 inflammasome signaling. Faseb j. 2020;34(4):5465–5482. doi: 10.1096/fj.201903287R. [PMC free article][PubMed] [CrossRef] [Google Scholar]
89. O’Brien C.A., Kreso A., Jamieson C.H. Cancer stem cells and self-renewal. Clin Cancer Res. 2010;16(12):3113–3120. doi: 10.1158/1078-0432.CCR-09-2824.[PubMed] [CrossRef] [Google Scholar]
90. Huang Z., Wu T., Liu A.Y., Ouyang G. Differentiation and transdifferentiation potentials of cancer stem cells. Oncotarget. 2015;6(37):39550–39563. doi: 10.18632/oncotarget.6098.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
91. Bao S., Wu Q., McLendon R.E., Hao Y., Shi Q., Hjelmeland A.B., Dewhirst M.W., Bigner D.D., Rich J.N. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–760. doi: 10.1038/nature05236. [PubMed] [CrossRef] [Google Scholar]
92. Dean M., Fojo T., Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5(4):275–284. doi: 10.1038/nrc1590.[PubMed] [CrossRef] [Google Scholar]
93. Li X., Lewis M.T., Huang J., Gutierrez C., Osborne C.K., Wu M.F., Hilsenbeck S.G., Pavlick A., Zhang X., Chamness G.C., Wong H., Rosen J., Chang J.C. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100(9):672–679. doi: 10.1093/jnci/djn123. [PubMed] [CrossRef] [Google Scholar]
94. Diehn M., Clarke M.F. Cancer stem cells and radiotherapy: new insights into tumor radioresistance. J Natl Cancer Inst. 2006;98(24):1755–1757. doi: 10.1093/jnci/djj505. [PubMed] [CrossRef] [Google Scholar]
95. Dominguez-Gomez G., Chavez-Blanco A., Medina-Franco J.L., Saldivar-Gonzalez F., Flores-Torrontegui Y., Juarez M., Diaz-Chavez J., Gonzalez-Fierro A., Duenas-Gonzalez A. Ivermectin as an inhibitor of cancer stemlike cells. Mol Med Rep. 2018;17(2):3397–3403. doi: 10.3892/mmr.2017.8231. [PubMed] [CrossRef] [Google Scholar]
96. Kim J.H., Choi H.S., Kim S.L., Lee D.S. The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation. Cancers (Basel) 2019;11(10) doi: 10.3390/cancers11101527.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
97. Wang J., Seebacher N., Shi H., Kan Q., Duan Z. Novel strategies to prevent the development of multidrug resistance (MDR) in cancer. Oncotarget. 2017;8(48):84559–84571. doi: 10.18632/oncotarget.19187.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
98. Niazi M., Zakeri-Milani P., Najafi Hajivar S., Soleymani Goloujeh M., Ghobakhlou N., Shahbazi Mojarrad J., Valizadeh H. Nano-based strategies to overcome p-glycoprotein-mediated drug resistance. Expert Opin Drug Metab Toxicol. 2016;12(9):1021–1033. doi: 10.1080/17425255.2016.1196186.[PubMed] [CrossRef] [Google Scholar]
100. Kibria G., Hatakeyama H., Harashima H. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch Pharm Res. 2014;37(1):4–15. doi: 10.1007/s12272-013-0276-2. [PubMed] [CrossRef] [Google Scholar]
101. Lespine A., Dupuy J., Orlowski S., Nagy T., Glavinas H., Krajcsi P., Alvinerie M. Interaction of ivermectin with multidrug resistance proteins (MRP1, 2 and 3) Chem Biol Interact. 2006;159(3):169–179. doi: 10.1016/j.cbi.2005.11.002. [PubMed] [CrossRef] [Google Scholar]
102. Pouliot J.F., L’Heureux F., Liu Z., Prichard R.K., Georges E. Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. Biochem Pharmacol. 1997;53(1):17–25. doi: 10.1016/s0006-2952(96)00656-9. [PubMed] [CrossRef] [Google Scholar]
103. Lespine A., Martin S., Dupuy J., Roulet A., Pineau T., Orlowski S., Alvinerie M. Interaction of macrocyclic lactones with P-glycoprotein: structure-affinity relationship. Eur J Pharm Sci. 2007;30(1):84–94. doi: 10.1016/j.ejps.2006.10.004. [PubMed] [CrossRef] [Google Scholar]
104. Jiang L., Wang P., Sun Y.J., Wu Y.J. Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-kappaB pathway. J Exp Clin Cancer Res. 2019;38(1):265. doi: 10.1186/s13046-019-1251-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
105. Loibl S., Gianni L. HER2-positive breast cancer. Lancet. 2017;389(10087):2415–2429. doi: 10.1016/s0140-6736(16)32417-5.[PubMed] [CrossRef] [Google Scholar]
106. Lim S.M., Syn N.L., Cho B.C., Soo R.A. Acquired resistance to EGFR targeted therapy in non-small cell lung cancer: Mechanisms and therapeutic strategies. Cancer Treat Rev. 2018;65:1–10. doi: 10.1016/j.ctrv.2018.02.006.[PubMed] [CrossRef] [Google Scholar]
107. Choi S.K., Kam H., Kim K.Y., Park S.I., Lee Y.S. Targeting Heat Shock Protein 27 in Cancer: A Druggable Target for Cancer Treatment? Cancers (Basel) 2019;11(8) doi: 10.3390/cancers11081195.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
108. Kumar R., Gururaj A.E., Barnes C.J. p21-activated kinases in cancer. Nat Rev Cancer. 2006;6(6):459–471. doi: 10.1038/nrc1892.[PubMed] [CrossRef] [Google Scholar]
109. Rane C.K., Minden A. P21 activated kinase signaling in cancer. Semin Cancer Biol. 2019;54:40–49. doi: 10.1016/j.semcancer.2018.01.006.[PubMed] [CrossRef] [Google Scholar]
110. Dammann K., Khare V., Gasche C. Tracing PAKs from GI inflammation to cancer. Gut. 2014;63(7):1173–1184. doi: 10.1136/gutjnl-2014-306768. [PubMed] [CrossRef] [Google Scholar]
111. Kumar R., Li D.Q. PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Adv Cancer Res. 2016;130:137–209. doi: 10.1016/bs.acr.2016.01.002. [PubMed] [CrossRef] [Google Scholar]
112. Guzzo C.A., Furtek C.I., Porras A.G., Chen C., Tipping R., Clineschmidt C.M., Sciberras D.G., Hsieh J.Y., Lasseter K.C. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. 2002;42(10):1122–1133. doi: 10.1177/009127002401382731. [PubMed] [CrossRef] [Google Scholar]
113. Geyer J., Gavrilova O., Petzinger E. Brain penetration of ivermectin and selamectin in mdr1a,b P-glycoprotein- and bcrp- deficient knockout mice. J Vet Pharmacol Ther. 2009;32(1):87–96. doi: 10.1111/j.1365-2885.2008.01007.x. [PubMed] [CrossRef] [Google Scholar]
114. Gao A., Wang X., Xiang W., Liang H., Gao J., Yan Y. Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin. J Pharm Pharmacol. 2010;62(3):393–399. doi: 10.1211/jpp.62.03.0016. [PubMed] [CrossRef] [Google Scholar]
A convergence of horrifying events have set into a motion an irreversible collapse of food production and crop harvests that will lead to global famine all the way through 2024. These events cannot be stopped for the simple reason that plants take time to grow. You can’t create crops instantly, and if they don’t get planted (or they get destroyed), there’s no instant replacement.
The reasons for the coming global famine include:
Floods and droughts causing sharp drops in crop production in China, Russia and the USA, among other nations.
Economic sanctions against Russia causing a halting of exports for food and fertilizer.
War in Ukraine, leading to a halting of the 2022 planting season for wheat, corn, soy and other crops.
War in the Black Sea, blocking ship movements in the ports (such as Odessa) which normally export crops.
The Biden admin’s shutting down of fossil duel production in the USA, adding significant costs to fertilizers and agricultural operations.
Global fiat currency money printing, making food inflation reach atrocious levels.
Importantly, all this coalesces into two primary problems that will now accelerate across the world:
Food SCARCITY
Food INFLATION
Scarcity, of course, means there’s no remaining supply no matter what the cost. Inflation means the food that is available will be significantly higher in price. Both of them cause people to panic, ultimately leading to widespread civil unrest (see below).
Understanding farm and crop inputs
Farmers are right now reporting a roughly 300% increase in their cost to produce crops such as wheat. This is due to three primary inputs:
The cost of fertilizer and seed.
The cost of fuel to power agricultural equipment.
The availability of tractors and other equipment (and their parts) in order to carry out mechanized agricultural operations.
Importantly, all three of these inputs are heavily strained due to the conditions mentioned above.
In addition to these factors, fuel costs significantly elevate transportation expenses to transport grains to grain storage and milling providers. Thus, rising fuel costs hit farmers twice: First for the cost of running their equipment, and secondly in the transportation costs.
Sadly, it looks like diesel fuel is headed toward $6 / gallon, and this is going to put severe upward pressure on food prices across the board. As I say in the podcast, elections have consequences… and rigged elections have dire consequences. (Joe Biden is punishing America with economic sanctions against our entire energy sector while having no such sanctions on Russia’s energy exports.)
Fertilizer costs have tripled, and fertilizer supply is growing scarce
Fertilizer prices have tripled and will likely go higher, especially as Russia has halted fertilizer exports and shut down natural gas pipelines to Western Europe. As a result, the fertilizer supply is growing scarce. About 5 billion people on the planet depend on fossil fuel-created fertilizer for their primary source of food. Thus, without fertilizer — if it were to go to zero — about 5 billion people starve to death.
I am not predicting the starvation of 5 billion people, since fertilizer production isn’t zero. But it is easily down by 25% – 30% right now, perhaps more, and that means somewhere approaching 2 billion people (or more) are going to face real famine / starvation in the crop seasons ahead. Very few people understand that food comes from fertilizer which is made using hydrocarbons. This is why left-wing activists are so eager to shut down pipelines, having no clue this will shut down their own food production as a result.
Extreme food scarcity to become apparent at the retail level this summer
There is a delay time between crop yield collapse and food scarcity at retail (grocery stores). Right now in March, we are eating the winter harvest of wheat. By late summer, we will be depending on wheat from the spring wheat crops around the world, and those crops just aren’t getting planted at the level necessary to feed the world.
The StrangeSounds.org website recently published a good overview of what they call the “wheat apocalypse.” From that article:
The wheat outlook looks grim… All over the world…
A limited supply of soft white wheat, the primary type of wheat grown in the Inland Northwest, has helped lead to a six-year low for wheat exports from the United States. That’s according to the USDA wheat report for February. The report also states that 71 percent of U.S. winter wheat is being hit by drought in 2022.
Egypt’s food security crisis now poses an existential threat to its economy. The fragile state of Egypt’s food security stems from the agricultural sector’s inability to produce enough cereal grains, especially wheat, and oilseeds to meet even half of the country’s domestic demand.
[China’s] Minister of Agriculture and Rural Affairs Tang Renjian said that rare heavy rainfall last year delayed the planting of about one-third of the normal wheat acreage.
Drought has shriveled Canada’s wheat crop to its smallest in 14 years, and its canola harvest to a nine-year low, a government report showed on Monday.
Parched soils and record-hot temperatures in Canada’s western crop belt sharply reduced farm yields of one of the world’s biggest wheat-exporting countries and largest canola-growing nation. The drought has forced millers and bakers to pay more for spring wheat, and drove canola prices to record highs.
On top of all that, Hungary has halted all grain exports in order to protect its domestic supply. In this article on Natural News, author JD Heyes lists the countries most likely to experience serious disruptions due to food scarcity. They include Egypt, Thailand and the Philippines.
By this summer, food shelves are going to look frighteningly empty across America, Canada and Western Europe
The upshot of all this is that food shelves are going to look downright frightening in 2022, and for the shelves that actually have food, it’s going to cost perhaps twice as much. Some items might see prices triple.
Even Reuters is now openly reporting that a United Nations agency says food inflation has hit 20%. And those are slightly old numbers. By the time they factor in the summer and fall of 2022, it’s going to be much closer to 50%.
Shockingly, food basics are going to require a larger and larger percentage of workers’ paychecks, taking away their ability to pay for fuel (which is also skyrocketing) or to purchase clothing, housing, etc.
The only factor that may actually reduce the demand for global food is the global vaccine die-off caused by mRNA / spike protein injections that are killing people are record numbers. The covid bioweapon, after all, is a depopulation weapon.
The net result is going to be global uprisings and social unrest on a scale we’ve never seen before
As covered in today’s podcast (below), the net effect of all this is going to be global uprisings, chaos and social unrest on an unprecedented scale.
Ever heard the saying about “nine meals from anarchy?” That’s what we’re about to witness later this year, in 2022.
It doesn’t mean that every city will collapse into instant chaos, but food scarcity, food inflation and energy inflation will create conditions of extreme poverty and desperation among the population. As a result, you’re going to witness more of the following:
Flash mob looting of grocery stores, followed by increased security at grocery retailers.
Gunpoint robberies of people exiting grocery stores, carrying groceries.
Highway robberies of transport trucks that are delivering goods to grocery retailers (ripped right out of Venezuela).
Increased carjackings, home invasions and crime derived from desperation and starvation. (While Democrats continue to “defund the police.”)
Hawaii Attorney Michael Green Files Class Action Lawsuit: “The Covid-19 Vaccine Has Killed 45,000 People in 72 hours”
Adverse Reactions from Covid Jabs Exposed @Adverse
Michael Green has filed a class-action lawsuit initially representing 1,200 first responders against the Governor’s vaccine mandates with thousands more expected to join. Honolulu Fire Captain Kaimi Pelekai gives emotional testimony about losing his job because he doesn’t want to put this experimental vaccine in his body after spending the last year taking care of COVID-19 patients. Attorney Sean Williams says that there are already effective treatments like hydroxychloroquine and ivermectin. And, according to the CDC, it is unnecessary to test asymptomatic people because they do not spread the virus. Please consider sending this video to any first responders in Hawaii who may be interested in joining this class action lawsuit.LBRY URLlbry://@TruthVault#0/Hawaii-Attorney-Michael-Green-Files-Class-Action-Lawsuit#dClaim IDd2368d9bff392f05e1804f6c0a5bd9a5dfc14f36255.47 MB