selisistat (SEN-196) / AOP Orphan Pharma - LARVOL DELTA

SIRT-1 activation by quercetin opposes the actions of three transcription factors: p53, ATF4, and NF-κB in a renal ischaemia reperfusion injury in rats. (PubMed, J Pharm Pharmacol) - "The results showed that Q preserved the kidney functions from via acting as antioxidant by upregulating the superoxide dismutase and SLC7A11 levels, downregulating the inflammatory markers, NF-κB, TNF-α, as well as suppressing ATF4/CHOP, and p53/miR34-a/p66Shc/caspase 3 apoptotic pathways. However, the use of EX527 showed a surge of the inflammatory and apoptotic responses and a depletion of renal antioxidant capacity; thus, reversing the observed protective actions to suggest the significant role of SIRT-1 activation by Q, still potential off-targets actions of the former cannot be excluded."

Journal • Preclinical • Acute Kidney Injury • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • Transplantation • ATF4 • CASP3 • MIR34A • SLC7A11 • TNFA

Tetramethylpyrazine alleviates ventricular remodeling after myocardial infarction by regulating Sirt1/p300/Yy1/sST2 signaling axis. (PubMed, Phytomedicine) - "We found that increased serum sST2 levels were significantly correlated with the progression of adverse ventricular remodeling following MI. Furthermore, our study provides the first preclinical evidence demonstrating that TMPZ attenuates this remodeling process by targeting the Sirt1/p300/Yy1/sST2 signaling axis. Collectively, these findings not only highlight sST2 as a promising therapeutic target but also establish a mechanistic rationale for developing novel interventions through pharmacological modulation of the Sirt1/sST2 pathway."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Myocardial Infarction • Oncology • ST2 • YY1

The impact of histone deacetylase inhibition on neurobehavioural outcomes in preclinical models of traumatic and non-traumatic spinal cord injury: a systematic review. (PubMed, Front Immunol) - "Valproate was the most frequently studied HDAC inhibitor (n=20), followed by 4-phenylbutyrate (4-PBA; n=7) and RGFP966 (n=3). Trichostatin A, tubastatin A, entinostat, PCI-34051, scriptaid, CI-994, TMP269, vorinostat, 3-TYP, SW-100 and ACY1215 were each evaluated in a single study. Three studies used the sirtuin-1 (HDAC class III) inhibitor EX527 administered with an activator molecule: melatonin (n=1), MLN4924 (n=1) and oxymatrine (n=1)...These results support further investigation of HDAC inhibitors in preclinical studies before translation into clinical trials. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023477882."

Journal • Preclinical • Review • CNS Disorders • Orthopedics • Pain • Psychiatry • Reperfusion Injury • SIRT1

Molecular hydrogen-mediated SIRT1 activation alleviates sepsis-associated encephalopathy by promoting mitophagy. (PubMed, Eur J Med Res) - "This study demonstrates that inhalation of 2% H2 exerts significant protective effects against SAE, in which SIRT1 plays a pivotal role by modulating PINK1-dependent mitophagy, thereby ameliorating neuroinflammation and neuronal apoptosis. By rescuing mitophagy deficits, SIRT1 targeting merits clinical exploration for SAE."

Journal • CNS Disorders • Cognitive Disorders • Infectious Disease • Inflammation • Septic Shock • IL1B • IL6 • STING • TNFA

Single-cell analysis integrated with RNA-Sequencing uncovers new action of Patchoulol on adipose tissue remodeling in obesity. (PubMed, Phytomedicine) - "Current findings provide a novel understanding of adipose tissue remodeling at single-cell level, and SIRT1 might be a critical pharmacological target of PAT that contributes to treat obesity and metabolic diseases."

Journal • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • Obesity • TNFA

Resveratrol mitigates diabetes-induced cardiac dysfunction via SIRT1/PPAR-α/PGC-1 pathway. (PubMed, Mol Genet Genomics) - "SIRT1 inhibitor (EX527) injections in rats reversed the beneficial effects of RES. In HG-treated H9C2 cells, RES improved cell viability, reduced apoptosis, alleviated oxidative stress and enhanced autophagy. RES ameliorates DCM through SIRT1/PPAR-α/PGC-1 signaling pathway in rats and improves efficacy of elderly DM patients in combination with evidence-based care."

IO biomarker • Journal • Cardiomyopathy • Cardiovascular • Diabetes • Fibrosis • Immunology • Metabolic Disorders • Type 2 Diabetes Mellitus • BCL2 • CASP3 • IL6 • TNFA

Genistein Ameliorates the Ischemic State of Random Skin Flap by Regulating Macrophage Polarization Through AMPK/SIRT1 Signaling Pathway. (PubMed, Phytother Res) - "In vitro, BMDMs were stimulated with LPS and treated with genistein, with or without AMPK (Compound C) or SIRT1 (EX-527) inhibitors, to investigate macrophage polarization and the underlying AMPK/SIRT1 signaling pathway...Genistein enhances the survival of random-pattern skin flaps by reprogramming macrophage polarization from M1 to M2 via the AMPK/SIRT1 signaling pathway. This study reveals a novel molecular mechanism for genistein's protective effect and highlights its potential as a therapeutic strategy to improve outcomes in reconstructive surgery."

Journal

ED-71 alleviates OVX-induced osteoporosis by inhibiting macrophage senescence through SIRT1/PGC-1α pathway: A potential therapeutic approach. (PubMed, Bone) - "SIRT1 inhibition with EX-527 disrupted ED-71's anti-senescence action. Additionally, ED-71 improved bone mass and aging in OVX mice. In conclusion, ED-71 alleviates macrophage senescence via the SIRT1/PGC-1α signaling axis, thereby enhancing BMSC osteogenic potential and mitigating bone loss in OVX-induced osteoporosis."

Journal • Osteoporosis • Rheumatology

The Roles of Sirt1 in Breast and Gynecologic Malignancies. (PubMed, Biology (Basel)) - "Preclinical studies show that pharmacological inhibition of SIRT1 (e.g., with EX-527 or cambinol) restores chemosensitivity and reduces tumor cell viability, suggesting potential for SIRT1 inhibitors as adjuncts in cancer therapy...Further investigation is needed to define therapeutic windows, molecular contexts, and combination strategies that could optimize SIRT1-targeted therapies. This review summarizes the current understanding of SIRT1's roles in breast and gynecologic malignancies."

Journal • Review • Breast Cancer • Cervical Cancer • Endometrial Cancer • Gynecologic Cancers • Oncology • Ovarian Cancer • Solid Tumor • Triple Negative Breast Cancer • SIRT1

SIRT1 Enhancement is Required for the Induction of Anti-Inflammatory Effect of Micheliolide in Carbon Tetrachloride Induced Liver Fibrosis in Mice. (PubMed, J Inflamm Res) - "The selective SIRT1 inhibitor EX-527 abrogated both the anti-liver injury and anti-fibrotic effects of MCL...MCL mitigates CCl4-induced liver injury and fibrosis by activating SIRT1 to suppress liver inflammation in mice. These findings uncover a novel molecular mechanism for the anti-liver fibrotic activity of MCL and highlight its potential as a therapeutic candidate for liver fibrosis."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Oncology • CCL2 • IL10 • IL1B • IL6 • SIRT1 • TNFA

Sirtuin downregulation mediates mitochondrial impairment causing cognitive decline in hepatic encephalopathy. (PubMed, Free Radic Biol Med) - "Pharmacological activation of Sirtuin 1 with SRT2104 suppressed HIF-1α levels and reduced VDAC1 expression, while inhibition with EX-527 exerted the opposite effect and worsened mitochondrial dysfunction. Loss of Sirtuin 6 further amplified HIF-1α transcriptional activity by reducing its interaction with Sirtuin 6 and diminishing Sirtuin 6-mediated repression, thereby promoting increased expression of the downstream target VDAC1. Together, these observations identify reduced nuclear Sirtuin 1 and Sirtuin 6 as converging upstream regulators of the HIF-1α-VDAC1 axis, contributing to mitochondrial dysfunction in HE."

Journal • CNS Disorders • Hepatic Encephalopathy • Metabolic Disorders • HIF1A • VDAC1

Morin alleviates sepsis-associated encephalopathy through inhibiting ferroptosis via SIRT1. (PubMed, Brain Res Bull) - "Morin alleviates SAE by inhibiting ferroptosis via SIRT1."

Journal • CNS Disorders • Cognitive Disorders • Infectious Disease • Inflammation • Septic Shock • ACSL4 • GPX4 • SIRT1 • SLC7A11

Alisol B 23-acetate alleviates high-fat diet-induced insulin resistance by activating the SIRT1/FOXO1 axis and PI3K/AKT pathway. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Importantly, the SIRT1 inhibitor EX527 abolished the beneficial effects of AB23A, including the upregulation of the p-AMPK, p-ACC, CPT1α, and p-FOXO1, as well as the activation of the PI3K/AKT pathways...AB23A ameliorates hepatic steatosis and insulin resistance by targeting SIRT1, promoting fatty acid oxidation, modulating downstream FOXO1 activity, and coactivating the PI3K/AKT signaling pathway. These findings highlight AB23A as a promising therapeutic candidate for MASLD."

Journal • Acute Myelogenous Leukemia • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

Curcumol ameliorates alcoholic liver disease through regulation of SIRT1 signaling pathway. (PubMed, Eur J Pharmacol) - "Inhibition of SIRT1 with a specific inhibitor, EX527, neutralized curcumol's influence on SIRT1 signaling pathway, expression or activation of lipid metabolism related enzymes and lipid accumulation in hepatocytes. These results indicated that curcumol was able to ameliorate ALD through regulation of SIRT1 signaling pathway and subsequent promotion of lipolysis and inhibition of lipogenesis."

Journal • Hepatology • Metabolic Disorders

Catalpol attenuates postmenopausal osteoporosis by activating SIRT1-mediated P53 deacetylation and inhibiting CASPASE-3-driven osteoblast apoptosis. (PubMed, Int Immunopharmacol) - "These findings support a SIRT1-centered mechanism whereby CAT engages SIRT1 in cells to restrain the P53-CASPASE-3 apoptotic program in osteoblasts and mitigate estrogen-deficiency bone loss in OVX mice."

Journal • Osteoporosis • Rheumatology • ACPP • ANXA5 • CASP3 • PSAP • SIRT1

Role of SIRT1-HMGB1-NLRP3 inflammasome axis in the protective effects of trans-chalcone on myocardial ischemia and reperfusion injury. (PubMed, Gen Physiol Biophys) - "SIRT1 inhibition by EX-527 diminished these protective effects, emphasizing SIRT1's role in trans-chalcone-mediated cardioprotection. These results indicate that trans-chalcone mitigates myocardial MIR injury by targeting SIRT1 to suppress HMGB1, enhance mitochondrial function, and reduce oxidative stress, inflammasome, and pyroptotic markers, positioning trans-chalcone as a promising therapeutic option for ischemic heart disease."

Journal • Cardiovascular • Coronary Artery Disease • Heart Failure • Inflammation • Myocardial Ischemia • Reperfusion Injury • CASP1 • HMGB1 • NLRP3 • SIRT1

Inhibiting silencing information regulator 1 is conducive to the suppression of hepatitis B virus replication by entecavir. (PubMed, J Pharmacol Exp Ther) - "In this study, we first probed into the effect of sirtuin 1 inhibitor III (EX527) on hepatitis B virus (HBV) replication following inhibition of silencing information regulator 1 (SIRT1) and whether EX527 can enhance the efficacy of entecavir (ETV) in anti-HBV therapy. SIGNIFICANCE STATEMENT: This study has important theoretical and practical significance. It explores the factors influencing the replication of the hepatitis B virus from a new perspective and provides new ideas for follow-up research."

Journal • Hepatitis B • Infectious Disease • Inflammation • Oncology • IL6 • TNFA

Targeting Deacetylase Sirt-1 Reprograms Treg Function in Immune Thrombocytopenia (ASH 2024) - "Furthermore, EX527, a Sirt-1 inhibitor and SRT1720, a Sirt-1 agonist, as well as lentiviral interference of Sirt-1 in Tregs were used to verify the target of anti-CD38 therapy. In both Group B and C, significantly ameliorated thrombocytopenia, increasedproportion of splenic Tregs, down-regulated Sirt-1 in Foxp3 positive frozen sections, and restoration of anti-/pro-inflammatory cytokine profiles was demonstrated, compared with Group A. Conclusion : In summary, CD38 monoclonal antibody potentially reprograms the immunosuppressive function of Tregs by inhibiting Sirt-1, which provides a novel target for the management of ITP. This study suggested versatile mechanisms of anti-CD38 therapy in autoimmune disorders and rationalized its long-term efficacy in patients with ITP."

IO biomarker • Graft versus Host Disease • Hematological Disorders • Immune Thrombocytopenic Purpura • Immunology • Thrombocytopenia • Thrombocytopenic Purpura • CD4 • CD8 • FOXP3 • IL2RA • ITGB3 • SIRT1

Nicotinamide mononucleotide rescues Di-n-butyl phthalate induced blood-brain barrier damage via NAD+/Sirt1/FOXO1a pathway activation. (PubMed, Ecotoxicol Environ Saf) - "DBP disrupts BBB integrity and cognitive function through NAD+ depletion-driven suppression of the Sirt1/FOXO1a pathway. NMN counteracts these effects, suggesting its potential as a therapeutic agent against environmental neurotoxins."

Journal • Cognitive Disorders • Inflammation • Metabolic Disorders

Resveratrol Attenuates H2O2-induced Aging and Apoptosis in Mouse Hippocampal Neuron HT22 Cells by Activating Autophagy via the SIRT1/FoxO1 Signaling Pathway. (PubMed, Mol Neurobiol) - "EX-527 treatment suggested resveratrol could not activate autophagy when the SIRT1/FoxO1 signaling pathway was blocked. These findings indicated that resveratrol activated autophagy via SIRT1/FoxO1 signaling pathway to protect against H2O2-induced aging and apoptosis in HT22 cells."

Journal • Preclinical • BCL2 • BECN1 • CASP3 • CDKN1A

Resveratrol inhibits porcine deltacoronavirus infection by activating SIRT1 to promote interferon production in vitro. (PubMed, Microb Pathog) - "Mechanistically, Res treatment increased SIRT1 expression, and the SIRT1 inhibitor EX-527 could block Res's antiviral activity...In conclusion, Res can activate SIRT1, upregulating the interferon signaling pathway and promoting IFN-β production, thereby inhibiting PDCoV replication. As such, Res may be a promising therapeutic agent for PDCoV control, facilitating the development of novel anti-PDCoV drugs."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • IFNB1 • KEAP1 • SIRT1

Evodiamine alleviates IL-1β-induced chondrocyte damage by regulating mitochondrial dysfunction via the SIRT1/PGC-1α pathway. (PubMed, J Mol Histol) - "However, the addition of the SIRT1 inhibitor EX-527 partially attenuated the protective effects of Evo against IL-1β-induced chondrocyte injury by exacerbating mitochondrial dysfunction. Evo promotes mitochondrial biosynthesis, reduces ROS production and improves mitochondrial function by activating SIRT1/PGC-1α pathway, thereby inhibiting IL-1β-induced chondrocyte injury."

Journal • Immunology • Inflammation • Metabolic Disorders • Osteoarthritis • Pain • Rheumatology • IL1B

Estradiol alleviated chemotherapy-induced premature ovarian failure by blocking the ferroptosis via activating ESR2/Sirt1/Nrf2 pathway. (PubMed, Biochem Pharmacol) - "We also revealed that E2 alleviated cisplatin or RSL3-induced decreases in cell viability and increased lipid peroxidation (LPO) and reactive oxygen species (ROS) levels in KGN and SVOG cells...Treating KGN or SVOG cells with the Sirt1 inhibitor EX527 prevented the ability of E2 to inhibit ferroptosis and Nrf2 protein expression. We demonstrated that estrogen receptor beta (ESR2) is involved in the positive regulation of Sirt1 expression. In summary, E2 supplementation alleviates chemotherapy-induced POF by inhibiting ferroptosis through the ESR2/Sirt1/Nrf2pathway activation."

Journal • Women's Health • ER • GPX4 • HMOX1 • SLC7A11

Luteoloside alleviates bleomycin-induced pulmonary fibrosis in mice via SIRT1-mediated protective effect against alveolar epithelial cell senescence. (PubMed, Sci Rep) - "The senescence of alveolar epithelial cells plays a central role in the pathogenesis of idiopathic pulmonary fibrosis, a disease currently lacking specific therapeutic approaches. Mechanistically, we proved through the inhibition effect of EX527 that luteoloside's protective effects were mediated through SIRT1. This study provides new insights into the mechanisms through which luteoloside modulates cellular senescence and pulmonary fibrosis, offering potential pathways for the development of novel therapeutic strategies."

Journal • Preclinical • Idiopathic Pulmonary Fibrosis • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • CDKN1A • SIRT1

Liangxue Huoxue decoction protects against sepsis-induced acute lung injury by restoring gut microbiota and inhibiting inflammation and oxidative stress via the SIRT1/NF-κB/Nrf2 signaling pathway. (PubMed, Fitoterapia) - "Liangxue Huoxue decoction(LXHX) is an effective empirical traditional Chinese medicine prescription,which has been clinically used for abdominal infectious disease for many years in Tianjin Nankai Hospital.Acute lung injury (ALI) is a severe inflammatory condition that causes lung inflammation and gut microbiota disruption.The aim of this study was to investigate the effects of LXHX on cecal ligation and puncture (CLP)-induced ALI and the related mechanisms.The principal components of LXHX were identified by high-performance liquid chromatography (HPLC).The effect of LXHX on gut microbiota was determined by 16S rRNA, while its anti-inflammatory, antioxidant, and anti-apoptotic effects were evaluated in lung tissue.16S rRNA sequence analysis showed that LXHX could partially restore the composition and diversity of intestinal flora.LXHX increased the Chao,Shannon,and Simpson index of the fecal microbiota,compared to CLP group.At the class and order level,the abundance of..."

IO biomarker • Journal • Acute Lung Injury • Infectious Disease • Inflammation • Pneumonia • Respiratory Diseases • Septic Shock • BAX • BCL2 • NFE2L2