February 3, 2023 – Ending the COVID-19 public health emergency, which the Biden administration plans to do in May 2023, could make it harder for some people—depending on their health insurance status—to access free vaccines and COVID-19 tests and treatments, according to experts.

The change could lead to inequities and even to future outbreaks, said Jose Figueroa, assistant professor of health policy and management at Harvard T.H. Chan School of Public Health, in a February 1 article in The National Desk.

Regarding COVID testing, Figueroa said that different people may have to pay different amounts, depending on their insurance coverage. “It’s unclear what individual [health] plans will do but that’s a major, major change,” he said. “There’s concerns that there’s going to be a lot less testing happening out in the community.”

Access to free vaccines could also end for some, further quelling uptake, which has been steadily dropping over time. “If when they’re free, not everyone’s taking them, can you imagine if you have to now pay for it?” he said. “It’s going to be less and that will contribute to potentially future outbreaks.”

Figueroa was also quoted in the New York Times and in Time magazine about the potential impacts of ending the COVID emergency. In addition to the loss of free services, millions who became eligible for Medicaid under emergency declarations could lose that coverage in certain states. “The majority of them are expected to be Black and Latino people, so there are concerns that health inequities will worsen,” Figueroa said in Time. He added that loss of services could mean that the virus could have more opportunities to spread. “Will this change the trajectory of the pandemic?” he said. “It’s something we are going to have to watch.”

Read The National Desk article: End of national emergencies brings new challenges to US COVID response

Read the Time article: The U.S. COVID-19 Public Health Emergency Ends in May. Here’s What Will Change

Read the New York Times article: What the End of the Covid Public Health Emergency Could Mean for You

Photo: iStock/Daisy-Daisy

For the Harvard Chan community: Find the latest updates, guidance, useful information, and resources about Coronavirus Disease 2019 (COVID-19) here.

In the wake of an outbreak of coronavirus that began in China in 2019, Harvard T.H. Chan School of Public Health experts have been speaking to a variety of media outlets and writing articles about the pandemic. We’ll be updating this article on a regular basis. Here’s a selection of stories in which they offer comments and context:

2023

February 1: The U.S. COVID-19 public health emergency ends in May. Here’s what will change (Time)

Ending the COVID-19 public health emergency will make it harder for some people—depending on their health insurance status—to access things like free vaccines, COVID-19 tests and treatments, and telehealth care. The change may also lead to higher hospital care costs for some COVID-19 patients. Health inequities could result, noted Jose Figueroa, assistant professor of health policy and management. “Will [the end of the public health emergency] change the trajectory of the pandemic?” he said. “It’s something we are going to have to watch.”

February 1: End of national emergencies brings new challenges to US COVID response (The National Desk)

Access to free testing will be one of the biggest changes when the COVID-19 public health emergency ends. Different people may have to pay different amounts for tests, depending on their insurance coverage. “It’s unclear what individual [health] plans will do but that’s a major, major change,” said Jose Figueroa, assistant professor of health policy and management. “There’s concerns that there’s going to be a lot less testing happening out in the community.” Access to free vaccines could also end for some, which could further quell vaccine uptake. “If when they’re free, not everyone’s taking them, can you imagine if you have to now pay for it?” he said. “It’s going to be less and that will contribute to potentially future outbreaks.”

February 1: What the End of the Covid Public Health Emergency Could Mean for You (New York Times)

Jose Figueroa, assistant professor of health policy and management, quoted.

January 30: FDA panel votes to make all COVID-19 shots bivalent (Everyday Health)

An advisory panel to the FDA recommended that all COVID-19 vaccines be the bivalent version going forward. The panel also discussed the possibility of establishing an annual COVID-19 booster shot—but held off. “I think it’s quite reasonable to think of another [update to the booster] for the fall [of 2023], but it’s hard to say that it’s going to be annual at this point,” said panel member Eric Rubin, adjunct professor of immunology and infectious diseases.

January 26: The COVID emergency might end after 3 long years – but the virus is still a threat (CBC)

Experts discussed how COVID will continue to threaten us for years to come. Although vaccinations, treatments, and prior immunity make COVID much less dangerous for most people, there are still those who remain vulnerable, including older people and other high-risk individuals. Bill Hanage, associate professor of epidemiology, noted that not much has been done to protect the most frail individuals living in nursing homes in North America. “I think that it’s kind of crazy that we [hadn’t] previously developed ways to robustly rapidly test people who work in nursing homes, to prevent them bringing in respiratory viruses,” he said.

January 19: Davos 2023: Chief executive of ‘world’s largest vaccine maker’ on the state of the pandemic (World Economic Forum)

Harvard Chan School Dean Michelle Williams was quoted.

January 19: Public health agencies are retooling as COVID-19 response winds down. A slim majority of adults trusts them to manage another pandemic (Morning Consult)

Vish Viswanath, Lee Kum Kee Professor of Health Communication, said that the CDC and other health institutions “have taken a real hit” in terms of trust during the pandemic. He cited politicization and communication mistakes among the reasons for the decline.

January 19: How scientists trained computers to forecast COVID-19 outbreaks weeks ahead (Los Angeles Times)

Mauricio Santillana, adjunct professor of epidemiology, and colleagues developed a machine learning system for predicting when and where COVID-19 outbreaks will occur. Said Santillana, “Our work is aimed at documenting what techniques and approaches might be useful not just for this [the COVID-19 pandemic], but the next pandemic.”

January 11: FDA vaccine advisers ‘disappointed’ and ‘angry’ that early data about new Covid-19 booster shot wasn’t presented for review last year (CNN)

Eric Rubin, adjunct professor of immunology and infectious diseases, was among members of an FDA advisory committee who expressed dismay that they weren’t told last year about data suggesting that Moderna’s then-new bivalent COVID booster may not be any more effective at preventing the disease than the original vaccines. The committee members said the information would have been important for them to have as they discussed whether or not the booster should be made available to the public. “It’s not a group of children,” Rubin said. “We understand how to interpret these results.”

January 10: Coronavirus FAQ: How do I avoid catching COVID while flying in 2023? (NPR)

With COVID surging in China and the highly contagious XBB variant circulating, experts are suggesting taking precautions when flying, such as wearing a high-quality mask. Leonard Marcus, founding co-director of the National Preparedness Leadership Initiative (NPLI) and co-director of NPLI’s Aviation Public Health Initiative, also recommended distancing during boarding and deplaning, wiping surfaces such as bathroom door handles and seat trays with alcohol wipes, and turning on air vents. “The ventilation pushes clean air from above to the floor,” he said. “The more of that the better.”

2022

December 19: 1,000 days later, experts say the COVID shutdown was the right move (WBUR)

William Hanage, associate professor of epidemiology, is among experts who think that Massachusetts Gov. Charlie Baker made the right decision in March 2020 in ordering non-essential businesses to shut down to stop the spread of the pandemic. If anything, Baker should have made the call sooner, he said. “A lot of people died in Massachusetts during that first surge, and not that many people needed to die,” he said.

December 18: ‘Tripledemic’ viruses still spreading. What science shows about being contagious. (NBC News)

Yonatan Grad, Melvin J. and Geraldine L. Glimcher Associate Professor of Immunology and Infectious Diseases, and other experts discussed how long people with COVID-19, flu, and respiratory syncytial virus (RSV) remain infectious.

December 16: Employees navigate working through covid when there are no more office precautions (BNN Bloomberg)

Even as COVID-19 cases spike in the U.S., Joseph Allen, associate professor of exposure assessment science and director of the Healthy Buildings program, said he doesn’t think people “should be forever masking and forever testing. That was part of the emergency of COVID.” Instead, he recommended that businesses upgrade their buildings’ ventilation and filtration systems and that people should stay home when they’re sick.

December 16: Winter surge: SARS-CoV-2, RSV, and the Flu (HMS News)

William Hanage, associate professor of epidemiology, was among experts from the Massachusetts Consortium on Pathogen Readiness quoted in this Q&A about COVID-19’s shifting landscape in the context of new variants as well as the spread of flu and respiratory syncytial virus (RSV).

December 16: As COVID cases rise, White House announces more prevention efforts, including free tests (Yahoo News)

COVID cases, hospitalizations, and deaths are on the rise. But members of the Massachusetts Consortium on Pathogen Readiness—including William Hanage, associate professor of epidemiology—told reporters on December 14 that they’re not particularly worried about the currently circulating variants, such as BQ.1 and BQ.1.1, because antivirals can effectively treat them and they don’t appear likely to cause more severe disease than other variants.

December 16: COVID-19 is about to explode in China. What that could mean for the United States (USA Today)

Now that China has lifted its restrictive COVID-19 policies, the country is likely to see waves of infections and deaths. William Hanage, associate professor of epidemiology, said that China could see more than 2 million deaths in the coming months. He and other experts noted that China is very vulnerable because its population is undervaccinated and lacks natural immunity from infection, and because the country has a limited supply of treatments.

December 12: Is COVID a common cold yet? (The Atlantic)

Yonatan Grad, Melvin J. and Geraldine L. Glimcher Associate Professor of Immunology and Infectious Diseases, said that COVID has not yet been tamed into a common cold; SARS-CoV-2 till seems to spread more efficiently and more quickly than a cold, and it’s more likely to trigger severe disease or long-term illness.

December 9: India’s measles outbreak a consequence of Covid-19 health services slowdown (IndiaSpend)

In this Q&A, K. Srinath Reddy, adjunct professor of epidemiology, spoke about how a slowdown in essential health services in India during the COVID-19 pandemic resulted in decreasing measles vaccination rates, leading to a current outbreak. “There were so many ways that COVID took our eye off other health conditions,” Reddy said.

December 9: Omicron completely changed the pandemic. Are we prepared for what’s next? (CBC News)

William Hanage, associate professor of epidemiology, quoted.

December 9: Want to improve air quality? Open some windows (Medpage Today)

Improving ventilation in indoor spaces is key to reducing transmission of infections such as the coronavirus, said Joseph Allen, associate professor of exposure assessment science and director of the Healthy Buildings program, in this Q&A. “Decades of science are showing [that the current standard is] not acceptable,” he said. “We got this virus spread entirely indoors that has slammed up against a building architecture and design that’s been designed without thinking about health. It’s no wonder we’ve had the disaster we’ve had.” He urged that building codes be updated to more stringent ventilation standards.

December 8: David Cutler on Cities After the Pandemic (IMF Podcasts)

Health economist David Cutler, Otto Eckstein Professor of Applied Economics in the Faculty of Arts and Sciences at Harvard University, spoke about an article he co-authored with Harvard colleague Edward Glaeser titled “Cities After the Pandemic.” He said that cities now need to put more emphasis on public health to keep economies healthy.

December 7: China’s Zero-Covid policy succeeded–until it didn’t. Here’s what went wrong and what experts think could happen next. (Forbes)

If China proceeds with lifting its stringent COVID restrictions, it should do so gradually, ensure that vulnerable people are vaccinated, and keep an eye on factors such as hospital capacity, said Winnie Yip, professor of the practice of global health policy and economics. She also stressed the need for public education programs about vaccination and what to do if one gets infected.

December 6: Bump or spike? COVID in wastewater has experts unsurprised but wary (WBUR)

William Hanage, associate professor of epidemiology, said that a post-Thanksgiving uptick in the level of COVID in Boston-area wastewater “is not out of line with the fluctuations we have seen over the last few months.” He predicted that levels will fall again, then increase again as people hold more holiday gatherings.

December 5: How China can pivot from ‘zero covid’ while preventing calamity (Washington Post)

Winnie Yip, professor of the practice of global health policy and economics, was quoted in this opinion piece by George Washington University’s Leana Wen. Yip said that China’s “zero COVID” policy, involving strict lockdown measures, should be scrapped. “People’s lives have been completely disrupted,” she said. “I think they are ready to hear and spread the message that you could get infected, but you’re protected by vaccines, there is treatment, and you can resume your normal life.”

December 2: China lifts some COVID lockdowns, but it’s unknown how fast policy will change (NPR)

Winnie Yip, professor of the practice of global health policy and economics, said that recent protests against the Chinese government’s tough pandemic control policies may have pushed the government to loosen those restrictions on a faster timeline.

February 2, 2023 – Noise pollution is a growing problem that can lead to sleep disruption and insomnia as well as chronic health conditions such as heart disease, cognitive impairment, depression, and anxiety, according to experts.

Much noise pollution comes from traffic. Other forms of noise pollution include the sounds of leaf blowers, construction, airplanes taking off and landing, and buzzing drones.

Loud noises can signal to the auditory system that something is wrong, triggering a fight-or-flight-response, which floods the body with stress hormones that cause inflammation and can lead to disease, said Peter James, associate professor in the Department of Environmental Health at Harvard T.H. Chan School of Public Health, in a January 5 Kaiser Health News article.

Low-income communities and those with a large proportion of nonwhite residents are disproportionately impacted by traffic noise, James and colleagues found in a 2017 paper. “We’ve made these conscious or subconscious decision as a society to put minority-race communities who have the least amount of political power in areas near highways and airports,” he said.

Read the Kaiser Health News article: Lost sleep and jangled nerves: The rising onslaught of noise harms mind and body

February 2, 2023 – Ten experts recently told the New York Times which false ideas about nutrition they would like to dispel. One of those experts—Harvard T.H. Chan School of Public Health’s Sara Bleich—said that she’d like to dispel the myth that “Fresh fruits and vegetables are always healthier than canned, frozen or dried varieties.”

Bleich, professor of public health policy at Harvard Chan School and outgoing director of nutrition security and health equity at the U.S. Department of Agriculture, said that canned, frozen, or dried fruits and vegetables can be just as nutritious as fresh items. “They can also be a money saver and an easy way to make sure there are always fruits and vegetables available at home,” she said. However, she warned consumers to check nutrition labels so they can choose products with a minimum of added sugars, saturated fats, and sodium.

The other nine experts quoted in the article tackled a variety of myths, including the idea that all fat is bad; that there’s a link between soy-based foods and breast cancer risk; and that children shouldn’t be fed peanut products in their first few years of life.

Read the New York Times article: 10 Nutrition Myths Experts Wish Would Die

January 31, 2023—Care for opioid use disorder can be effective whether provided in-person or via telemedicine, according to a new study co-authored by researchers from Harvard T.H. Chan School of Public Health.

Seeking to understand if and how the sudden rise of telemedicine during the COVID-19 pandemic affected quality of care for opioid use disorder, the study authors examined the insurance claims of 11,801 patients in care for the disorder in the year before the pandemic and in its first year. Between the two groups, they compared factors such as health care visits attended, medications prescribed, and clinical events such as overdoses or infections related to drug injection.

The researchers observed no meaningful differences between the groups. In the study, published January 24 in JAMA Network Open, they wrote that the results “suggest that telemedicine is a comparable alternative for delivering care for [opioid use disorder] but not one that will substantially change care quality or access in the short term.”

Michael Barnett, associate professor of health policy and management at Harvard Chan School and a co-author of the study, said in a January 24 article in The Washington Times, “[Telemedicine] largely replicated the standard model for care delivery. There is still much work to be done to improve care, but telemedicine does not appear to have created any barriers or safety issues.”

And though remote care won’t be every patient’s preference—in-person visits have unique, irreplicable benefits—“it can make a huge difference for people who would otherwise need to travel long distances or be stuck in traffic to get to an appointment,” Barnett said. “Or to enhance privacy for sensitive issues like addiction.”

Read the Washington Times article: Study supports using telemedicine for opioid addiction

Read the study: Telemedicine Use and Quality of Opioid Use Disorder Treatment in the US During the COVID-19 Pandemic

January 27, 2023—Among Massachusetts adults with low incomes, those experiencing food insecurity reported greater disruptions in their diets during the early months of the COVID-19 pandemic than those not experiencing food insecurity, according to a new study led by researchers from Harvard T.H. Chan School of Public Health.

In a survey of 1,256 adults conducted in late 2020, the researchers found that many who experienced food insecurity were eating less—of both healthy and unhealthy items—since the start of the pandemic. But the study also found that food pantries and the Supplemental Nutrition Assistance Program (SNAP) provided a buffer for those experiencing food insecurity. Compared with people who didn’t use either pantries or SNAP, those who used pantries tended to consume higher amounts of both healthy and unhealthy foods, whereas SNAP participants consumed higher amounts of mostly healthy foods.

The study was published online January 5, 2023, in Frontiers.

“We know that access to food during the first year of the COVID-19 pandemic was especially difficult for those who were acutely affected by disruptions in the economy, the job market, and daily life,” said first author Matthew Lee, a PhD candidate in the Department of Nutrition. “For folks in Massachusetts living with lower incomes, our study shows that nutrition assistance programs—food pantries and SNAP in particular—are critically important in helping people to secure the foods they need to sustain themselves and others around them. We need to continue to support efforts to bolster and improve these programs and policies.”

Other Harvard Chan authors included Mary Kathryn Poole, Eric Rimm, and Erica Kenney.

Read the study: Food insecurity and the role of food assistance programs in supporting diet quality during the COVID-19 pandemic in Massachusetts

January 27, 2023 – Reusable “period underwear” that people use in place of traditional, disposable menstrual products may contain toxic compounds linked with long-term health risks.

A January 20 New York Times article discussed a recently settled lawsuit involving the period underwear brand Thinx. The suit alleged that Thinx underwear contains chemicals called per- and polyfluoroalkyl substances (PFAS). These water- and stain-resistant compounds—called “forever chemicals” because they accumulate in the environment and in people’s bodies and don’t degrade—are widely used in consumer products, from cookware to cleaning products to cosmetics. Studies have linked PFAS with issues such as period irregularities, ovarian disorders, high blood pressure in pregnant people, and risk of low birthweight in babies exposed in utero.

Experts worry about how PFAS affects the body during vulnerable phases, such as when someone gets their first period, is pregnant, or is undergoing menopause, said Shruthi Mahalingaiah, assistant professor of environmental, reproductive, and women’s health at Harvard T.H. Chan School of Public Health. Mahalingaiah noted that she had purchased a pair of period underwear for her daughter, choosing what she thought were organic or natural products. “If I, someone with expertise, still have difficulties identifying what’s safe for my children, I don’t suspect it’s any easier for anyone else,” she said.

It’s unclear whether other period products contain PFAS or other toxins because they’re not rigorously tested by the Food and Drug Administration and manufacturers aren’t required to list all the materials used in them, according to the article.

Read the New York Times article: What to Know About PFAS in Period Underwear

January 26, 2023 — In the face of longstanding health disparities magnified during the COVID-19 pandemic, Massachusetts Gov. Maura Healey can take concrete steps to promote health equity, according to Harvard T.H. Chan School of Public Health’s Lumas Joseph Helaire.

In a January 9 opinion piece in CommonWealth Magazine, Helaire, assistant dean for population health management and health equity education and visiting lecturer in the Department of Social and Behavioral Sciences, cited recent findings from the Blue Cross Blue Shield of Massachusetts Foundation and Manatt Health that Black and Hispanic people in Massachusetts face a two to three times greater risk of contracting COVID-19, being hospitalized due to COVID-19, or dying from COVID-19 than white or Asian people.

“These disparities are not new nor are they unique to Massachusetts, but we cannot take solace in the fact that our failures are longstanding or widespread,” Helaire wrote. He offered three recommendations to the governor:

• Address the social determinants of health—from housing to nutrition to education—to keep people well and prevent illness in the first place.
• Invest in efforts to collect better, or never before available, data on health outcomes and demographics that can expose inequities and drive solutions.
• Leverage state resources to diversify the ranks of the Commonwealth’s health officials, health care providers, and public health experts to better represent and serve marginalized populations.

“Massachusetts has long been a national leader in enacting reforms that drive our health system forward,” Helaire wrote. “Right now, we have an opportunity to continue that legacy in a way that expands equity and erases a system that assigns health care winners and losers based on the circumstances of one’s birth.”

Read the opinion piece in CommonWealth Magazine: 3 steps for addressing health equity in Mass.

January 26, 2023—Evidence suggests that moderate alcohol consumption may provide some health benefits, including lower risk of cardiovascular disease and type 2 diabetes. But any potential benefits must be weighed against potential risks, such as increased risk of breast cancer—not to mention the many harms that can result from excessive drinking—leading some experts to conclude that no amount of alcohol is safe to consume.

According to Eric Rimm, professor of epidemiology and nutrition at Harvard T.H. Chan School of Public Health, the problem is not alcohol itself but the way it’s used. Excessive alcohol consumption can be dangerous; in fact, it’s the leading factor in the deaths of young men, he noted on the January 16, 2023 episode of the podcast Food, We Need to Talk. But that doesn’t mean other adults can’t enjoy it in moderation.

Rimm said that he would never suggest that someone start drinking alcohol for health reasons, but for those who already enjoy it, he said, “The biggest thing is just do it in a healthy way…stop at one or two [drinks].”

Listen to Food, We Need to Talk podcast: Resolutions—Is Alcohol *Actually* Healthy?

Learn more

Alcohol and health: It’s complicated (Harvard Chan School news)

photo: iStock/abeyer

January 17, 2023 – Office workers in the U.S., the U.K., China, and India were exposed to complex mixtures of chemicals that can disrupt hormonal functions, according to a study that analyzed chemical traces picked up by silicone wristbands worn by the workers. The chemicals included plasticizers, fragrances, flame retardants, and pesticides, which are found in a wide range of common products.

Led by researchers from Harvard T.H. Chan School of Public Health, the study found that every one of the 243 office workers in the study—who wore silicone wristbands during a one-week period in 2019—was exposed to chemical mixtures that mimicked or blocked sex hormones or thyroid hormone in human cells in the laboratory.

The study is the first to report on in vitro sex hormone activity of personal chemical exposures via analysis of silicone wristbands. It was published online January 10 in the journal Chemosphere.

Lead author Anna Young, research associate with the Harvard Healthy Buildings Program, and colleagues analyzed extracts of the wristbands for nearly 100 known chemicals as well as more than 1,000 chemical signatures that they tentatively identified. In the lab, they looked at how these various chemicals interacted with hormone receptors in human cells. Hormone receptors regulate physiological processes in the body, the authors noted, so interference with them can have critical consequences on reproductive, developmental, and metabolic health, as well as raise the risk for certain hormone-related cancers.

The researchers found that that workers’ exposures to both known and unidentified chemical mixtures were strongly linked with interference with estrogen, androgen, and thyroid hormone receptors in human cells. Often, the higher the levels of chemicals in the mixtures were, the higher the interference, the study found. There were some differences by gender and country. For example, women were typically exposed to mixtures with more different kinds of chemicals and with higher sex hormone interference than men—likely because they tend to use more personal care products than men. Also, office workers in China and India tended to have higher exposures to several chemicals that were identified as playing a key role in mixtures linked with higher levels of hormonal activity.

The authors noted that their findings don’t yet provide evidence of negative health effects of these chemical mixtures in human bodies. But, they added, “Our study provides valuable data on how buildings and products influence our exposures to complex cocktails of hundreds of both known and unknown chemicals and how those chemical mixtures have strong hormone-mimicking activities.”

Other Harvard Chan School authors of the study included Joseph Allen, Brent Coull, and Russ Hauser.

Read the study: Hormone receptor activities of complex mixtures of known and suspect chemicals in personal silicone wristband samplers worn in office buildings

Learn more

Chemical-laden indoor dust may interfere with sexual development, reproduction (Harvard Chan School news)

Keratinocytes are the most abundant cells in the epidermis, and as part of the frontline immunologic defense system, keratinocytes function as a barrier to exogenous attacks. Protease-activated receptor 2 (PAR2) is expressed in human keratinocytes and activated in several inflammatory conditions, such as atopic dermatitis (AD). In this study, we demonstrated the differentiation of human induced pluripotent stem cell into keratinocytes by the improved, robust differentiation procedure and confirmed that human induced pluripotent stem cell–derived keratinocyte-like cells (iKera) express PAR2, which is activated by external addition of the ligand peptide and trypsin. The activation of PAR2 led to the release of calcium from intracellular calcium storage, followed by the release of the proinflammatory cytokine tumor necrosis factor α. Moreover, PAR2 antagonist I-191 (CAS No. 1690172-25-8) inhibited calcium release in a dose-dependent manner. This is the first study to demonstrate that iKera expresses a functional PAR2 protein. Furthermore, our results indicate crosstalk between the PAR2- and IL-4–mediated inflammatory axes in iKera, suggesting that iKera can be used as a platform for a broad range of mechanism-targeted drug screening in AD.

Epithelial-mesenchymal transition (EMT) is a crucial biologic process for breast cancer metastasis, and inhibition of EMT could be an effective approach to suppress metastatic potential of mammary cancer. High expression of low-density lipoprotein receptor-related protein 6 (LRP6) is usually observed in breast carcinoma and predicts poor prognosis. In the present study, we investigated whether chlorogenic acid (CA) can inhibit the EMT of breast cancer cells and underlying molecular mechanism. We found that CA treatment transformed MCF-7 cell morphology from spindle shape (mesenchymal phenotype) to spherical shape (epithelial phenotype). CA clearly increased epithelial biomarkers’ expression (E-cadherin and ZO-1) but decreased mesenchymal proteins’ expression (ZEB1, N-cadherin, vimentin, snail, and slug). In addition, CA attenuated MMP-2 and MMP-9 activities and inhibited cell migration and invasion. CA downregulated the expression of LRP6 in MCF-7 cells. Knockdown LRP6 with siRNA repressed cell mobility and invasion, wheras overexpression of LRP6 promoted EMT and antagonized the EMT inhibitory effect of CA on MCF-7 cells. Furthermore, CA directly interacted with Wnt/β-catenin signaling coreceptor LRP6 and reduced LRP6, p-LRP6, and β-catenin expression levels in MCF-7 cells. In vivo study revealed that CA notably reduced tumor volume and tumor weight. CA decreased the expression of LRP6, N-cadherin, ZEB1, vimentin, MMP2, MMP9, and increased the expression of E-cadherin and ZO-1. In conclusion, CA inhibited EMT and invasion of breast cancer by targeting LRP6.

DNA topoisomerase IIα (TOP2α/170; 170 kDa) and topoisomerase IIβ (TOP2β/180; 180 kDa) are targets for a number of anticancer drugs, whose clinical efficacy is attenuated by chemoresistance. Our laboratory selected for an etoposide-resistant K562 clonal subline designated K/VP.5. These cells exhibited decreased TOP2α/170 and TOP2β/180 expression. We previously demonstrated that a microRNA-9 (miR-9)-mediated posttranscriptional mechanism plays a role in drug resistance via reduced TOP2α/170 protein in K/VP.5 cells. Here, it is hypothesized that a similar miR-9 mechanism is responsible for decreased TOP2β/180 levels in K/VP.5 cells. Both miR-9-3p and miR-9-5p are overexpressed in K/VP.5 compared with K562 cells, demonstrated by microRNA (miRNA) sequencing and quantitative polymerase chain reaction. The 3'-untranslated region (3'-UTR) of TOP2β/180 contains miRNA recognition elements (MRE) for both miRNAs. Cotransfection of K562 cells with a luciferase reporter plasmid harboring TOP2β/180 3'-UTR plus miR-9-3p or miR-9-5p mimics resulted in statistically significant decreased luciferase expression. miR-9-3p and miR-9-5p MRE mutations prevented this decrease, validating direct interaction between these miRNAs and TOP2β/180 mRNA. Transfection of K562 cells with miR-9-3p/5p mimics led to decreased TOP2β protein levels without a change in TOP2β/180 mRNA and resulted in reduced TOP2β-specific XK469-induced DNA damage. Conversely, K/VP.5 cells transfected with miR-9-3p/5p inhibitors led to increased TOP2β/180 protein without a change in TOP2β/180 mRNA and resulted in enhancement of XK469-induced DNA damage. Taken together, these results strongly suggest that TOP2β/180 mRNA is translationally repressed by miR-9-3p/5p, that these miRNAs play a role in acquired resistance to etoposide, and that they are potential targets for circumvention of resistance to TOP2-targeted agents.

Extensive bowel resection caused by various diseases that affect the intestines, such as Crohn's disease, volvulus, and cancer, leads to short bowel syndrome (SBS). Teduglutide is the only approved glucagon-like peptide-2 (GLP-2) drug for SBS; however, it requires daily administration. A novel GLP-2 analog with a prolonged duration of action to reduce dosing frequency and promote a greater efficacy may provide patients with a better quality of life. In the present study, the sustained exposure of HM15912 was characterized in normal male rats. The efficacy of HM15912 on intestinal growth and absorption capacity was also evaluated in normal male mice, rats, and SBS rats. HM15912 exhibited a remarkably extended half-life (42.3 hours) compared with teduglutide (0.6 hours) in rats. Despite somewhat lower in vitro potency on GLP-2 receptor than human GLP-2 or teduglutide, this longer-lasting mode of action promotes HM15912 to be more effective in terms of small intestinal growth than existing GLP-2 analogs even with a less frequent dosing interval of as little as once a week in rodents, including SBS rats. Furthermore, the small intestinal weight was approximately doubled, and the D-xylose absorption was significantly increased after pre-treatment of existing GLP-2 analogs on the market or under clinical development followed by HM15912 in rodents. These results indicate that HM15912 possesses a significant small bowel trophic effect driven by continuously increased exposure, supporting that HM15912 may be a novel treatment option with greater efficacy and the longest dosing interval among existing GLP-2 analogs for SBS with intestinal failure.

Hydrogen sulfide (H₂S), a novel gasotransmitter, is involved in the regulation of gut motility. Alterations in the balance of H₂S play an important role in the pathogenesis of diabetes. This study was conducted to investigate the role of H₂S in the colonic hypomotility of mice with streptozotocin (STZ)-induced diabetes. A single intraperitoneal injection of STZ was used to induce the type 1 diabetes model. Male C57BL/6 mice were randomized into a control group and an STZ-treated group. Immunohistochemistry, Western blotting, H₂S generation, organ bath studies and whole-cell patch clamp techniques were carried out in single smooth muscle cells (SMCs) of the colon. We found that STZ-induced diabetic mice showed decreased stool output, impaired colonic contractility, and increased endogenous generation of H₂S (p < 0.05). H₂S-producing enzymes were upregulated in the colon tissues of diabetic mice (p < 0.05). The exogenous H₂S donor sodium hydrosulfide (NaHS) elicited a biphasic action on colonic muscle contraction with excitation at lower concentrations and inhibition at higher concentrations. NaHS (0.1 mM) increased the currents of voltage-dependent calcium channels (VDCCs), while NaHS at 0.5 mM and 1.5 mM induced inhibition. Furthermore, NaHS reduced the currents of both voltage-dependent potassium (K_V) channels and large conductance calcium-activated potassium (BK) channels in a dose-dependent manner. These results show that spontaneous contraction of colonic muscle strips from diabetic mice induced by STZ was significantly decreased, which may underlie the constipation associated with diabetes mellitus (DM). H₂S overproduction with subsequent suppression of muscle contraction via VDCCs on SMCs may contribute in part to the pathogenesis of colonic hypomotility in DM.

Indobufen possesses anticoagulant and antithrombotic effects that can improve micro-inflammation and renal function. This study aimed to examine whether indobufen could improve the microinflammatory state in patients on continuous ambulatory peritoneal dialysis (CAPD) and explore its therapeutic effects on peritoneal transport function. A total of 60 patients undergoing CAPD from October 2019 to October 2020 were selected and randomized to the control and indobufen groups. All patients received conventional treatments. Blood routine and the serum and peritoneal effusion levels of tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), cellular fibronectin (cFN), and vascular endothelial growth factor were determined before and after 6 months of treatment. The peritoneal equilibrium test (PET) was used to evaluate peritoneal transport function. There were no significant differences in PET results, microinflammatory state, and biochemical indices between the two groups before treatment (P > 0.05). After 6 months of treatment, platelet-to-lymphocyte ratio and serum and peritoneal effusion TNF-α levels in the indobufen group were decreased compared with the control group (P < 0.05). Serum and peritoneal effusion TGF-β1 and cFN levels in the indobufen group were reduced compared with the control group (P < 0.05). PET results in the indobufen group were decreased compared with baseline (P < 0.05). The difference in PET results between the two groups before and after treatment was statistically significant (P < 0.05). Indobufen could improve the peritoneal transport function in patients undergoing CAPD. The underlying mechanism might be related to the improvement of the microinflammatory state and peritoneal fibrosis.

Development of neurocognitive disorder in human immunodeficiency virus (HIV)-infected patients has been linked to dysregulation of dopamine by the HIV-1 transactivator of transcription (Tat) protein, a negative allosteric modulator of dopamine transporter (DAT). Using fast scan cyclic voltammetry, the present study determined the effects of in vivo Tat expression on dopamine release in the caudate putamen of inducible Tat transgenic (iTat-tg) mice and the impact of a novel DAT allosteric modulator, Southern Research Institute (SRI)-32743, on the Tat effect. We found that 7- or 14-day doxycycline (Dox)-induced Tat expression in iTat-tg mice resulted in a 2-fold increase in phasic but not tonic stimulated baseline dopamine release relative to saline control mice. To determine whether the Tat-induced increase in dopamine release is mediated by DAT regulation, we examined the effect of an in vitro applied DAT inhibitor, nomifensine, on the dopamine release. Nomifensine (1 nM–10 µM) concentration-dependently enhanced phasic stimulated dopamine release in both saline- and Dox-treated iTat-tg mice, while the magnitude of the nomifensine-mediated dopamine release was unchanged between saline and Dox treatment groups. A single systemic administration of SRI-32743 prior to animal sacrifice reversed the increased dopamine release in the baseline of phasic dopamine release and nomifensine-augmented dopamine levels in Dox-treated iTat-tg mice, while SRI-32743 alone did not alter baseline of dopamine release. These findings suggest that Tat expression induced an increase in extracellular dopamine levels by not only inhibiting DAT-mediated dopamine transport but also stimulating synaptic dopamine release. Thus, DAT allosteric modulators may serve as a potential therapeutic intervention for HIV infection-dysregulated dopamine system observed in HIV-1 positive individuals.

Targeting neuronal Kv7 channels by pharmacological activation has been proven to be an attractive therapeutic strategy for epilepsy. Here, we show that activation of Kv7 channels by an opener SCR2682 dose-dependently reduces seizure activity and severity in rodent models of epilepsy induced by a GABAa receptor antagonist pentylenetetrazole (PTZ), maximal electroshock, and a glutamate receptor agonist kainic acid (KA). Electroencephalographic recordings of rat cerebral cortex confirm that SCR2682 also decreases epileptiform discharges in KA-induced seizures. Nissl and neuronal nuclei staining further demonstrates that SCR2682 also protects neurons from injury induced by KA. In Morris water maze navigation and Y-maze tests, SCR2682 improves PTZ- and KA-induced cognitive impairment. Taken together, our findings demonstrate that pharmacological activation of Kv7 by novel opener SCR2682 may hold promise for therapy of epilepsy with cognitive impairment.