NOTICE: This Consumer Medicine Information (CMI) is intended for persons living in Australia. Consumer Medicine Information (CMI) summary The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist. WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine. 1. Why am I using BRUFEN PLUS 200/12.8? For more information, see Section BRUFEN PLUS 200/12.8 contains the active ingredients ibuprofen and codeine phosphate hemihydrate. BRUFEN PLUS 200/12.8 is used to provide temporary relief of acute to moderate pain and inflammation in patients over the age of 12 years.For more information, see Section 1. Why am I using BRUFEN PLUS 200/12.8? in the full CMI. 2. What should I know before I use BRUFEN PLUS 200/12.8? Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. You may develop addition, dependence and tolerance. For more information, see Section Do not use if you have ever had an allergic reaction to BRUFEN PLUS 200/12.8 or any of the ingredients listed at the end of the CMI.You may develop addition, dependence and tolerance. For more information, see Section 2. What should I know before I use BRUFEN PLUS 200/12.8? in the full CMI. 3. What if I am taking other medicines? Some medicines may interfere with BRUFEN PLUS 200/12.8 and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI. 4. How do I use BRUFEN PLUS 200/12.8? More instructions can be found in Section The usual dose of BRUFEN PLUS 200/12.8 is 2 tablets followed by, if necessary, 1 or 2 tablets every 4 hours.More instructions can be found in Section 4. How do I use BRUFEN PLUS 200/12.8? in the full CMI. 5. What should I know while using BRUFEN PLUS 200/12.8? Things you should do Remind any doctor, dentist or pharmacist you visit that you are using BRUFEN PLUS 200/12.8. If your symptoms do not improve after a few days, talk to your doctor. If you become pregnant while taking this medicine, stop taking it and tell your doctor immediately. Things you should not do Do not take more than 6 tablets in 24 hours. BRUFEN PLUS 200/12.8 is not recommended for use in children under the age of 12 years. You should not take BRUFEN PLUS 200/12.8 for more than three days at a time. Driving or using machines Be careful driving or operating machinery until you know how BRUFEN PLUS 200/12.8 affects you. BRUFEN PLUS 200/12.8 may cause dizziness, light-headedness or drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous. Drinking alcohol You must not drink alcohol while taking BRUFEN PLUS 200/12.8. Looking after your medicine Store below 30°C Store in a cool dry place away from moisture, heat or sunlight. For more information, see Section 5. What should I know while using BRUFEN PLUS 200/12.8? in the full CMI. 6. Are there any side effects? Tell your doctor or pharmacist if you notice any of the following and they worry you: nausea or vomiting, constipation, or dizziness, light-headedness, drowsiness. For more information, including what to do if you have any side effects, see Section Contact your doctor immediately or go to the Emergency Department at your nearest hospital if any of the following happen: asthma, shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin, fainting. These may be the sign of an allergic reaction.For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI. WARNING: Limitations of Use BRUFEN PLUS 200/12.8 should only be used when your doctor decides that other treatment options are not able to effectively manage your pain or you cannot tolerate them. Hazardous and Harmful Use BRUFEN PLUS 200/12.8 poses risks of abuse, misuse and addiction which can lead to overdose and death. Your doctor will monitor you regularly during treatment. Life Threatening Respiratory Depression BRUFEN PLUS 200/12.8 can cause life-threatening or fatal breathing problems (slow, shallow, unusual or no breathing), even when used as recommended. These problems can occur at any time during use, but the risk is higher when first starting BRUFEN PLUS 200/12.8 and after a dose increase, if you are older, or have an existing problem with your lungs. Your doctor will monitor you and change the dose as appropriate. Use of Other Medicines While Using BRUFEN PLUS 200/12.8 Using BRUFEN PLUS 200/12.8 with other medicines that can make you feel drowsy such as sleeping tablets (e.g. benzodiazepines), other pain relievers, antihistamines, antidepressants, antipsychotics, gabapentinoids (e.g. gabapentin and pregabalin), cannabis and alcohol may result in severe drowsiness, decreased awareness, breathing problems, coma and death. Your doctor will minimise the dose and duration of use; and monitor you for signs and symptoms of breathing difficulties and sedation. You must not drink alcohol while using BRUFEN PLUS 200/12.8. 1. Why am I using BRUFEN PLUS 200/12.8? BRUFEN PLUS 200/12.8 contains the active ingredients ibuprofen and codeine phosphate hemihydrate. Ibuprofen belongs to a family of medicines called non-steroidal anti-inflammatory drugs (NSAIDs). This group of medicines work by relieving pain, inflammation (e.g. swelling, redness, soreness) and fever. Codeine is an opioid analgesic that works in the brain and spinal cord to relieve pain. BRUFEN PLUS 200/12.8 is used to provide temporary relief of acute to moderate pain and inflammation in patients over the age of 12 years. Once taken, your body processes the codeine into its active form, morphine, in the liver. In about 8% of people, they may experience less pain relief compared to others as their body doesn't convert codeine to morphine very well. 2. What should I know before I use BRUFEN PLUS 200/12.8? Warnings Do not give BRUFEN PLUS 200/12.8 to children under the age of 12 years. Do not use BRUFEN PLUS 200/12.8 if: asthma, shortness of breath wheezing or difficulty breathing swelling of the face, lips, tongue or other parts of the body rash, itching or hives on the skin fainting you are allergic to ibuprofen, codeine phosphate hemihydrate, other opioid analgesics or any medicine including aspirin, other NSAID or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include: Always check the ingredients to make sure you can use this medicine. you are also taking other medicines that contain one or more NSAID medicine, whether prescribed by your doctor or obtained without prescription. Many medicines used to treat headache, period pain and other aches and pains contain aspirin or NSAIDs. If you are not sure if the medicines you are taking any of these medicines , ask your doctor or pharmacist. you are in the last three months of pregnancy. you are breastfeeding or planning to breastfeed. you are vomiting blood or material that looks like coffee grounds you are bleeding from the rectum (back passage), have black sticky bowel motions (stools) or bloody diarrhoea you have a stomach or duodenal ulcer or have had one in the past you have or have had a history of ulcerative colitis or Crohn's disease you have chronic constipation or severe diarrhoea you have shallow breathing you consume large amounts of alcohol regularly you have severe heart, liver or kidney failure you are an ultra-rapid CYP2D6 metaboliser you are currently taking a Monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping treatment with a MAOI. you are aged between 12 and 18 years of age and have compromised respiratory function including having had your tonsils or adenoids removed. Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal. Check with your doctor if you: difficulty breathing, wheezing, chronic cough, allergies, asthma or other breathing conditions a history of drug dependence, including alcohol dependence skin rash (dermatitis) and skin irritation a history of stomach ulcer stomach problems or recent gastrointestinal surgery liver disease kidney disease heart problems/failure including swelling of ankles or feet thyroid problems or low blood pressure a head injury or intercranial pressure prostate problems a tendency for convulsions, fits a recent head injury have or have had any other medical conditions: Tell your doctor if you take sedatives (medicines used to help you relax or sleep). Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes. Tell your doctor if you are over 65 years of age. If you have not told your doctor about any of the above, tell them before you start taking BRUFEN PLUS 200/12.8. During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects Pregnancy and breastfeeding Check with your doctor if you are pregnant or intend to become pregnant. Unless advised by your doctor, do not take BRUFEN PLUS 200/12.8 during the first 6 months of pregnancy. Your doctor will decide if you should take BRUFEN PLUS 200/12.8 during the first 6 months. BRUFEN PLUS 200/12.8 is should not be taken during the last three months of pregnancy. BRUFEN PLUS 200/12.8 given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn. Talk to your doctor if you are breastfeeding or intend to breastfeed. BRUFEN PLUS 200/12.8 should not be taken while breastfeeding except on your doctor's advice. Codeine passes into the breast milk. Addiction You can become addicted to BRUFEN PLUS 200/12.8 even if you take it exactly as prescribed. BRUFEN PLUS 200/12.8 may become habit forming causing mental and physical dependence. If abused it may become less able to reduce pain. Dependence As with all other opioid containing products, your body may become used to you taking BRUFEN PLUS 200/12.8. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking BRUFEN PLUS 200/12.8 suddenly, so it is important to take it exactly as directed by your doctor. Tolerance Tolerance to BRUFEN PLUS 200/12.8 may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect. 3. What if I am taking other medicines? Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop. Some medicines may interfere with BRUFEN PLUS 200/12.8 and affect how it works. These include: medicines used to help you relax, sleep or relieve anxiety, such as benzodiazepines, barbiturates and sedatives gabapentinoids (gabapentin, pregabalin) aspirin, salicylates or other NSAID medicines aminoglycoside antibiotics, medicines used to treat bacterial infections atropine warfarin, clopidogrel, ticlopidine or other medicines used to stop blood clots or thin the blood medicines that are used to treat high blood pressure, e.g. ACE inhibitors, diuretics (fluid tablets) or heart problems including heart failure methotrexate, a medicine used to treat arthritis and some types of cancer zidovudine, a medicine used to treat HIV infection mifepristone quinolone, a medicine used to treat bacterial infections medicines used to relieve stomach cramps or spasms medicines used to treat diarrhoea (e.g. kaolin, pectin, loperamide) medicines used to prevent travel sickness, such as hydroxyzine metoclopramide, a medicine used to treat nausea and vomiting medicines that affect serotonin levels (serotonergic medicines) selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs), medicines used to treat depression such as moclobemide phenothiazines and antipsychotic agents, medicines used to treat mental disorders lithium and other medicines used to treat depression or anxiety, e.g. MAOIs (even if taken within the last 14 days) medicines such as prednisone, prednisolone, cortisone, ciclosporin and tacrolimus which reduce the activity of your immune system quinidine, a medicine used to treat abnormal or irregular heartbeat medicines used to treat diabetes probenecid, a medicine used to treat gout phenytoin, a medicine used to treat epilepsy medicines used to treat Parkinson's disease other opioids to treat pain or suppress cough colestyramine, a medicine used to treat high cholesterol cimetidine, a medicine used to reduce stomach acid production herbal medicines such as ginkgo biloba mexiletine, a medicine used to treat abnormal heart beat naloxone, a medicine used in the treatment of an opioid overdose These medicines may be affected by BRUFEN PLUS 200/12.8 or may affect how well it works. You may different amounts of your medicines, or you may need different medicines. Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine. Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect BRUFEN PLUS 200/12.8. 4. How do I use BRUFEN PLUS 200/12.8? Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet. If you do not understand the instructions on the box, ask your doctor or pharmacist for help. How much to take The usual dose of BRUFEN PLUS 200/12.8 is 2 tablets followed by, if necessary, 1 or 2 tablets every 4 hours. Do not take more than 6 tablets in 24 hours. If you do not understand the instructions on the pack, ask your doctor or pharmacist for help. Follow the instructions provided and use BRUFEN PLUS 200/12.8 until your doctor tells you to stop. How to take BRUFEN PLUS 200/12.8 Swallow the tablets whole with a glass of water. It can be taken with food or on an empty stomach. How long to take BRUFEN PLUS 200/12.8 You should not take BRUFEN PLUS 200/12.8 for more than three days at a time unless instructed to by your doctor. If your symptoms persist, worsen or new symptoms develop, talk to your doctor. If you use too much BRUFEN PLUS 200/12.8 If you or someone else take too much (overdose), and experience one or more of the symptoms below, immediately call triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you has accidentally taken BRUFEN PLUS 200/12.8 that was prescribed for you. If someone takes an overdose they may experience one or more of the following symptoms: slow, unusual or difficult breathing drowsiness, dizziness or unconsciousness slow or weak heartbeat nausea or upset stomach, vomiting and/or gastric irritation convulsions or fits excitability blurred vision, ringing in the ears or rapid uncontrollable movements of the eyes. If you think that you or someone else have used too much BRUFEN PLUS 200/12.8, you may need urgent medical attention. You should immediately: phone the Poisons Information Centre (Australia telephone 13 11 26) for advice, or contact your doctor, or go to the Emergency Department at your nearest hospital. You should do this even if there are no signs of discomfort or poisoning. Depending on your body’s individual ability to break down codeine, you may experience signs of overdose even when you take BRUFEN PLUS 200/12.8 as recommended by your doctor. If overdose symptoms occur, seek immediate medical advice. When seeking medical attention, take this leaflet and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which have been taken. 5. What should I know while using BRUFEN PLUS 200/12.8? Things you should do If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking BRUFEN PLUS 200/12.8. Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine. If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery. If your symptoms do not improve after a few days, talk to your doctor. Your doctor will assess your condition and decide if you should continue to take BRUFEN PLUS 200/12.8. Call your doctor straight away if you: become pregnant while taking this medicine and stop taking it immediately. Remind any doctor, dentist or pharmacist who treat you that you are using BRUFEN PLUS 200/12.8. Things you should not do Do not take high doses of the medicine for long periods of time unless your doctor tells you to. Products containing codeine should not be taken for prolonged periods. Codeine may be habit forming. Do not give your medicine to anyone else, even if they have the same condition as you. Do not take BRUFEN PLUS 200/12.8 to treat any other complaints unless your doctor tells you to. Do not take more than the recommended dose unless your doctor tells you to. Excessive use can be harmful and increase the risk of heart attack, stroke or liver damage. Driving or using machines Be careful before you drive or use any machines or tools until you know how BRUFEN PLUS 200/12.8 affects you. BRUFEN PLUS 200/12.8 may cause dizziness, light-headedness or drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous. If you drink alcohol, dizziness, light- headedness and/or drowsiness may be worse. Drinking alcohol Tell your doctor if you drink alcohol. Using BRUFEN PLUS 200/12.8 with alcohol may result in severe dizziness, light-headedness or drowsiness, decreased awareness, breathing difficulties, coma and death. Withdrawal Continue taking your medicine for as long as your doctor tells you. If you stop taking this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms: nervousness, restlessness, agitation, trouble sleeping or anxiety body aches, weakness or stomach cramps loss of appetite, nausea, vomiting or diarrhoea increased heart rate, breathing rate or pupil size watery eyes, runny nose, chills or yawning increased sweating Products containing codeine should not be used for prolonged periods; codeine may be habit forming. Brufen Plus 200/12.8 given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn. Looking after your medicine Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well. Keep your tablets in a cool dry place where the temperature stays below 30°C. Follow the instructions in the carton on how to take care of your medicine properly. Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it: in the bathroom or near a sink, or in the car or on window sills. Keep it where young children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines. Getting rid of any unwanted medicine If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal. Do not use this medicine after the expiry date. 6. Are there any side effects? All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects. If you are over 65 years of age you may have an increased chance of getting side effects. Less serious side effects Less serious side effects What to do Gastrointestinal related: stomach upset including nausea (feeling sick), vomiting heartburn, indigestion constipation diarrhoea, pain in the stomach loss of appetite Head and neurology related: sleeplessness, nightmares changes in mood, for example depression, restlessness, irritability sore or dry mouth or tongue dizziness, light-headedness, drowsiness headache hearing disturbance central sleep apnoea Respiratory related: shallow breathing cough suppression Skin related: a rash that always appears in the exact same spot on your skin (fixed eruption) Speak to your doctor if you have any of these less serious side effects and they worry you. Serious side effects Serious side effects What to do Gastrointestinal related: severe pain or tenderness in the stomach vomiting blood or material that looks like coffee grounds bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhoea Allergy related: shallow breathing or shortness of breath flushing of the face swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing asthma, wheezing, shortness of breath, pain or tightness in the chest symptoms of sunburn (such as redness, itching, swelling, blistering) which may occur more quickly than usual Heart related: fast heart beat Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects. Serious side effects What to do Skin related: yellowing of the skin and eyes, known as jaundice sudden or severe itching, skin rash, hives, skin peeling Urinary related: a change in the colour of your urine, blood in the urine a change in the amount or frequency of urine passed, burning feeling when passing urine fluid retention unusual weight gain, swelling of ankles or legs Infection related: signs of frequent or worrying infections such as fever, severe chills, sore throat or mouth ulcers Bleeding related: bleeding or bruising more easily than normal, reddish or purplish blotches under the skin signs of anaemia, such as tiredness, being short of breath and looking pale Head and neurology related: unusual or extreme mood swings dizziness, light-headedness severe dizziness, spinning sensation severe or persistent headache difficulty hearing, deafness tingling or numbness of the hands or feet Eyes related: eye problems such as blurred vision, sore red eyes, itching Pregnancy related: low amniotic fluid in the womb during pregnancy newborns with impaired kidney function Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects. Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell. Other side effects not listed here may occur in some people. Reporting side effects After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems . By reporting side effects, you can help provide more information on the safety of this medicine. Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines. 7. Product details This medicine is only available with a doctor's prescription. What BRUFEN PLUS 200/12.8 contains Active ingredient (main ingredient) Ibuprofen and codeine phosphate hemihydrate Other ingredients (inactive ingredients) pregelatinised maize starch microcrystalline cellulose croscarmellose sodium colloidal anhydrous silica Opadry complete film coating system OY-58900 White (ID 3446) Do not take this medicine if you are allergic to any of these ingredients. What BRUFEN PLUS 200/12.8 looks like BRUFEN PLUS 200/12.8 are white to off-white capsule-shaped, biconvex, film-coated tablets (AUST R 298439). BRUFEN PLUS 200/12.8 are available in blister packs containing 30 tablets.

How postbiotics work Potential health benefits Comparison with probiotics and prebiotics Future of postbiotics Postbiotics, defined as bioactive compounds produced by beneficial microbes such as lactic acid bacteria during the fermentation of prebiotic substrates, have recently gained significant attention in health sciences. Unlike probiotics, which contain live microorganisms, postbiotics include non-living microbial cells, cellular structures, and metabolites such as bacteriocins, exopolysaccharides, and peptidoglycan.1 Postbiotics' rising popularity stems from notable advantages over probiotics, including enhanced stability, safety, and longer shelf life. These advantages reduce the risks associated with live microbial consumption, such as potential pathogen transmission and antimicrobial resistance. Increasing research highlights postbiotics' beneficial mechanisms, primarily their ability to modulate protective actions against pathogens, fortify epithelial barriers, and regulate immune responses. Due to these promising health effects, postbiotics are gaining traction across various sectors, especially in the food industry for bio-preservation and in the pharmaceutical and biomedical fields for treating gastrointestinal disorders and enhancing immune functions. This growing interest aligns with the demand for safe and effective functional foods addressing sub-health conditions, promoting general well-being, and managing gastrointestinal issues such as diarrhea and bloating. As scientific understanding deepens, postbiotics stand poised to complement probiotics significantly, marking a transformative shift towards comprehensive, preventive healthcare strategies and innovative therapeutic applications.1 This article explores postbiotics, explaining what they are, how they differ from probiotics, and their potential benefits for gut health. ​​​​​​​Image Credit: ArtemisDiana/Shutterstock.com How postbiotics work Unlike probiotics, postbiotics do not contain live cells but consist of metabolites, including bacteriocins, short-chain fatty acids (SCFAs), and various organic acids. Their production involves controlled fermentation processes followed by techniques such as enzymatic hydrolysis, thermal treatment, and extraction, ensuring the isolation of the beneficial compounds while maintaining their biological efficacy.2,3 The primary mode of action of postbiotics involves modifying the gut environment, thereby enhancing the gut microbiota composition. They reduce intestinal pH, creating conditions that selectively favor beneficial microbes while suppressing pathogens such as Escherichia coli, Salmonella, and Clostridium perfringens. Specifically, SCFAs produced as postbiotic metabolites act as energy substrates for intestinal cells, facilitating the growth of beneficial bacteria like Lactobacillus and Bifidobacterium. This results in improved intestinal barrier function, reduction in inflammation, and enhanced resistance to pathogenic colonization.2,3 In addition, postbiotics modulate the immune response by upregulating anti-inflammatory cytokines and downregulating pro-inflammatory signals. This balanced immune modulation reduces gut inflammation, enhancing overall gastrointestinal health and resilience.2 Research highlights postbiotics’ significant role in promoting growth performance, particularly in poultry. Dietary supplementation with postbiotics has been shown to improve nutrient absorption, optimize feed efficiency, and support better overall animal growth. For example, poultry-fed diets enriched with postbiotics demonstrate increased body weight gain, improved feed conversion rates, and healthier gut morphology compared to control groups.2,3 Moreover, postbiotics positively affect the quality of animal products. In poultry, the inclusion of postbiotics in diets leads to improvements in meat characteristics, including increased tenderness, reduced lipid peroxidation, enhanced color, and overall better sensory properties.2 Download your PDF copy now! Potential health benefits Postbiotics contain bioactive substances, including SCFAs, exopolysaccharides, bacteriocins, and various proteins. These compounds exhibit diverse functional properties that are beneficial for gut and overall health. For instance, SCFAs such as acetate, propionate, and butyrate, produced from microbial fermentation, are notable for their capacity to strengthen the gut barrier by enhancing the integrity of tight junction proteins, thus preventing pathogen invasion and systemic inflammation.4 The anti-inflammatory properties of postbiotics significantly contribute to their health benefits. Studies have shown that these metabolites can modulate inflammatory responses by inhibiting pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). For example, specific proteins derived from Lactobacillus species, such as surface-layer proteins (SLPs), demonstrated anti-inflammatory effects by reducing Nuclear Factor kappa-light-chain-enhancer of activated B (NF-κB) activation, a key pathway in inflammation.4 Postbiotics further support immune functions by influencing mucosal immunity. They promote the growth of beneficial gut microbiota, directly compete with pathogenic bacteria for adhesion sites, and enhance mucosal defense mechanisms through antimicrobial peptides. Research has shown that postbiotic administration increases beneficial microbes like Bifidobacteria while decreasing harmful pathogens such as Escherichia coli.4 Emerging evidence also suggests postbiotics can aid metabolic regulation, demonstrating potential anti-obesity and glucose homeostasis effects. Their stability, safety profile, and efficacy make them an attractive alternative or complement to probiotics, especially in immunocompromised individuals. While extensive research continues to expand understanding of the mechanisms and specific health outcomes associated with postbiotics, current findings underscore their potential in clinical nutrition and therapy.4 Prebiotics and Probiotics: What’s the Difference? Comparison with probiotics and prebiotics Probiotics, prebiotics, and postbiotics are integral elements in gut microbiome management, each playing a unique yet interconnected role. Probiotics are live beneficial microorganisms, like Lactobacillus and Bifidobacterium, directly impacting gut microbial composition and health. Prebiotics, such as inulin and fructooligosaccharides (FOS), act as food for these beneficial bacteria, enhancing their proliferation and activity.5 Postbiotics, the latest addition to microbiome-focused interventions, represent non-living microbial cells or bioactive substances produced by probiotics during fermentation. Unlike probiotics, postbiotics are stable and less susceptible to environmental stressors such as heat or stomach acids, making them particularly advantageous in formulation and shelf stability. They offer benefits like modulating immune responses, enhancing gut barrier integrity, and exerting anti-inflammatory effects without the risks associated with administering live microorganisms, especially in immunocompromised individuals.5 Several postbiotic products have entered the market, including heat-killed Lactobacillus plantarum preparations used to manage gastrointestinal discomfort and fermented formulas containing SCFAs to support gut health.5 However, postbiotic commercialization faces regulatory hurdles, primarily due to inconsistent definitions and the complex classification between dietary supplements and medicinal products. Regulatory bodies differ internationally, complicating standardized approvals.5 Integrating postbiotics into the broader microbiome conversation requires clearer regulatory frameworks and robust clinical evidence. Their continued development alongside probiotics and prebiotics promises to enrich microbiome management, offering safer and potentially more effective solutions for maintaining gut and overall health.5 Breaking down prebiotics, probiotics and postbiotics Play Future of postbiotics Emerging research indicates postbiotics offer superior stability, safety, and cost-effectiveness compared to traditional probiotics. Unlike probiotics, postbiotics withstand harsh gastrointestinal conditions, have extended shelf-life, and eliminate risks associated with live bacterial strains.5,6 Current market products include pasteurized Akkermansia muciniphila, utilized for obesity and insulin resistance management, and heat-inactivated Bifidobacterium bifidum (e.g., MIMBb75), effective against Irritable Bowel Syndrome (IBS). Additionally, bacterial lysate OM-85 (Broncho-Vaxom) is commercially available for respiratory immune support.6 Clinical trials and pre-clinical studies underline diverse medical applications. For instance, postbiotics like SCFAs, especially butyrate, demonstrate anti-inflammatory and immunomodulatory effects beneficial in conditions like rheumatoid arthritis, inflammatory bowel disease, and metabolic disorders. In food industries, postbiotic applications include functional food ingredients enhancing nutritional profiles and shelf-life stability.6 Despite promising advances, regulatory challenges persist. Clear guidelines distinguishing postbiotics from probiotics remain underdeveloped, complicating product standardization, labeling, and market authorization. Current regulations primarily address viable probiotics, necessitating updated frameworks explicitly tailored for postbiotic substances.6 Ongoing clinical studies continue to evaluate the efficacy, safety profiles, and mechanistic actions of various postbiotic compounds, promising deeper insights and validation of therapeutic claims. Addressing existing knowledge gaps through rigorous clinical research will be crucial for the successful integration and acceptance of postbiotics within mainstream medicine and the food industry. Dairy and Gut Health: The Good, the Bad, and the Controversial References

What is dietary fiber? Mechanisms of action Fiber and disease prevention Sources of fiber Industrial processing and fiber loss Key takeaways Chronic diseases such as heart disease, diabetes, and cancer claim millions of lives each year — but what if the solution to reducing these risks was as simple as adding more fiber to your diet? Despite being one of the most powerful tools for disease prevention, fiber remains the most overlooked nutrient in modern diets. This article examines the role of dietary fiber in lowering the risk of chronic diseases. It explores the current knowledge on the best sources of dietary fiber and how to incorporate more fiber into the daily diet. ​​​​​​​Image Credit: Yulia Furman/Shutterstock.com What is dietary fiber? Dietary fiber is a crucial component of a healthy diet, known for its role in promoting digestive health and preventing chronic diseases. Fiber is categorized into two main types: soluble fiber, which dissolves in water and forms a gel-like substance, and insoluble fiber, which adds bulk to stool and facilitates bowel movements.1 Both types contribute to overall health, influencing digestion, modulating gut bacteria and metabolism, and controlling systemic inflammation. Despite the well-documented health benefits of dietary fiber, many individuals fail to meet the recommended daily intake. This deficiency has significant public health implications, as low fiber consumption is linked to increased risks of metabolic disorders, gastrointestinal diseases, kidney disease, cancer, and cardiovascular conditions.2–4 Therefore, understanding the mechanisms by which fiber exerts its protective effects is essential for developing dietary guidelines and intervention strategies to reduce the burden of chronic disease. Additionally, cultural and socioeconomic factors also influence fiber consumption, highlighting the need for targeted dietary interventions and public health policies to bridge the gap in fiber intake across populations. Why More Young Adults Are Getting Colorectal Cancer Mechanisms of action Fiber exerts its health benefits through multiple physiological mechanisms, such as gastrointestinal function, metabolic regulation, and modulation of inflammation. Fiber enhances bowel motility, prevents constipation, and supports gut microbiota diversity, which plays a role in immune regulation and metabolic health.5 The fermentation of dietary fiber by gut microbiota also produces metabolites such as short-chain fatty acids (SCFAs), which strengthen the gut barrier and reduce systemic inflammation.2,6 Additionally, fiber improves stool consistency and water retention, promoting regular bowel movements and reducing the risk of conditions such as diverticulosis and irritable bowel syndrome.1 Soluble fiber also regulates the metabolism by slowing gastric emptying, leading to improved glycemic control and lipid metabolism. This helps prevent insulin resistance and type 2 diabetes.4,6 Moreover, fiber aids in weight management by promoting satiety and reducing overall caloric intake, further reducing the risk of obesity-related diseases. Dietary fiber also modulates gut hormone secretion, influencing appetite regulation and energy balance, which are critical for long-term metabolic health.2 The SCFAs, such as butyrate, produced during the fermentation of fibers also have anti-inflammatory effects and contribute to gut integrity. These fatty acids regulate immune function, modulating cytokine production and reducing markers of systemic inflammation.5 This process plays a crucial role in preventing chronic inflammatory conditions, including autoimmune diseases, non-alcoholic fatty liver disease, and neurodegenerative disorders. Mayo Clinic Minute: How dietary fiber makes you healthier Play Fiber and disease prevention Cardiovascular disease Numerous meta-analyses have established that fiber intake is inversely associated with cardiovascular disease (CVD) risk. Higher dietary fiber consumption is linked to lower total cholesterol and low-density lipoprotein (LDL) levels, improved blood pressure regulation, and reduced inflammation.2,3 One study also found that every 7 g/day increase in dietary fiber correlates with a 9% reduction in CVD risk.1 In addition, fiber reduces the risk of atherosclerosis by binding to bile acids, which facilitates their excretion and lowers cholesterol levels.2 Whole grains, in particular, contain high levels of beta-glucans, which have been shown to reduce blood pressure and improve endothelial function. High-fiber diets are also associated with improved arterial elasticity, which contributes to better circulation and reduced cardiovascular strain.7 Fiber intake has also been associated with lower C-reactive protein (CRP) levels, a key marker of systemic inflammation that plays a role in cardiovascular disease progression.5 Type 2 diabetes Dietary fiber also improves insulin sensitivity and glycemic control by modulating digestion and glucose absorption. Epidemiological studies suggest that individuals with the highest fiber intake have a 20–30% reduced risk of developing type 2 diabetes.4,6 Cereal fibers, in particular, have shown significant protective effects.5 Additionally, soluble fiber slows carbohydrate absorption, reducing postprandial glucose spikes. This stabilizes blood sugar levels and lowers the demand for insulin, decreasing the likelihood of insulin resistance. Fiber also promotes a more diverse gut microbiota, which has been linked to improved metabolic health.8 High-fiber diets reduce systemic inflammation, a major factor in the pathogenesis of type 2 diabetes. Furthermore, fiber enhances the production of gut-derived hormones such as glucagon-like peptide-1 (GLP-1), which plays a role in glucose metabolism and appetite regulation.4,5 Colorectal cancer The consumption of dietary fiber, especially from whole grains, is strongly associated with a reduced risk of colorectal cancer. Fiber enhances stool bulk and reduces gut transit time, minimizing exposure of colonic cells to carcinogens. Additionally, the fermentation of fiber generates SCFAs, which support colonic health and exhibit anti-cancer properties.1,7 Studies suggest that fiber alters the gut microbiota composition in a way that reduces the production of harmful metabolites and enhances detoxification pathways. Certain types of fiber, such as resistant starch, have been shown to increase the production of butyrate, which has protective effects on colonic epithelial cells and may prevent tumor formation.2 Furthermore, fiber intake is associated with a reduction in pro-inflammatory cytokines that contribute to cancer progression.1 Download your PDF copy now! Sources of fiber Research suggests that optimal fiber intake is best achieved through whole foods rather than supplements. Key dietary sources include whole grains such as brown rice, oats, and whole wheat bread, as well as legumes like lentils, chickpeas, and black beans. Fruits and vegetables, especially broccoli, carrots, and leafy greens, as well as nuts and seeds like chia seeds, flaxseeds, and almonds, are also excellent sources of dietary fiber.7 Current dietary guidelines recommend fiber intakes of 25 g per day for women and 38g per day for men, yet most individuals consume significantly less.2 However, increasing fiber intake requires dietary changes, such as replacing refined grains with whole grains, consuming more plant-based foods, and choosing fiber-rich snacks. Additionally, dietary education programs can help individuals better understand fiber sources and implement gradual changes to improve long-term adherence. Industrial processing and fiber loss Unfortunately, modern food processing significantly reduces fiber content in many staple foods. Refining grains removes the bran and germ, stripping away essential fiber and nutrients. Processed foods often lack the fermentable fibers necessary for gut health.8 Encouraging whole-food consumption over refined options is essential for maximizing fiber intake. Fiber-rich foods also undergo chemical and thermal processing that can alter their structure, reducing their fermentability and bioavailability. The widespread consumption of processed and ultra-processed foods contributes significantly to the global fiber deficit. Implementing policies that promote whole grain consumption and educate consumers about fiber-rich diets can help counteract these effects. Furthermore, reformulating processed foods to include functional fiber additives, such as inulin and resistant starch, could be an additional strategy to improve fiber intake in modern diets. Key takeaways Dietary fiber is a key factor in preventing chronic diseases, including cardiovascular disease, type 2 diabetes, and colorectal cancer. However, despite the clear health benefits, fiber intake remains insufficient in many populations. Given its numerous health benefits, policymakers and healthcare professionals should advocate for fiber-rich diets as part of chronic disease prevention strategies. Greater awareness and improved dietary habits can also significantly reduce the burden of preventable diseases and improve overall public health. Moreover, future research should also focus on personalized nutrition strategies to optimize fiber intake based on individual health needs and genetic predispositions. References Gill, S. K., Rossi, M., Bajka, B., & Whelan, K. (2021). Dietary fibre in gastrointestinal health and disease. Nature Reviews. Gastroenterology & Hepatology, 18(2), 101–116. https://doi.org/10.1038/s41575-020-00375-4 Timm, D. A., & Slavin, J. L. (2008). Dietary Fiber and the Relationship to Chronic Diseases. American Journal of Lifestyle Medicine, 2(3), 233–240. https://doi.org/10.1177/1559827608314149 McRae M. P. (2017). Dietary Fiber Is Beneficial for the Prevention of Cardiovascular Disease: An Umbrella Review of Meta-analyses. Journal of Chiropractic Medicine, 16(4), 289–299. https://doi.org/10.1016/j.jcm.2017.05.005 McRae M. P. (2018). Dietary Fiber Intake and Type 2 Diabetes Mellitus: An Umbrella Review of Meta-analyses. Journal of Chiropractic Medicine, 17(1), 44–53. https://doi.org/10.1016/j.jcm.2017.11.002 Ma, W., Nguyen, L. H., Song, M., Wang, D. D., Franzosa, E. A., Cao, Y., Joshi, A., et al. (2021). Dietary fiber intake, the gut microbiome, and chronic systemic inflammation in a cohort of adult men. Genome Medicine, 13(1), 102. https://doi.org/10.1186/s13073-021-00921-y Weickert, M. O., & Pfeiffer, A. F. H. (2018). Impact of Dietary Fiber Consumption on Insulin Resistance and the Prevention of Type 2 Diabetes. The Journal of Nutrition, 148(1), 7–12. https://doi.org/10.1093/jn/nxx00 Mayo Clinic. (2022, December 10). Whole grains: Hearty options for a healthy diet. Available at https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/whole-grains/art-20047826 [Accessed on March 13, 2025] Capuano E. (2017). The behavior of dietary fiber in the gastrointestinal tract determines its physiological effect. Critical Reviews in Food Science and Nutrition, 57(16), 3543–3564. https://doi.org/10.1080/10408398.2016.1180501 Further Reading

BioAFM is seeing increasingly widespread use in biomedical and biological studies due to its extremely high resolution and its capacity to perform experiments with live cells in liquid and under physiologically relevant and ambient conditions. BioAFM also offers nanometer-resolution surface mapping suitable for an array of electrical and mechanical properties, including stiffness, elasticity, conductivity, and surface potential. Bruker BioAFM technology empowers life science researchers to explore how these properties influence key cellular functions, including communication, signaling, cell division, differentiation, tumor metastasis, and infection. Image Credit: Sanjaya Viraj Bandara/Shutterstock.com What is a BioAFM? A BioAFM is a specialized atomic force microscope designed for studying soft matter and biological samples. These instruments are ideal for measuring fragile, soft, and complex samples under near-physiological conditions. BioAFMs enable the analysis of single molecules, bacteria, living cells, nucleic acids, and tissues without compromising their structural integrity. Their versatility allows for non-invasive measurements of biological samples, including label-free imaging in liquid environments, making them a powerful tool for life science research. How are BioAFMs adapted for use in biological studies? BioAFMs feature specialized stages, sample and cantilever holders, and measurement modes, all of which have been specifically designed to accommodate life science samples and experiments. Another unique feature of Bruker BioAFM instruments is their capacity to be configured with a wide range of optional accessories and advanced modes, expanding measurement capabilities and sample compatibility to accommodate even the most challenging biological and soft matter samples. Distinct capabilities and features of Bruker BioAFM instruments include: High-speed AFM capabilities of up to 50 frames per second facilitate the accurate visualization of molecular dynamics. Damage of delicate biological samples is prevented thanks to precise force control. Fully integrated correlated analysis is made possible via a comprehensive range of advanced optical techniques. Specific data analysis methods are available for soft samples, including contact point imaging. A large z range (>100 µm) enables cell adhesion experiments and the measurement of challenging biological samples featuring steep, highly corrugated surfaces. Advanced automation features facilitate self-regulating measurement routines designed to maximize throughput and improve accuracy. These features include automated detector alignment, experimental workflow creation, and scanning parameter adjustment. An Optical Tiling software feature is available for navigating around large samples. Cantilever holders can be cleaned and autoclaved, allowing direct access to biohazards in biosafety laboratories while also enabling sample preparation, loading, experiments, and disposal steps to be performed within the BSL facility. Various accessories can be used to investigate a wide range of biological and soft matter samples on different-sized substrates, shapes, and materials (for example, coverslips, Petri dishes, or biochips) and under different environmental conditions (for example, temperature, atmosphere, gas, or pH value). The automated, large area, multiparametric characterization of densely packed cell layers and highly corrugated tissue samples can be achieved without the need for microtome cutting. What are the benefits of using a BioAFM? Atomic force microscopy delivers three-dimensional images of surface features and topography, and BioAFMs extend, enhance, and optimize this technique to accommodate the specific needs and challenges of biological research. BioAFM offers a number of distinct advantages over other methods. These include: The high spatiotemporal resolution allows users to investigate the morphology and surface structure at the sub-molecular resolution, highlighting interactions in the piconewton range. Samples can be studied in liquid and under near-physiological conditions. These capabilities are unique to atomic force microscopy and are ideal for the investigation of living cells in a medium. BioAFM’s capacity for the label-free and non-invasive investigation of living cells is ideally suited to use with delicate biological samples. BioAFM can be used in conjunction with other advanced optical microscopy techniques, offering correlated measurements and complementary datasets that offer researchers a more comprehensive insight into complex biological processes. What are the benefits of automated BioAFM measurements? Bruker’s range of BioAFM instruments boasts specialized software functions and capabilities designed to support the high-performance AFM-based investigation of soft matter and biological samples. Automated instrument procedures are available, including alignment, operation, and calibration, while automated measurement routines and advanced data analysis capabilities enable the straightforward and streamlined experimental setup and running while improving results’ accuracy and reproducibility. Advanced automation features include: Bruker BioAFM instruments incorporate advanced automation and remote control features to streamline complex experiments and enhance research efficiency: ExperimentPlanner enables users to predefine settings and parameters, allowing for the automated execution of intricate experiments. ExperimentControl, a browser-based tool, supports remote monitoring of long-term lab experiments from any device. When used alongside ExperimentPlanner, these tools enable self-regulating, long-term experiments that mimic real-life conditions. Researchers can oversee and control their studies remotely, reducing the need for hands-on involvement in lengthy, repetitive procedures. SmartMapping provides the flexibility to define multiple two-dimensional force maps and preselect regions of interest (ROI) for automated examination. This feature facilitates the systematic study of large sample areas with precision. Automated large-area, multi-region imaging is achieved through the integration of DirectTiling, DirectOverlay 2, and MultiScan software, extending the optical viewing field. Their seamless optical integration ensures an accurate correlation between AFM and optical data. Leveraging these advanced features enhances and expands the capabilities of Bruker BioAFM systems to: Increase productivity and throughput Generate statistically relevant datasets Highlight parameter correlation and cross-correlation by automated cycling through relevant parameters Enable long-term, unattended, self-regulating experiment series Allow the remote monitoring of long-term lab experiments These types of automated features enable enhanced throughput, standardized batch analysis routines, and statistically relevant datasets—essential considerations in biological research, especially for researchers working in the nanomedical and clinical fields. Why is it advisable to integrate a BioAFM with an optical/fluorescence microscope? A significant benefit of Bruker’s BioAFM instrumentation is its ability to be easily combined with advanced optical microscopy techniques such as STED or fluorescence microscopy, enabling complementary datasets and correlated measurements. Integrating Bruker’s BioAFMs with advanced optical imaging techniques is seamless, thanks to a specialized AFM stage designed for compatibility with most commercially available inverted and confocal optical microscopes. The AFM head is positioned on the stage, and software such as Bruker’s DirectOverlay feature is then used to colocalize optical and AFM images. This allows for a direct correlation of acquired AFM and optical data. There is no need to transfer the sample between setups, and the system supports a wide range of camera and detector types. Easy optical image import, advanced calibration algorithms, and visualization routines enable precise navigation across the sample, allowing for multidimensional characterization within a single experiment. Compatible techniques include epifluorescence, confocal, phase contrast, and super-resolution microscopy methods such as STED, TIRF, and STORM. The capacity to acquire real-time, correlative data sets is especially key to the field of life science research. This is because: It empowers researchers to study biological samples’ topography using AFM while simultaneously observing fluorescently labeled cellular components. It allows the multiparametric observation of in situ dynamics, including protein folding, receptor-ligand interactions, single-molecule protein dynamics, and mechanosensitive signaling pathways. Correlative AFM and Advanced Optical Microscopy in Life Science Research eBook What sample preparation is needed for using BioAFM? BioAFM is a label-free technique that allows measurements in both air and liquid, making it ideal for studying live cells under near-physiological conditions. Unlike other imaging methods, it does not require a vacuum, nor does it necessitate freezing, drying, coating, or microtome sectioning of samples before measurement. For optimal results, the sample must adhere to a suitable surface substrate, such as a Petri dish, coverslip, or mica. When measuring in liquid, the sample should be immersed in an appropriate buffer solution. To ensure high-quality imaging, it is recommended to thoroughly clean the substrate beforehand to eliminate contaminants or artifacts that could interfere with measurements. Acknowledgments Produced from materials originally authored by Bruker Nano GmbH. About Bruker BioAFM Bruker BioAFM, former JPK Instruments AG, is a lead­ing man­u­fac­tur­er of nano-an­a­lyt­i­cal in­stru­ments - par­tic­u­lar­ly based on atom­ic force mi­cro­scope (AFM) and op­ti­cal tweez­ers sys­tems - for life sci­ences and soft mat­ter ap­pli­ca­tions. We combine the highest technical skills with visionary applications. Our work applies nanotechnology in ways to provide solutions to challenges facing researchers in life sciences and soft matter today. Driven by inspiration and ambition, it is our conviction that only the best tools are good enough for the research of life. We are listening with the ear of a scientist in detail to the current challenges of our customers and find individual solutions for individual problems. This is how we understand our business. Primary Activity Material Manufacturer Scanning Probe Technology for Soft Matter and Life Sciences

Hypospadias is characterized by an ectopic urethral opening and abnormal penile curvature, affecting approximately 1 in 200 live male births. While its origins are believed to stem from a combination of genetic and environmental factors, androgen signaling pathways are thought to play a significant role in the condition's development. Despite progress in identifying the genetic components, the precise molecular mechanisms remain poorly understood. Previous studies have suggested that the Wnt/β-catenin signaling pathway is involved in urethral development, but the specific contributions of transcription factors such as MAFB and CCAAT/enhancer-binding protein alpha (CEBPA) have yet to be fully explored. This gap in understanding highlights the need for in-depth research to elucidate the pathways involved in hypospadias. On September 13, 2024, a study (DOI: 10.1016/j.gendis.2024.101432) published in Genes & Diseases and led by researchers from the Children's Hospital of Chongqing Medical University in China identified MAFB and CEBPA as crucial regulators of urothelial cell growth. By influencing cell proliferation and apoptosis through the Wnt/β-catenin signaling pathway, MAFB and CEBPA play a significant role in the genetic mechanisms of hypospadias. This research lays a strong foundation for future studies aimed at developing targeted therapies for this prevalent congenital condition. The study focused on the roles of MAFB and CEBPA in urothelial cell growth, utilizing human foreskin samples and mouse models. The researchers found that expression levels of MAFB and CEBPA were significantly reduced in the foreskin tissues of hypospadias patients. Using RNA sequencing and Western blot analysis, they discovered that MAFB knockdown led to suppressed CEBPA protein expression, inhibiting the Wnt/β-catenin pathway and causing cell cycle arrest and increased apoptosis in urothelial cells. Furthermore, MAFB overexpression promoted cell proliferation and activated the Wnt/β-catenin pathway, while CEBPA knockdown reversed these effects. These findings highlight the pivotal role of the MAFB-CEBPA axis in regulating urothelial cell growth and suggest that disruptions in this pathway may contribute to hypospadias development. The study also pinpointed potential therapeutic targets for future interventions. Our findings provide a deeper understanding of the molecular mechanisms underlying hypospadias. By identifying the roles of MAFB and CEBPA in urothelial growth, we have uncovered potential targets for therapeutic intervention, which could lead to improved outcomes for patients with this condition." Dr. Xing Liu, corresponding author of the study The discovery of the MAFB-CEBPA regulatory pathway holds immense potential for advancing the treatment and prevention of hypospadias. By targeting this pathway, researchers could develop novel therapies to correct or prevent the malformation during early development. Additionally, the study opens exciting new avenues for exploring the genetic and molecular underpinnings of other congenital disorders related to urethral development. Future research may focus on identifying additional genetic factors and environmental influences that interact with the MAFB-CEBPA pathway, further advancing our understanding of hypospadias and related conditions.

Why do medications that are supposed to help patients with chronic inflammatory diseases sometimes lead to blood clots? This is one of the questions that a team of researchers from Aarhus University has sought to answer in a study that has just been published in the journal Inflammopharmacology. The study suggests that disturbances in the JAK-STAT signalling pathway, an important communication pathway in the body, may contribute to this side effect. "In the study, we uncover the potential links between components of the JAK-STAK signalling pathway, blood markers in patients with blood clots, and the genetic factors that contribute to the risk of blood clots in patients. This helps improve our understanding of why we see an increased risk of blood clots when using JAK inhibitors," explains Stine Rabech Haysen, former medical student at the Department of Biomedicine at Aarhus University, who is the first author of the publication. The potential of the study In the study, researchers used publicly available data from a number of published studies about patients with blood clots and compared them with a healthy control group. They found no direct genetic explanation, but they did find a statistically significant enrichment of genes that are subject to regulatory control of the JAK-STAT signalling pathway among genes whose expression is altered in patients with blood clots. "Although we cannot draw definitive conclusions about the mechanistic link between the use of JAK inhibitors and the risk of blood clots, our study demonstrates the potential of using data mining to identify and shed light on possible mechanisms of drug side effects," says one of the study's senior authors, associate professor at the Department of Biomedicine Per Qvist. What does this mean for patients? Although JAK inhibitors rarely lead to blood clots, it's important to understand the mechanism behind them so that the risk can be reduced. "For the average person, our study means that we're getting closer to understanding why some drugs can have dangerous side effects like blood clots. And going forward, our method could help identify and prevent serious side effects, potentially making drug treatment safer," explains the other senior author of the study, associate professor at the Department of Biomedicine Tue Wenzel Kragstrup. The researchers will now test the method on other types of medication to see if it can be used to detect side effects more widely.

Early-life adversity affects more than half of the world's children and is a significant risk factor for cognitive and mental health problems later in life. In an extensive and up-to-the-minute review of research in this domain, scholars from the University of California, Irvine illuminate the profound impacts of these adverse childhood experiences on brain development and introduce new paths for understanding and tackling them. Their study, published in Neuron, examines the mechanisms behind the long-term consequences of childhood stress (adversity). Despite extensive research spanning over seven decades, the authors point out that significant questions remain unanswered. For example, how do adults – from parents to researchers – fully comprehend what is perceived as stressful by an infant or child? Such conceptual queries, as well as the use of cutting-edge research tools, can provide a road map, guiding experts toward developing innovative methods and providing solutions to this pressing mental health issue. Our research suggests that the unpredictability of a child's early environment may be just as important as more traditionally recognized forms of adversity, such as abuse or neglect. Our review has important implications for how we approach early intervention and prevention strategies." Dr. Tallie Z. Baram, lead author, Donald Bren Professor of Pediatrics and one of the world's leading researchers in this field She and co-author Matthew Birnie, a UC Irvine postdoctoral scholar, identify several key areas for further investigation: What does the developing brain perceive as stressful? Which aspects of stress most significantly influence brain maturation? Which developmental ages are most vulnerable to adversity? What are the molecular mediators of stress effects on the brain? How can transient stressful experiences lead to enduring dysfunction? One notable discovery is a novel form of early-life stress: unpredictable sensory inputs from caregivers and the environment. This factor plays a substantial role in adverse neurodevelopmental outcomes, even after controlling for well-known adverse childhood experiences, which are collectively referred to as ACEs. The review highlights the limitations of current ACE scoring systems in accurately predicting individual outcomes and underscores the complexity of early-life stress. Emerging factors, such as societal and anthropogenic characteristics like inequality and pollution, are gaining recognition as potential contributors. Animal models have been instrumental in unraveling the mechanisms underlying brain development effects. Research has revealed that different types of stress can yield distinct outcomes, influenced by the nature and timing of stress, as well as species, strain and sex variations. At the molecular level, early-life stress can substantially alter neuronal gene expression through epigenetic mechanisms. These changes may lead to long-term modifications in how the brain responds to subsequent experiences. At the circuit level, early stress can disrupt the maturation of brain networks by interfering with crucial developmental processes, including neuronal oscillations and synaptic pruning. "We're gradually comprehending how early-life stress can 'reprogram' the brain at multiple levels, from individual molecules to entire neural circuits. This knowledge presents new avenues for targeted interventions," Baram said. The review also identifies key molecular mediators of early-life stress effects, including glucocorticoids and neuropeptides like corticotropin-releasing hormones. Ongoing research is uncovering novel roles for these molecules in specific neural circuits affected by early stress. In light of these findings, the researchers propose redefining early-life stress as "early-life adversity" to better encompass the diverse experiences that can impact brain development, even those not traditionally perceived as stressful. "This review emphasizes the need for a more comprehensive understanding of early-life adversity," Baram said. "By focusing on how the developing brain processes and responds to these experiences, we can develop more effective strategies to prevent and mitigate their long-term effects." The researchers suggest increased funding for and attention to this critical area of study, highlighting its potential to enhance mental health outcomes and reduce the societal burden of early-life adversity. Baram is also the Danette Shepard Chair in Neurological Studies and director of UC Irvine's Conte Center, which is supported by a Silvio O. Conte Center grant from the National Institute of Mental Health. Conte Center grants are bestowed on the most promising multidisciplinary and often cross-species approaches to improving the diagnosis and treatment of mental health issues. National Institutes of Health awards P50MH096889 and RO1 MH132680 as well as the Hewitt Foundation for Biomedical Research supported the work.

Researchers from Charité – Universitätsmedizin Berlin and the Max Delbrück Center have detailed the precise mechanism through which the inflammatory signaling molecule IL-12 contributes to Alzheimer's disease. The study was published in in the journal "Nature Aging." Microglia, the brain's immune cells, usually serve as diligent guardians. They eliminate intruders such as microbes and clear away cellular debris – including the plaques typical of Alzheimer's disease. However, as our brains age, microglia also change. While some continue to function effectively, others gradually lose their protective role and start secreting small amounts of inflammatory messengers. One such messenger is interleukin-12 (IL-12). Through meticulous analyses, research teams led by Professor Frank Heppner, Director of the Department of Neuropathology at Charité – Universitätsmedizin Berlin, and Professor Nikolaus Rajewsky, Director of the Berlin Institute for Medical Systems Biology at the Max Delbrück Center (MDC-BIMSB), along with additional partners, have identified how IL-12 might trigger and accelerate Alzheimer's dementia. Their study, published in "Nature Aging," could pave the way for new combination therapies. For decades, Alzheimer's research focused almost exclusively on amyloid-beta and tau deposits, while inflammation was considered a side effect. Only recently have we begun to recognize that inflammatory processes may be a primary driver of disease progression." Professor Frank Heppner, Director of the Department of Neuropathology at Charité – Universitätsmedizin Berlin In 2012, Heppner's lab reported in Nature Medicine that blocking IL-12 and IL-23 significantly reduced Alzheimer's-related brain changes in mice. "But we couldn't unravel the underlying mechanism with standard techniques," Heppner explains. He reasoned that single cell analyses might provide more decisive clues, so he asked Rajewsky to collaborate. Sticky and tangled brain cells Throughout life, cells refer to their genetic instructions to respond to external stimuli. Researchers use single-cell analyses to observe this process, reconstructing which genes are being read and translated into proteins in thousands of individual cells simultaneously. These analyses generate massive datasets, which can now be analyzed with the help of artificial intelligence and machine learning. However, a major challenge in using single cell sequencing technology is isolating individual cells from a tissue sample without damaging them or causing unintended changes. "In aging mouse brains – especially those with Alzheimer's plaques – cells are so stuck together and tangled that separating them cleanly is nearly impossible," Rajewsky explains. His team spent several years perfecting a workaround. Instead of isolating entire cells, they extract cell nuclei from brain tissue and analyze the RNA present in each cell. By cross-referencing with publicly available data, such as the Allen Brain Atlas, they can ensure that their method provides a representative snapshot of all cell populations. For the present study, they sequenced RNA from over 80,000 cell nuclei and developed specialized workflows to process the data. They also reconstructed communication between cells. "Our teams repeatedly sat together to try to interpret this highly complex data," Rajewsky says. "This painstaking early optimization was crucial – without it, we would not have been able to detect these connections." How IL-12 damages the Alzheimer's brain IL-12, previously known primarily for its role in autoimmune diseases like Crohn's disease and rheumatoid arthritis, appears to play a pivotal role in Alzheimer's progression. It damages two key brain cell types: mature oligodendrocytes, which normally produce myelin ­– the fatty insulating layer around nerve fibers essential for rapid signal transmission; and interneurons, which are particularly important for cognition and memory. IL-12 binding to interneurons causes them to die. A vicious circle begins: As more microglia produce IL-12, more brain cells sustain damage. Meanwhile, remaining functional microglia become overburdened by the task of clearing the additional cellular debris, and thus fail to remove Alzheimer's plaques. To verify this mechanism, researchers tested it in mice and in human tissue. When Heppner's team blocked IL-12 in cell cultures and mouse models, they could stem disease-related changes. Electron micrographs of mouse brain tissue taken at the Max Planck Institute for Multidisciplinary Sciences in Göttingen also showed how myelin structure and nerve fiber density changed depending on whether the IL-12 signaling pathway was present or absent. Mass spectrometric analyses (lipidomics) at the University of Zurich confirmed the altered composition of the fat-rich insulating layer. Study of autopsy tissue from Alzheimer's patients provided further confirmation of the results – the more advanced the disease, the more IL-12 was present in the tissue. Cell cultures with human oligodendrocytes were also extremely sensitive to IL-12. Potential combination therapy "We now have a highly detailed picture of this mechanism, with single-cell technologies serving as a crucial catalyst. The only remaining question is which cell type IL-12 impacts first – oligodendrocytes, interneurons, or both simultaneously," says Heppner, who is also Group Leader in Neuroimmunology at the Deutschen Zentrums für Neurodegenerative Erkrankungen (DZNE). The study has immediate implications as there are already drugs on the market that block IL-12. The researchers hope that clinicians will build on their findings and initiate clinical trials. "If these drugs prove effective, they would be a new arrow in the quiver. Alzheimer's doesn't just have one cause. One axis of the disease is also controlled by the immune system, at least in some patients. Slowing neurodegeneration will require combination therapy," Heppner emphasizes. Such an approach could start early in the disease process, as IL-12 can be measured in blood or cerebrospinal fluid, he adds. Meanwhile, the teams at Charité and the Max Delbrück Center are exploring a new hypothesis: Could microplastic in the brain drive microglia to produce IL-12? "Microglia may struggle to process microplastic, triggering inflammatory reactions," Rajewsky suggests. "This could reveal a link between environmental factors and widespread diseases." While unproven, both teams consider it a compelling and important research direction.

Hepatitis B virus infection remains one of the leading causes of liver disease, including cirrhosis and hepatocellular carcinoma. Despite widespread vaccination and antiviral treatments, millions of people still suffer from chronic hepatitis B virus (HBV) infection. The primary challenge in curing the disease lies in the persistence of covalently closed circular DNA (cccDNA), a stable viral DNA form that resides in the nucleus of infected liver cells. Current therapies, such as nucleos(t)ide analogues and interferons, fail to eliminate cccDNA, allowing the virus to rebound after treatment is stopped. These challenges underscore the need for novel therapeutic strategies that specifically target cccDNA to achieve a functional cure. In a review (DOI: 10.1016/j.gendis.2024.101215) published in Genes & Diseases on February 3, 2024, a team of researchers from Chongqing Medical University, in collaboration with other institutions, delves into the epigenetic regulation of HBV cccDNA. The study examines the molecular mechanisms governing cccDNA activity and explores potential therapeutic approaches to silence its transcription. By focusing on chromatin-modifying enzymes, viral proteins, and noncoding RNAs, the researchers hope to uncover new pathways for a functional cure for chronic hepatitis B. The review highlights the complex biology of cccDNA, which forms minichromosomes in the infected liver cell nucleus. These minichromosomes bind with histone and nonhistone proteins, becoming transcriptionally active and sustaining viral replication. Key epigenetic mechanisms—such as DNA methylation, histone modifications, and the involvement of noncoding RNAs—regulate cccDNA activity. For example, DNA methylation suppresses viral transcription, while histone modifications like acetylation and succinylation can either activate or silence cccDNA transcription, providing potential targets for intervention. One of the most compelling findings is the role of the HBV protein HBx in maintaining cccDNA transcriptional activity. HBx interacts with host factors to alter the epigenetic landscape of cccDNA, promoting an open chromatin state that facilitates viral gene expression. The study also explores emerging therapeutic strategies, including targeting HBx, utilizing epigenetic modifiers, and employing gene-editing technologies like CRISPR/Cas9 to disrupt cccDNA. These innovative approaches offer the potential to permanently silence cccDNA, paving the way for a functional cure. Dr. Juan Chen, the corresponding author of the study, emphasized the importance of epigenetic regulation in controlling cccDNA. Our findings underscore the critical role of epigenetic mechanisms in HBV pathogenesis. By targeting these pathways, we can develop therapies that not only suppress viral replication but also offer a functional cure for chronic hepatitis B." Dr. Juan Chen, corresponding author of the study The implications of this review are far-reaching for the future of HBV therapies. Epigenetic modifiers, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, could be repurposed or newly designed to specifically target cccDNA. Furthermore, CRISPR/Cas9 technology offers a precise method for disrupting cccDNA, potentially leading to a permanent cure. By combining these strategies with current antiviral treatments, researchers could significantly enhance their effectiveness, bringing us closer to a functional cure for chronic hepatitis B. This research not only advances our understanding of HBV biology but also sets the stage for the next generation of therapeutic innovations in the fight against viral hepatitis.

Glioblastoma has remained one of the toughest cancers to treat, resisting even the latest advances in immunotherapy. But new research from Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, suggests a way forward: suppressing a protein called ZNF638 triggers an antiviral immune response, making immune checkpoint inhibitors more effective. The discovery not only offers a potential new treatment strategy but also identifies ZNF638 as a biomarker that could help personalize immunotherapy for patients. The findings appear in the March 17 issue of the Journal of Clinical Investigation. Glioblastoma is the most common type of brain tumor in adults, with about 12,000 cases in the United States each year. Despite the disease's prevalence, outcomes for patients with glioblastoma have barely improved in the last 20 years. With a strongly immunosuppressive microenvironment, highly variable presentations between patients, and physically challenging surgical conditions, glioblastoma remains exceptionally difficult to treat. Brain tumors are one of the most formidable foes in medicine. Our current treatment options are simply insufficient." Ashish H. Shah, M.D., senior author of the study, neurosurgeon and researcher at Sylvester Immune checkpoint inhibition has been successfully used to treat more than a dozen diverse cancers, but because brain cancers are in such a strongly immune-suppressive environment, the treatment has largely failed in the case-by-case attempts to date. "For many other cancers, immunotherapies have completely changed the field, but for brain tumors, we haven't seen that same improvement," Shah said. "At least, not yet." Learning what could make immune checkpoint therapies more effective - or effective at all - for glioblastoma patients is critical for understanding how to treat patients best. According to Shah's new study, viral mimicry may be the answer. Viral mimicry Viral mimicry, a tool at the leading edge of cancer treatment, may be the key path forward in making immune checkpoint inhibition effective for treating glioblastoma. The goal of viral mimicry is to trick the body into thinking the tumor has a viral infection, prompting an immune response. Over millions of years, the human genome has collected fragments of viruses called human endogenous retroviruses. Most of the time, our body silences these retroviral genes through various mechanisms, particularly the HUSH protein complex. In viral mimicry, clinicians trigger the patient's body to "un-silence" these inactive viral fragments. These ancient fragments are not strong enough to cause a real viral infection, but they still trigger an anti-viral immune response. That antiviral response can make tumors more susceptible to immunotherapies. "We're using evolution to attack tumors," Shah said. Viral mimicry was first successfully used to make ovarian cancer more susceptible to ICI in 2015. It has since been used in at least four other cancers, and it's a rapidly developing area of research. But it had not been successfully applied to brain tumors until Shah's new work. Un-silencing ancient viruses The question for Shah and his team, then, was how they could use viral mimicry to make immune checkpoint inhibitors work for glioblastoma. For that, they turned to ZNF638, a key regulator of the group of proteins that keep retroviruses silent. By suppressing ZNF638 in the tumor, they might create a viral mimicry response, opening the doors to immune checkpoint inhibitors effectively treating glioblastoma at last. The researchers first searched cancer databases, documenting associations between ZNF638 and immune-related factors such as immune cell infiltration. They analyzed glioblastoma patients' genetic data and found that patients who were more responsive to immune checkpoint inhibitor therapy naturally had lower expressions of ZNF638 and higher survival rates. Cell-based experiments and single-cell RNA sequencing revealed that tumors with low ZNF638 tended to have more immune cell infiltration, and the monitoring system for retroviruses was active. This ZNF638-antiviral connection was seen in published patient data, too. It was possible that targeting ZNF638 could create "viral mimicry" conditions in tumors. Armed with these results, the researchers tested the impacts of suppressing ZNF638 in preclinical tests, targeting it only in the tumor cells and leaving healthy brain tissue untouched. Combining ZNF638 targeting with immune checkpoint inhibitor therapy improved the treatment's efficacy: ZNF638 suppression had decreased tumor growth, increased T-cell lymphocyte infiltration and improved survival times. "The most surprising findings were in the clinical data, where patients with low ZNF638 expression had improved responses to immunotherapy," said Jay Chandar, a fourth-year medical student in Shah's lab and study co-author. "That strongly supported our whole idea that knocking down ZNF638 would make tumors more susceptible to immunotherapy." "With previous trials using ICI to treat glioblastoma having largely failed, it's exciting to find a novel therapeutic target and see that viral mimicry could help," said Deepa Seetharam, Ph.D., a postdoctoral scholar in the Department of Neurosurgery and study co-author. "I'm optimistic this could improve prognoses for glioblastoma patients." The future of immunotherapy for glioblastoma The promising results point to the potential for ZNF638 to be a biomarker, shaping personalized treatment plans. Immune checkpoint inhibitors are not currently approved for treating glioblastoma, so previous patients have been on a case-by-case basis, Shah said. Using ZNF638 as a biomarker could help change that by predicting which patients would likely be responsive to ICI therapy. While a novel biomarker is the most immediate outcome, the long-term goal remains developing a brain-penetrating drug to target ZNF638 in glioblastoma, allowing ICI to be used effectively to treat more patients. "Then we'll really be changing the game," Shah said. "A synergistic treatment like that is the future of immunotherapy in treating glioblastoma."

A new analysis led by surgeons at UCLA Health finds that psychological prehabilitation can significantly enhance recovery after surgery. The research, led by Anne E. Hall in the lab of Dr. Justine Lee analyzed data from 20 randomized controlled trials (RCTs) conducted between 2004 and 2024, involving a total of 2,376 patients. It is published in the Annals of Surgery What is psychological prehabilitation? Prehabilitation is a proactive approach aimed at improving surgical outcomes through preventive measures. Traditionally, it has focused on physical function and patient education. However, mental health has recently gained attention due to its crucial role in postoperative recovery, including reducing persistent opioid use. Study methods The researchers conducted a systematic review, meta-analysis, and meta-regression of RCTs retrieved from databases such as MEDLINE, EMBASE, CENTRAL, and Google Scholar. They included studies with more than 50 adult surgical patients and evaluated the effects of different preoperative psychotherapy-based interventions, including cognitive behavioral therapy (CBT), supportive psychotherapy, and acceptance and commitment therapy (ACT), on postoperative outcomes. Key findings The study found that psychological prehabilitation significantly reduces the length of hospital stay, pain, anxiety, and depression after surgery. Specifically, the analysis showed: A reduction in length of hospital stay (LOS) by an average of 1.62 days; A decrease in pain by an average of 3.52 points; Lower anxiety levels regardless of which validated anxiety scale was used; Reduced depression levels regardless of which validated depression scale was used. Interestingly, the type of psychotherapy and the kind of surgery did not significantly affect the outcomes, except for anxiety. Implications for healthcare The findings suggest that incorporating psychological prehabilitation into pre-surgery routines could lead to better overall recovery for patients. This approach may also help reduce healthcare costs associated with prolonged hospital stays and postoperative complications. Future research The study highlights the need for further research to compare different types, durations, and delivery methods of psychotherapy to determine the most effective strategies for specific postoperative outcomes.