Tag: 12/1/24

Categories : AntibioticsTags :

Treating Tuberculosis when Antibiotics Become Ineffective

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Tuberculosis bacteria. Credit: CDC

An international research team has found a number of substances with a dual effect against tuberculosis (TB): They make the bacteria causing the disease less pathogenic for human immune cells whilst boosting the activity of conventional antibiotics. They published their findings in the journal Cell Chemical Biology.

Infectious disease specialist Dr Jan Rybniker and colleagues have identified new, antibiotic molecules that target Mycobacterium tuberculosis and make it less pathogenic for humans.

Diagram by the United States-based National Institute of Allergy and Infectious Diseases showing the medicine options for drug-resistant tuberculosis. (Via Flickr, CC BY 2.0 Deed)

In addition, some of the discovered substances may allow for a renewed treatment of tuberculosis with available medications – including strains of the bacterium that have already developed drug resistance.

Although treatable with antibiotics, it still ranks among the infectious diseases that claim the most lives worldwide: According to the World Health Organization (WHO), only COVID was deadlier than TB in 2022. The disease also caused almost twice as many deaths as HIV/AIDS. More than 10 million people continue to contract TB every year, mainly due to insufficient access to medical treatment in many countries.

Limited targets

Multidrug-resistant tuberculosis is emerging especially in eastern Europe and Asia. That is of particular concern to researchers because like all bacteria that infect humans, Mycobacterium tuberculosis possesses only a limited number of targets for conventional antibiotics.

That makes it increasingly difficult to discover new antibiotic substances in research laboratories.

Working together with colleagues from the Institute Pasteur in Lille, France, and the German Center for Infection Research (DZIF), the researchers at University Hospital Cologne have now identified an alternative treatment strategy for the bacterium.

The team utilized host-cell-based high-throughput methods to test the ability of molecules to stem the multiplication of bacteria in human immune cells: From a total of 10,000 molecules, this procedure allowed them to isolate a handful whose properties they scrutinized more closely in the course of the study.

Two-pronged attack

Ultimately, the researchers identified virulence blockers that utilise target structures that are fundamentally distinct from those targeted by classical antibiotics.

“These molecules probably lead to significantly less selective pressure on the bacterium, and thus to less resistance,” said Jan Rybniker, who heads the Translational Research Unit for Infectious Diseases at the Center for Molecular Medicine Cologne (CMMC) and initiated the study.

In deciphering the exact mechanism of action, the researchers also discovered that some of the newly identified chemical substances are dual-active molecules.

Thus, they not only attack the pathogen’s virulence factors, but also enhance the activity of monooxygenases — enzymes required for the activation of the conventional antibiotic ethionamide.

Ethionamide is a drug that has been used for many decades to treat TB. It is a so-called prodrug, a substance that needs to be enzymatically activated in the bacterium to kill it. Therefore, the discovered molecules act as prodrug boosters, providing another alternative approach to the development of conventional antibiotics.

In cooperation with the research team led by Professor Alain Baulard at Lille, the precise molecular mechanism of this booster effect was deciphered.

Thus, in combination with these new active substances, drugs that are already in use against tuberculosis might continue to be employed effectively in the future.

The discovery offers several attractive starting points for the development of novel and urgently needed agents against tuberculosis.

“Moreover, our work is an interesting example of the diversity of pharmacologically active substances. The activity spectrum of these molecules can be modified by the smallest chemical modifications,” Rybniker added.

However, according to the scientists it is still a long way to the application of the findings in humans, requiring numerous adjustments of the substances in the laboratory.

Source: University of Cologne

Categories : UncategorizedTags :

Activating Specific Neurons Extends the Lifespan of Mice

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Photo by Kanashi ZD on Unsplash

Studies have recently begun to reveal that the lines of communication between the body’s organs are key regulators of aging. When these lines are open, the body’s organs and systems work well together. But with age, communication lines deteriorate, and organs don’t get the molecular and electrical messages they need to function properly.

A new study from Washington University School of Medicine in St. Louis identifies, in mice, a critical communication pathway connecting the brain and fat tissue in a feedback loop that appears central to energy production throughout the body. The research suggests that the gradual deterioration of this feedback loop contributes to the increasing health problems that are typical of natural aging.

The study, which appears in Cell Metabolism, has implications for developing future interventions that could maintain the feedback loop longer and slow the effects of advancing age.

The researchers identified a specific set of neurons in the brain’s hypothalamus that, when active, sends signals to the body’s fat tissue to release energy. Using genetic and molecular methods, the researchers studied mice that were programmed to have this communication pathway constantly open after they reached a certain age. The scientists found that these mice were more physically active, showed signs of delayed aging, and lived longer than mice in which this same communication pathway gradually slowed down as part of normal aging.

“We demonstrated a way to delay aging and extend healthy life spans in mice by manipulating an important part of the brain,” said senior author Shin-ichiro Imai, MD, PhD, the Theodore and Bertha Bryan Distinguished Professor in Environmental Medicine and a professor in the Department of Developmental Biology at Washington University. “Showing this effect in a mammal is an important contribution to the field; past work demonstrating an extension of life span in this way has been conducted in less complex organisms, such as worms and fruit flies.”

These specific neurons, in a part of the brain called the dorsomedial hypothalamus, produce an important protein: Ppp1r17. When this protein is present in the nucleus, the neurons are active and stimulate the sympathetic nervous system, which governs the body’s fight or flight response.

The fight-or-flight response is well known for having broad effects throughout the body, including causing increased heart rate and slowed digestion. As part of this response, the researchers found that the neurons in the hypothalamus set off a chain of events that triggers neurons that govern white adipose tissue stored under the skin and in the abdominal area. The activated fat tissue releases fatty acids into the bloodstream for fuelling physical activity, as well as another important protein, an enzyme called eNAMPT, which returns to the hypothalamus and allows the brain to produce fuel for its functions.

This feedback loop is critical for fuelling the body and the brain, but it slows down over time. With age, the researchers found that the protein Ppp1r17 tends to leave the nucleus of the neurons, and when that happens, the neurons in the hypothalamus send weaker signals. With less use, the nervous system wiring throughout the white adipose tissue gradually retracts, and what was once a dense network of interconnecting nerves becomes sparse. The fat tissues no longer receive as many signals to release fatty acids and eNAMPT, leading to fat accumulation, weight gain and less energy for the brain and other tissues.

The researchers, including first author Kyohei Tokizane, PhD, a staff scientist and a former postdoctoral researcher in Imai’s lab, found that when they used genetic methods in old mice to keep Ppp1r17 in the nucleus of the neurons in the hypothalamus, the mice were more physically active, with increased wheel-running, and lived longer than control mice. They also used a technique to directly activate these specific neurons in the hypothalamus of old mice, and they observed similar anti-aging effects.

The high end of the life span of a typical laboratory mouse is generally about 900–1000 days. In this study, all of the control mice that had aged normally died by 1000 days of age. Those that underwent interventions to maintain the brain-fat tissue feedback loop lived 60 to 70 days longer than control mice. This is a roughly 7% increase in lifespan, which translates to a 75-year human lifespan being extended about five more years. The mice receiving the interventions also were more active and looked younger, with thicker and shinier coats, at later ages, suggesting more time with better health as well.

Imai and his team are continuing to investigate ways to maintain the feedback loop between the hypothalamus and the fat tissue. One route they are studying involves supplementing mice with eNAMPT, the enzyme produced by the fat tissue that returns to the brain and fuels the hypothalamus, among other tissues. When released by the fat tissue into the bloodstream, the enzyme is packaged inside compartments called extracellular vesicles, which can be collected and isolated from blood.

“We can envision a possible anti-aging therapy that involves delivering eNAMPT in various ways,” Imai said. “We already have shown that administering eNAMPT in extracellular vesicles increases cellular energy levels in the hypothalamus and extends life span in mice. We look forward to continuing our work investigating ways to maintain this central feedback loop between the brain and the body’s fat tissues in ways that we hope will extend health and life span.”

Source: Washington University School of Medicine

Categories : Healthcare Politics and RegulationsTags :

SAHPRA Signs MoU With Medicines Control Authority Of Zimbabwe

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The South African Health Products Regulatory Authority (SAHPRA) has signed a Memorandum of Understanding (MoU) with the Medicines Control Authority of Zimbabwe (MCAZ).

The MoU between SAHPRA and MCAZ will allow the regulators to develop a cooperative partnership towards ensuring access to safe, quality, and effective health products in the respective countries.

Areas of cooperation
SAHPRA and MCAZ will cooperate in joint products reviews and inspections to enable efficient access to health products. This partnership will also focus on detection and curbing of substandard and falsified health products moving between the two countries, which has off late been a major challenge that the two regulators have identified.

“The forging of partnerships such as this MoU with the Medicines Control Authority of Zimbabwe, a fellow African National Regulatory Authority, is key to further enhancing and building capacity on the continent”, indicates SAHPRA CEO, Dr Boitumelo Semete-Makokotlela.

“This landmark event marks a significant step towards strengthening the regulatory frameworks of both Zimbabwe and South Africa in the pharmaceutical sector. The MoU is designed to facilitate cooperation and collaboration between the two countries in the areas of medicines regulation, quality control, and pharmacovigilance”, shares MCAZ Director-General, Mr Richard Rukwata.

Categories : Mental Health Metabolic DisordersTags :

Feeling Depressed Linked to Short-term Increase in Bodyweight

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Photo by I Yunmai on Unsplash

Increases in symptoms of depression are associated with a subsequent increase in bodyweight when measured one month later, new research from the University of Cambridge has found.

The study, published in PLOS ONE, found that the increase was only seen among people with overweight or obesity, but found no link between generally having greater symptoms of depression and higher bodyweight.

Research has suggested a connection between weight and mental health – with each potentially influencing the other – but the relationship is complex and remains poorly understood, particularly in relation to how changes in an individual’s mental health influence their bodyweight over time.

To help answer this question, researchers at Cambridge’s Medical Research Council (MRC) Epidemiology Unit examined data from over 2,000 adults living in Cambridgeshire, UK, who had been recruited to the Fenland COVID-19 Study.

Participants completed digital questionnaires on mental wellbeing and bodyweight every month for up to nine months during the COVID-19 pandemic (August 2020 – April 2021) using a mobile app developed by Huma Therapeutics Limited.

Questions assessed an individual’s symptoms of depression, anxiety and perceived stress.

A higher score indicated greater severity, with the maximum possible scores being 24 for depression, 21 for anxiety and 40 for stress.

The team then used statistical modelling to explore whether having poorer mental wellbeing than usual was related to changes in bodyweight one month later.

The researchers found that for every increment increase in an individual’s usual score for depressive symptoms, their subsequent weight one month later increased by 45g.

This may seem small but would mean, for example, that in an individual whose depressive symptoms score rose from five to 10 (equal to an increase from ‘mild’ to ‘moderate’ depressive symptoms) it would relate to an average weight gain of 225g (0.225kg).

This effect was only observed in those individuals with overweight (defined as BMI 25-29.9kg/m2) or with obesity (BMI of over 30kg/m2). Individuals with overweight had on average an increase of 52g for each increment point increase from their usual depressive symptoms score and for those with obesity the comparable weight gain was 71g.

The effect was not seen in those individuals with a healthy weight.

First author Dr Julia Mueller from the MRC Epidemiology Unit said: “Overall, this suggests that individuals with overweight or obesity are more vulnerable to weight gain in response to feeling more depressed. Although the weight gain was relatively small, even small weight changes occurring over short periods of time can lead to larger weight changes in the long-term, particularly among those with overweight and obesity.

“People with a high BMI are already at greater risk from other health conditions, so this could potentially lead to a further deterioration in their health. Monitoring and addressing depressive symptoms in individuals with overweight or obesity could help prevent further weight gain and be beneficial to both their mental and physical health.”

The researchers found no evidence that perceived stress or anxiety were related to changes in weight.

Senior author Dr Kirsten Rennie from the MRC Epidemiology Unit said: “Apps on our phones make it possible for people to answer short questions at home more frequently and over extended periods of time, which provides much more information about their wellbeing. This technology could help us understand how changes in mental health influence behaviour among people with overweight or obesity and offer ways to develop timely interventions when needed.”

Although previous studies have suggested that poor mental health is both a cause and consequence of obesity, the research team found no evidence that weight predicted subsequent symptoms of depression.

The research was supported by the Medical Research Council.

The original text of this story is licensed under Creative Commons CC BY-SA 4.0.

Source: University of Cambridge.  Note: Content may be edited for style and length.

Journal Reference:

  1. Julia Mueller, Amy L. Ahern, Rebecca A. Jones, Stephen J. Sharp, Alan Davies, Arabella Zuckerman, Benjamin I. Perry, Golam M. Khandaker, Emanuella De Lucia Rolfe, Nick J. Wareham, Kirsten L. Rennie. The relationship of within-individual and between-individual variation in mental health with bodyweight: An exploratory longitudinal study. PLOS ONE, 2024; 19 (1): e0295117 DOI: 10.1371/journal.pone.0295117
Categories : Cardiovascular Disease GeneticsTags :

A Genetic Clue to Pulmonary Hypertension Risk

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Photo by Sangharsh Lohakare on Unsplash

University of Pittsburgh Schools of Medicine researchers uncovered a fundamental mechanism that controls the body’s response to limited oxygen and regulates blood vessel disease of the lung.

By combing through genomes of more than 20 000 individuals in the US, France, England and Japan and combining the results with molecular studies in the lab, the team discovered a shared genetic trait that could predict a higher risk of pulmonary hypertension and its more severe form, pulmonary arterial hypertension, and influence the development of drug therapies that target the body’s response to limited oxygen. The findings were published in Science Translational Medicine.

“This new level of knowledge will help identify people who may be at a higher genetic risk of pulmonary hypertension and jump-start precision medicine practices to offer customised treatments,” said senior author Stephen Chan, MD, PhD.

Pulmonary hypertension encompasses a range of conditions of various causes that manifest in high blood pressure in the arteries of the lung and the right side of the heart.

The disease is accompanied by a decreased supply of oxygen to the lung tissue and the blood, is chronic and deadly, and its molecular origins and genetic background remain unsolved.

Using a combined approach of genomics and biochemistry, the Chan lab found a gene pair that had an important function in regulating blood vessel metabolism and disease.

This gene pair included a long non-coding RNA molecule – a messenger that facilitates the transformation of the body’s genetic code into protein products – and a protein binding partner, and their interaction was frequently active in cells exposed to low oxygen compared to normal cells.

Taking the findings a step further, the team discovered that a single DNA letter change directing expression of this RNA-protein pair under low oxygen conditions was associated with a higher genetic risk of pulmonary hypertension across diverse patient populations.

According to Chan, pulmonary hypertension is a borderline orphan disease, and the limited number of patients with pulmonary hypertension makes it challenging to find genetic variations that are rare but still impactful enough to eclipse individual differences.

With that in mind, Pitt scientists turned to collaborators around the globe and to public research datasets to ensure that the findings are relevant across a diverse global population.

Chan hopes that his findings will spur the development of targeted therapies relevant to oxygen sensitivity in blood vessel lining and that their pending patent application will contribute to the growth on an entirely new field of epigenetic and RNA drug therapeutics that work not by manipulating the genome but by changing how it is being read.

Source: University of Pittsburgh