Resolution Therapeutics’ Post

RNA interference with Fazirsiran reduces globule burden in alpha-1-antitrypsin deficiency liver disease. A phase 2 placebo controlled trial (SEQUOIA) Within a multinational phase 2 study with Fazirsiran, an RNA interference drug, in alpha-1-antitrypsin (AAT) deficiency liver disease we were able to show efficacy (94% reduction in Z-AAT and reduced globule burden and reduced hepatic inflammation), without severe side effects and without change in lung function. Details of the study can now be read in Gastroenterology.

A 5:2 intermittent fasting regimen ameliorates NASH and fibrosis and blunts HCC development via hepatic PPARα and PCK1. The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARalpha) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARalpha targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARalpha signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer. Source: Cell Metab https://lnkd.in/eH57-Jia

#Chronic_liver_diseases often progress to liver #fibrosis, leading to #cirrhosis and #hepatocellular_carcinoma. Recent studies highlight the therapeutic potential of #microRNA (miRNA)_targeted treatments. Notably, #miR_155 inhibition shows promise in reducing liver fibrosis. Increased hepatic miR-155 expression has been observed in patients with cirrhosis and bile duct ligation (BDL) and CCl4-induced mouse models of liver fibrosis. Therapeutic inhibition of miR-155, achieved via a rAAV8-anti-miR-155 tough decoy, significantly reduces liver damage and fibrosis in BDL mice. The inhibition of #miR_155 leads to decreased protein levels of transforming growth factor β (#TGF_β), #p_SMAD2/3, and #p_STAT3. These reductions are crucial as TGF-β and STAT3 signaling pathways are pivotal in activating #hepatic_stellate_cells (HSCs), which drive fibrosis. In miR-155-deficient (miR-155 knockout [KO]) mice, liver fibrosis is notably reduced following CCl4 administration or BDL. Hepatic stellate cells from these KO mice show less activation and lower mesenchymal marker expression, indicating a direct link between #miR_155 and stellate cell activation. Understanding the molecular pathways of liver fibrosis is crucial for developing effective therapies. Targeting #miR_155 and its downstream signaling pathways, such as #STAT3, could revolutionize treatment approaches, potentially reversing #fibrosis and improving patient outcomes in #chronic_liver_diseases. #Hepatic_stellate_cells #miRNA #Chronic_liver_diseases #Fibrosis #Cirrhosis #Hepatocellular_carcinoma #microRNA REF: https://lnkd.in/g4QbJgXH

Nonalcoholic steatohepatitis (#NASH) , now renamed as metabolic dysfunction associated-steatohepatitis (#MASH), is a silent but progressive liver disease, often an advanced form of Nonalcoholic fatty liver disease (#NAFLD) or Metabolic-dysfunction associated fatty liver disease (#MAFLD). Characterized by inflammation and damage resulting in liver fibrosis, MASH can advance to cirrhosis or liver cancer, presenting a significant healthcare challenge due to its stealthy progression and lack of approved pharmacological treatments. However, a new beacon of hope has emerged with the unprecedented success of the phase 3 trial of #resmetirom, a selective thyroid hormone receptor beta agonist. Read more: https://lnkd.in/g5E7z87e

🔬 Delving into autoimmune breakthroughs! We're thrilled to share the progress we´ve made in combating #type1diabetes with Ahead´s innovative technology. Our latest research, published in the Journal of Autoimmunity, offers an in-depth look into the mechanism of action of macrophages in the generation of tolerance in our immunotherapy. 📚 📖 Explore the details of the study: https://lnkd.in/gsMe6Ejd

📃Scientific paper: Evaluation of liver fibrosis in chronic hepatitis B patients with 2D shear wave elastography with propagation map guidance: a single-centre study Abstract: Background The aims of this study were to evaluate liver fibrosis with two-dimensional (2D) shear wave elastography (SWE) in patients with chronic hepatitis B (CHB), to compare 2D-SWE with histopathology and to determine the change in liver stiffness values after antiviral therapy. Material and methods A total of 253 patients with CHB were included in this prospective study. 2D-SWE with propagation map guidance to measure liver stiffness, fibrosis-4 index (FIB-4) and aspartate aminotransferase to platelet ratio index (APRI) scoring and additional liver biopsy were performed in patients with CHB. Liver stiffness was measured again at 24 and 48 weeks in all patients. The Spearman rank correlation test was used to analyse the correlation between variables, and receiver operating curve analysis was used to evaluate the diagnostic performance in terms of fibrosis. Results Liver stiffness measurements made with 2D-SWE demonstrated a significant positive correlation with the fibrosis stage and FIB-4 score ( r _ s  = 0.774 and 0.337, respectively, p  < 0.001 for both). The area under the curve value for kPa for the prediction of significant fibrosis was 0.956 (95% CI_s) (0.920–0.991), and the optimal cut-off value was 8.2 kPa (sensitivity: 92.7% and specificity: 78.9%); these values were 0.978 (95% CI_s, 0.945–1.000) and 10.1 kPa (sensitivity: 92.9% and specificity: 96.4%) for the prediction of severe fibrosis. After antiviral treatment, a decrease in liver stiffness values ... Continued on ES/IODE ➡️ https://etcse.fr/XCD ------- If you find this interesting, feel free to follow, comment and share. We need your help to enhance our visibility, so that our platform continues to serve you.

Interesting new finding by Zhang et al. published in the prestigious journal, Nature Communications, describes the role of a developmental signaling pathway, the Hedgehog pathway, in development of non-alcoholic steatohepatitis (NASH), a liver disease that causes liver malfunction and can lead to liver cirrhosis and liver cancer. Currently there are no therapies for NASH. This work is quite relevant to the efficacy of MAX BioPharma's oxysterol drug candidate for NASH, Oxy210, which has shown to have significant inhibitory effect on the development of NASH. Oxy210 is a powerful compound that inhibits 3 major drivers of NASH: Hedgehog signaling, TGF-beta signaling, and Toll-Like Receptor signaling. As such it exerts potent anti-inflammatory and anti-fibrotic effects in the liver. #oxysterol #maxbiopharma #NASH #NAFLD #fibrosis Philip Sell Metaba https://lnkd.in/gZZ8ZC2Q https://lnkd.in/gZZ8ZC2Q

In a world-first finding, they've identified a way to restore the faulty function of ion channels on #immune cells using a well-known drug typically used for other medical purposes. The breakthrough, published in the journal Frontiers in #immunology, builds on previous research showing long COVID patients share similar issues with #ionchannels as those with chronic fatigue syndrome (also known as myalgic encephalomyelitis or ME/CFS). The team had previously shown success in restoring ion channel function in ME/CFS patients using a drug called #naltrexone, and now they've achieved similar results with #longcovid patients. #covid19 First author Ph.D. candidate Etianne Sasso said the research team had previously reported restoring the function of these ion channels of immune cells in laboratory trials. "Ion channels are integral membrane proteins that facilitate the passage of ions (charged particles) across the cell membrane," Sasso said. "We found that by restoring the function of these ion channels, important ions such as calcium were again able to move in and out of immune cells, controlling many of the body's biological processes." This breakthrough offers hope for alleviating various ME/CFS symptoms, including brain fog, muscle fatigue, and issues with the cardiovascular and gastrointestinal systems. Professor Sonya Marshall-Gradisnik, senior author and Director of NCNED, said the significance of this discovery, achieved through the gold standard test called electrophysiology, will help in better understanding long COVID and ME/CFS paving the way for potential therapies. The NCNED is preparing to launch two clinical trials, one for long COVID and another for ME/CFS, testing the effectiveness of low-dose Naltrexone. This drug, typically used for #opioid #addiction, has shown promising results in restoring ion channel function in previous research and in anecdotal reports from patients. "We will be undertaking two clinical trials testing the efficacy of low dose naltrexone where the first will be in long COVID patients while the second trial will, for the first time, be in ME/CFS patients," Professor Marshall-Gradisnik said. "Should these trials prove successful, it could mean a vastly improved quality of life for countless individuals struggling with long COVID and ME/CFS." #chronicdisease #infectiousdisease #biopharma Brent Alexander Brown Chinua Imarogbe #cdc #nih World Health Organization FDA https://lnkd.in/gFHn5u76

Bruton's Tyrosine Kinase : Potential therapeutic target for Alcoholic Liver Disease BTK is a validated therapeutic target in Haematological malignancies. Now BTK has been shown to be associated with development of Alcoholic Liver Disease. Pharmacological BTK inhibition reduced proinflammatory cytokines and attenuated neutrophil-mediated liver damage in a mouse model of alcohol-associated hepatitis. BTK activation was also found to be increased in patients with alcohol-associated hepatitis, indicating translational relevance of the identified mechanism of alcohol-induced liver injury.

I am delighted to share this project regarding the modulation of regulatory T cells, published at the beginning of this month. Special thanks to the team, who were always engaged. Lima, A.D.R et al. Dimethyl fumarate modulates the regulatory T cell response in the mesenteric lymph nodes of mice with experimental autoimmune encephalomyelitis. "Dimethyl fumarate (DMF, Tecfidera) is an oral drug utilized to treat relapsing-remitting multiple sclerosis (MS). DMF treatment reduces disease activity in MS. Gastrointestinal discomfort is a common adverse effect of the treatment with DMF. This study aimed to investigate the effect of DMF administration in the gut draining lymph nodes cells of C57BL6/J female mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We have demonstrated that the treatment with DMF (7.5 mg/kg) significantly reduces the severity of EAE. This reduction of the severity is accompanied by the increase of both proinflammatory and anti-inflammatory mechanisms at the beginning of the treatment. As the treatment progressed, we observed an increasing number of regulatory Foxp3 negative CD4 T cells (Tr1), and anti-inflammatory cytokines such as IL-27, as well as the reduction of PGE2 level in the mesenteric lymph nodes of mice with EAE. We provide evidence that DMF induces a gradual anti-inflammatory response in the gut draining lymph nodes, which might contribute to the reduction of both intestinal discomfort and the inflammatory response of EAE. These findings indicate that the gut is the first microenvironment of action of DMF, which may contribute to its effects of reducing disease severity in MS patients" https://lnkd.in/ez9_yrWp