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

Ameliorative effect of sea cucumber on physical fatigue induced by forced ambulation and its underlying mechanism. (PubMed, J Pharmacol Sci) - "In contrast, EX-527, the selective Sirt1 inhibitor, abolished the SC-induced anti-fatigue effect and the enhanced Sirt1/NRF2/SOD1-GPx1-catalase pathway in the soleus muscle. Consequently, we propose that SC attenuates fatigue by modulating the Sirt1/NRF2/SOD1-GPx1-catalase pathway in the soleus muscle."

Journal • CNS Disorders • Fatigue • Psychiatry • CAT • GPX1 • SOD1

Wheat-grain moxibustion improves sleep in perimenopausal insomnia rats by regulating the SIRT1/Nrf2 signaling pathway (PubMed, Zhen Ci Yan Jiu) - "WGM can improve the sleep and spontaneous activity of PI rats, which may be related to its functions in alleviation of hypothalamic oxidative stress and pyroptosis by regulating the SIRT1/Nrf2 signaling pathway."

Journal • Preclinical • CNS Disorders • Insomnia • Sleep Disorder • CAT • HMOX1 • IL18 • IL1B • KEAP1 • NLRP3

Quercetin enhances skin flap survival via SIRT1-regulated mitophagy promotion and pyroptosis inhibition. (PubMed, J Ethnopharmacol) - "QUE promotes skin flap survival by mitigating pyroptosis via the SIRT1/NF-κB/NLRP3 pathway, while concurrently enhancing mitophagy through the SIRT1/PINK1/Parkin axis, thereby offering a novel therapeutic candidate for preventing flap necrosis."

Journal • Cardiovascular • Inflammation • Reperfusion Injury • NLRP3

Berberine Attenuates Intracranial Aneurysm Formation by Activating SIRT1 to Suppress HMGB1 Acetylation and NF-κB Signaling. (PubMed, Neurochem Res) - "The SIRT1/HMGB1/NF-κB signaling axis was investigated by Western blotting, immunofluorescence, pharmacological inhibition (EX-527), genetic manipulation (SIRT1 overexpression or HMGB1 knockdown/overexpression), and mitochondrial-targeted therapies (Antimycin A, MitoTEMPO)...By maintaining mitochondrial integrity, BBR restores bioenergetic and redox equilibrium, breaking the inflammatory-metabolic vicious cycle. These coordinated responses inhibit the formation and evolution of cerebral aneurysms."

Journal • Cardiovascular • Inflammation • Metabolic Disorders • Vascular Neurology • ELANE • HMGB1 • SIRT1

Activation of autophagy through Sirt1/AMPK/mTOR mediates the protective effects of fraxin against insulin resistance and steatosis in rats. (PubMed, Exp Anim) - "The specific autophagy inhibitor chloroquine (CQ) was used to verify whether the regulatory effects of fraxin were dependent on autophagy activation. Mechanistically, fraxin activated autophagy and modulated the Sirt1/AMPK/mTOR pathway, which were abolished by the Sirt1 inhibitor EX527. In conclusion, fraxin alleviates IR and hepatic steatosis in HFD/STZ-induced diabetic rats by activating autophagy through Sirt1/AMPK/mTOR pathway, suggesting its potential as a therapeutic agent for diabetes-associated metabolic disorders."

Journal • Preclinical • Diabetes • Dyslipidemia • Metabolic Disorders • Type 2 Diabetes Mellitus • AMPK • IRS1 • SIRT1

Ginsenoside Rg2 ameliorates acute cold exposure/rewarming-induced myocardial injury via modulating HMGB1/TLR4/NF-κB and PGC-1α signaling pathways: Role of SIRT1. (PubMed, Phytomedicine) - "This study provides the first evidence that ginsenoside Rg2 has considerable cardioprotective effects against ACE/R. The cardioprotective mechanism is mediated through SIRT1 activation, which subsequently suppresses the HMGB1/TLR4/NF-κB-mediated inflammatory cascade and enhances PGC-1α-driven mitochondrial biogenesis. By clarifying the pharmacological actions of Rg2 and presenting a fresh perspective on the pathophysiology of ACE/R-induced cardiovascular injury, these results underscore the compound's promise as a treatment."

Journal • Cardiovascular • Inflammation • Metabolic Disorders • HMGB1 • TLR4

Succinate Mediates Immune-Angiogenic Response by Activating Macrophage M2 Polarization in Oxygen-Induced Retinopathy. (PubMed, FASEB J) - "Ex527 inhibited macrophage M2-type polarization after succinate induction, preventing abnormal retinal vascular development in oxygen-induced retinopathy (OIR) mice...In summary, succinate regulates macrophage M2 polarization via the SIRT1/AMPKα pathway and mediates RNV formation. It also influences endothelial cell angiogenic capacity by promoting VEGFR2 internalization."

Journal • Age-related Macular Degeneration • Cardiovascular • Inflammation • Retinal Disorders • CXCR3 • KDR • RBP4 • SUCNR1

Oleuropein restores oocyte competence during SIRT1 inhibition via SIRT1/NRF2-mediated redox and metabolic reprogramming in porcine oocytes. (PubMed, Theriogenology) - "Herein, we investigated whether oleuropein (OLE) restores oocyte quality compromised by the SIRT1 inhibitor EX527...The SIRT1 activator resveratrol (2 μM) produced comparable effects. Collectively, these results indicate that OLE mitigates the detrimental effects of SIRT1 inhibition via the SIRT1/NRF2 axis and promotes cytoplasmic maturation, suggesting potential applications in assisted reproduction."

Journal • Preclinical • Metabolic Disorders • ACACA • NRF1 • PLIN2 • PPARG • SOD2

Homoplantaginin alleviates high glucose-induced vascular endothelial barrier dysfunction by regulating Yes-associated protein 1. (PubMed, Phytomedicine) - "HPG protects against HG-mediated VE barrier dysfunction via the YAP1/SIRT1/HMGB1 pathway. This study provides valuable insights into HPG as a potential candidate compound for the treatment of diabetic macrovascular complications."

Journal • Diabetes • Dyslipidemia • Inflammation • Metabolic Disorders • Type 1 Diabetes Mellitus • CDH5 • CLDN1 • HMGB1 • OCLN • TJP1 • YAP1

Nuciferine Ameliorates Lipotoxicity-Mediated Myocardial Ischemia-Reperfusion Injury by Reducing Reverse Electron Transfer Mediated Oxidative Stress. (PubMed, Nutrients) - "The Sirtuin 1 (Sirt1) inhibitor selisistat (EX527) abolished nuciferine's protection, while DMM mirrored its efficacy, underscoring nuciferine's dual role in inhibiting SDH-mediated RET and activating Sirt1 in alleviating I/R injury under metabolic stress conditions. These findings suggest that nuciferine confers cardioprotection by simultaneously attenuating RET-related oxidative stress and activating Sirt1."

Journal • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury

SIRT1: An Emerging Role in Regulated Cell Death in Ischemic Stroke. (PubMed, CNS Neurol Disord Drug Targets) - "Moreover, SIRT1 modulators, including resveratrol, SRT1720, EX-527, and Sirtinol, have demonstrated neuroprotective effects in preclinical and clinical trials. Thus, future research should aim to overcome these obstacles and develop novel SIRT1 modulators with better clinical translation potential, ultimately improving IS treatment outcomes. This review further explores the therapeutic implications of SIRT1 modulation in IS treatment and highlights the urgent need for more clinical validation to support its broader application."

Journal • Cardiovascular • Inflammation • Ischemic stroke • NLRP3 • NOS3 • RIPK1 • SIRT1

High-intensity interval training promotes cartilage repair and ameliorates ferroptosis via SIRT1 in osteoarthritis. (PubMed, Biochem Biophys Res Commun) - "Pharmacologic inhibition of SIRT1 (EX527) reversed these benefits, underscoring SIRT1's pivotal role in mediating HIIT's therapeutic effects...In conclusion, while direct evidence of ferroptosis markers such as lipid peroxidation and mitochondrial changes is lacking, HIIT alleviates ferroptosis-associated cartilage damage and promotes cartilage repair in OA through SIRT1-dependent mechanisms. These findings support HIIT as a potential non-pharmacological strategy for OA management and provide a mechanistic basis for exercise-based interventions aimed at preserving joint function and reducing OA-related disability."

Journal • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology • ACSL4 • GPX4 • IL1B • SIRT1

SGPP2 Ameliorates Chronic Heart Failure by Attenuating ERS via the SIRT1/AMPK Pathway. (PubMed, Curr Issues Mol Biol) - "Rescue experiments further demonstrated that both Tu and EX527 significantly promoted ERS and cellular injury, thereby counteracting the protective effects of SGPP2. SGPP2 alleviates IHF by inhibiting ERS modulated by the SIRT1/AMPK pathway."

Journal • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • CLU • CTSK • RSAD2 • SLC2A1 • STAT3

Nutritional Modulation of Melatonin-SIRT1 Signaling by Octanoic Acid-Rich Enteral Nutrition Protects Against Radiation-Induced Intestinal Injury. (PubMed, Food Sci Nutr) - "Then mice were randomly assigned to five groups: Sham, RI, RI + OA-rich EN, RI + OA-rich EN + Luzindole, RI + OA-rich EN + EX527 to examine whether OA-rich EN alleviated RIII through the melatonin-silent information regulator 1 (SIRT1) pathway...This is the first confirmation that OA-rich EN alleviated RIII by promoting melatonin secretion, which in turn activated the SIRT1/PGC-1α/PPARγ pathway. Our findings highlight OA-rich EN as a promising nutritional strategy to improve intestinal health and reduce treatment-related complications in patients receiving abdominal radiotherapy."

Journal • Oncology

Oxymatrine Alleviates Atherosclerosis by Regulating Macrophage Senescence via the SIRT1-P53 Signaling Pathway. (PubMed, Phytother Res) - "Functional validation assays revealed that the effects of OMT were aborted by EX527 and SIRT1 shRNA...Furthermore, Idasanutlin attenuated the functional effects of OMT, which indicated the pivotal role of P53...Consequently, this process delays macrophage senescence-induced foam cell formation, ultimately ameliorating AS. Our findings suggest OMT as a promising therapeutic candidate for AS."

Journal • Atherosclerosis • Cardiovascular • Targeted Protein Degradation • APOE • SIRT1

Galangin enhances skin flap survival by inhibiting ferroptosis via SIRT1-mediated FOXO1 deacetylation. (PubMed, Burns) - "Gal enhances skin flap survival by suppressing ferroptosis, oxidative stress, and inflammation via activation of the SIRT1/FOXO1 pathway."

Journal • Cardiovascular • Inflammation • Reperfusion Injury • SIRT1

Electroacupuncture alleviates depression-like behavior after spinal cord injury via SIRT1/HMGB1 signaling axis mediated ferroptosis. (PubMed, Behav Brain Res) - "These findings demonstrate that EA protects against SCI-induced depression by inhibiting ferroptosis through activation of the SIRT1/HMGB1 signaling axis. This study unveils a novel mechanism underlying EA's neuroprotective effects in SCI-related depression and highlights ferroptosis modulation as a potential therapeutic strategy. By integrating traditional Chinese medicine with modern molecular pathophysiology, this work offers new insights into EA's mechanisms in treating SCI-induced depression and proposes a promising avenue for future therapeutic interventions."

Journal • CNS Disorders • Depression • Inflammation • Orthopedics • Psychiatry • GPX4 • HMGB1

Electroacupuncture Pretreatment Ameliorates Perioperative Neurocognitive Disorder in Aged Mice by Inhibiting Ferroptosis Through the SIRT1/NRF2/GPX4 Pathway. (PubMed, J Cell Mol Med) - "The PND model was established using sevoflurane anesthesia and tibial fracture surgery...Additionally, intraperitoneal injection of silent information regulator sirtuin 1 (SIRT1) inhibitor EX527 (5 mg/kg) was administered for five consecutive days before surgery and intraperitoneal injection of ferrostatin-1 (Fer-1) (2 mg/kg) was administered before anesthesia...In conclusion, the occurrence and progression of PND are closely related to ferroptosis. EA stimulation of the Baihui and Dazhui acupoints can improve PND, possibly by regulating ferroptosis through the SIRT1/NRF2/GPX4 signalling pathway."

Journal • Preclinical • Anesthesia • CNS Disorders • Cognitive Disorders • Developmental Disorders • Musculoskeletal Diseases • Orthopedics • GPX4 • SLC7A11 • TFRC

LncRNA SNHG1 Knockdown Ameliorates HIV-1 gp120V3 Loop-Induced Microglial Neuroinflammation by Regulating the Autophagy Process. (PubMed, Inflammation) - "In contrast, the Sirt1 inhibitor EX527 activated the Wnt pathway, decreased the LC3B II/I ratio, and worsened neuroinflammation. Thus, lncRNA SNHG1 knockdown might regulate autophagy via the Sirt1-Wnt pathway to alleviate HIV-1 gp120-induced neuroinflammation, offering a new approach for HAND prevention and treatment."

Journal • CNS Disorders • Cognitive Disorders • Developmental Disorders • Human Immunodeficiency Virus • Infectious Disease • Inflammation • SNHG1

Trichosanthes kirilowii Maximowicz attenuates dexamethasone induced atrophy in C2C12 myotubes through a Sirtuin 1 associated mechanism. (PubMed, Sci Rep) - "TK also restored Sirtuin 1 (SIRT1) expression suppressed by DEX, and inhibition of SIRT1 with EX527 reduced TK's beneficial effects, indicating a SIRT1-dependent mechanism...These findings suggest that TK protects against muscle atrophy by modulating SIRT1-related anabolic and catabolic pathways. TK may offer therapeutic potential for sarcopenia and glucocorticoid-induced muscle wasting."

Journal • Muscular Atrophy • Sarcopenia • FBXO32 • Myogenin • SIRT1

Nicotinamide riboside alleviates sepsis-induced acute kidney injury by suppressing ferroptosis. (PubMed, J Mol Med (Berl)) - "Sepsis-induced acute kidney injury (SAKI) is the predominant type of acute kidney injury encountered in intensive care units. Using EX527 or SIRT1 knockdown abolished NR-mediated ferroptosis alleviation. SIRT1 overexpression mimicked NR's protective function in inhibiting ferroptosis."

Journal • Acute Kidney Injury • Chronic Kidney Disease • Critical care • Infectious Disease • Nephrology • Renal Disease • Septic Shock • ACSL4 • GPX4

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