oltipraz (PMK-N01GI1) / Canopus BioPharma, Pharmaking - LARVOL DELTA

The Nrf2/GPX4 antioxidant pathway suppresses ferroptosis to protect against hearing impairment in cochlear ischemia-reperfusion injury. (PubMed, Int Immunopharmacol) - "This study demonstrates that ferroptosis mediates I/R-induced cochlear damage and that the Nuclear factor erythroid 2-related factor 2 (Nrf2) agonist oltipraz (OPZ) confers protection...OPZ (75 mg/kg) administration preserved SV ultrastructure and restored hearing function (threshold improvement of ∼26 dB). These data highlight ferroptosis as a key driver of I/R-induced SSNHL and establish Nrf2/HO-1 activation as a therapeutic strategy, with OPZ showing potential clinical relevance."

Journal • Cardiovascular • Otorhinolaryngology • Reperfusion Injury • GPX4

Oxygen concentration modulates HDAC1-Mediated regulation of osteogenic signaling pathways in dental pulp cells. (PubMed, Front Cell Dev Biol) - "Pharmacological inhibition studies using Oltipraz (HIF-1α inhibitor) and Valproic acid (HDAC inhibitor) elucidated pathway interactions...The biphasic response to hypoxia gradients suggests microenvironmental optimization strategies could enhance pulp regenerative outcomes. These insights provide mechanistic foundations for developing HDAC-targeted approaches in endodontic regeneration."

Journal • HDAC1 • HIF1A • RUNX2

Oltipraz ameliorates pressure overload-induced pathological cardiac hypertrophy in mice. (PubMed, J Cardiovasc Pharmacol) - "Interestingly, our results also demonstrated that Nrf-2 knockdown abolished the protective effects of OPZ in vitro. Taken together, these data revealed that OPZ ameliorates the pathological cardiac hypertrophy via activating Nrf-2 signaling."

Journal • Preclinical • Inflammation

Upregulation of Nrf2 attenuates Angiostrongylus cantonensis-induced parasitic meningitis in mice. (PubMed, Parasit Vectors) - "Our findings revealed the albendazole-Nrf2 activator co-treatment effectively suppressed excessive inflammation compared with the anthelmintics drug (albendazole) treatment alone, and Nrf2 activation might produce a synergistic effect in the inflammatory response of the brain in mice with angiostrongyliasis."

Journal • Preclinical • CNS Disorders • Infectious Disease • Inflammation • Oncology • IL17A • IL6 • KIT • NQO1 • TNFA

Nrf2 alleviates acute ischemic stroke induced ferroptosis via regulating xCT/GPX4 pathway. (PubMed, Free Radic Biol Med) - "In vitro experiments, we investigated the mechanism of action of Nrf2 on the establishment of a ferroptosis cell model induced by Erastin by overexpressing or silencing Nrf2 expression using shRNA in SH-SY5Y cells.Ferroptosis played an important role in AIS, and Fer-1 inhibited iron accumulation and alleviated neuronal damage caused by AIS.Oltipraz attenuated AIS-induced neuronal damage and cerebral infarction by increasing cortical blood flow (CBF). Furthermore, both ML385 treatment and Nrf2 knockout mice exacerbated oxidative stress injury and iron overload and downregulated the expression of both xCT and GPX4. Consistent with the in vivo results, Nrf2 conferred ferroptosis resistance in vitro upon exposure to compounds that induce ferroptosis, by modulating the xCT/GPX4 pathway.The present study confirmed that Nrf2 could attenuate AIS-induced neuronal ferroptosis and oxidative stress by regulating xCT/GPX4."

Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Ischemic stroke • GPX4 • NFE2L2 • SLC7A11

Fifty Years of Aflatoxin Research in Qidong, China: A Celebration of Team Science to Improve Public Health. (PubMed, Toxins (Basel)) - "A series of placebo-controlled clinical trials were conducted using oltipraz (a repurposed drug), chlorophyllin (an over-the-counter drug), and beverages prepared from 3-day-old broccoli sprouts (rich in the precursor phytochemical for sulforaphane)...This 50-year effort to understand the etiology of liver cancer in Qidong provides the strongest evidence for aflatoxin mitigation as a public health strategy for reducing liver cancer burden in exposed, high-risk populations. Also highlighted are the challenges and successes of international team science to solve pressing public health issues."

Clinical • Journal • Review • Hepatitis B • Hepatology • Infectious Disease • Liver Cancer • Oncology • Solid Tumor

Down-regulation of Selenoprotein K impairs the proliferation and differentiation of chicken skeletal muscle satellite cells by inhibiting the Nrf2 antioxidant signaling pathway. (PubMed, Free Radic Res) - "Notably, SELENOK knockdown-induced inhibition of SMSCs proliferation and differentiation was alleviated by Oltipraz, an activator of the Nrf2 pathway. This study provided novel insights, demonstrating that SELENOK is a key player in SMSCs proliferation and differentiation by influencing the Nrf2 antioxidant signaling pathway."

Journal • Targeted Protein Degradation • CAT • CCND1 • GPX4 • HMOX1 • KEAP1 • MYF6 • NES • PAX7 • SQSTM1

IL-27 regulates macrophage ferroptosis by inhibiting the Nrf2/HO1 signaling pathway in sepsis-induced ARDS. (PubMed, Inflamm Res) - "Oltipraz may alleviate ARDS-related lung injury by up-regulating Nrf2 expression and concurrently inhibiting macrophage ferroptosis."

Journal • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Septic Shock • GPX4 • NFE2L2 • PACERR • PTGS2

CT-sensitized nanoprobe for effective early diagnosis and treatment of pulmonary fibrosis. (PubMed, J Nanobiotechnology) - "Moreover, a dual-drug combination of oltipraz and rosiglitazone was co-loaded into the nanoparticles for the treatment of early-diagnosed PF. Remarkable therapeutic efficacy was observed in model mice with early PF using these nanoparticles. Our findings present a promising strategy for the early diagnosis of PF, potentially offering a valuable time window for effective treatment of this life-threatening disease."

Journal • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Unraveling morphine tolerance: CCL2 induces spinal cord apoptosis via inhibition of Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis. (PubMed, Brain Behav Immun) - "Our data emphasize that chemokine CCL2 inhibited the Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis, alleviating the occurrence of apoptosis in spinal cord, thereby participating in morphine tolerance. This may provide new targets for the treatment of morphine tolerance."

Journal • Inflammation • Neuralgia • Pain • CCL2

Effects of Oltipraz on the Glycolipid Metabolism and the Nrf2/HO-1 Pathway in Type 2 Diabetic Mice. (PubMed, Drug Des Devel Ther) - "The negative control (NC), T2DM model (T2DM), and T2DM models treated with oltipraz (OLTI) and metformin (MET) were constructed. In summary, OLTI improves blood glucose and insulin resistance, decreases blood lipid metabolism, reduces inflammation and apoptosis, suppresses oxidative stress through the Nrf2/HO-1 signaling pathway, mitigates pancreatic and liver tissue injury, and enhances pancreatic β-cell insulin secretion, thereby mitigating T2DM symptoms. Moreover, Reg3g could be an important target for OLTI treatment of T2DM."

Journal • Preclinical • Diabetes • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Oncology • Type 2 Diabetes Mellitus

Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Activates Hedgehog Interacting Protein (Hhip)-Mediated Renal Tubular Cell Senescence in Diabetic Akita Mice (KIDNEY WEEK 2024) - "In vitro, Nrf2 activators (oltipraz or CDDO-Me) significantly stimulated Hhip gene expression (promotor activity, Hhip mRNA and protein expression), while also promoted cellular senescence. Nrf2 activates Hhip gene expression in RPTCs. In diabetes, activation of both Nrf2 and Hhip works in concert to accelerate tubular senescence in DKD."

Preclinical • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Glomerulonephritis • Metabolic Disorders • Nephrology • Renal Disease • CDKN1A • HHIP

Heat exposure promotes sarcopenia via gut microbiota-derived metabolites. (PubMed, Aging Cell) - "And Nrf2 activator (Oltipraz) supplementation alleviates muscle atrophy and dysfunction induced by heat exposure. Our findings reveal the detrimental effects of heat exposure on muscle function and provide new strategies for treating sarcopenia."

Journal • Metabolic Disorders • Muscular Atrophy • Sarcopenia • Transplantation

NRF2-HIF2α Signaling Attenuates Endothelial Cell Senescence and Maintains Intercellular Junctions in Diabetes. (PubMed, Int J Biol Sci) - "Through its simultaneous modulation of NRF2 and HIF-2α, Oltipraz significantly reduces cellular senescence and prevents the deterioration of intercellular junctions in HUVECs subjected to high glucose concentrations (25 mM). Our research positions Oltipraz as a promising therapeutic candidate for mitigating diabetes-induced vascular endothelial damage, potentially offering benefits against diabetes-related atherosclerosis and valvular calcification."

Journal • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Metabolic Disorders • Targeted Protein Degradation • CDH1 • EPAS1 • GPX1 • NOX4 • OCLN

Oltipraz attenuated cerebral ischemia-reperfusion injury through inhibiting the oxidative stress and ferroptosis in mice. (PubMed, Int Immunopharmacol) - "Finally, mechanistic analysis revealed that OPZ significantly upregulated the Nrf2 expression and Nrf2 knockout (Nrf2 KO) abolished the OPZ-mediated protective effects. Taken together, these findings demonstrate that OPZ ameliorates cerebral I/R injury by suppressing the oxidative stress and ferroptosis."

Journal • Preclinical • Cardiovascular • Reperfusion Injury • ACSL4 • GPX4 • NFE2L2 • SLC7A11

Unveiling the Potential of Estrogen: Exploring its Role in Neuropsychiatric Disorders and Exercise Intervention. (PubMed, Pharmacol Res) - "Hence, we review how the estrogen signaling mediates the mechanism of exercise intervention in neuropsychiatric disorders. We aim to provide a theoretical perspective for neuropsychiatric disorders affecting female health and provide theoretical support for the design of exercise prescriptions."

Journal • Review • Alzheimer's Disease • CNS Disorders • Depression • Mental Retardation • Movement Disorders • Parkinson's Disease • Psychiatry • APP • ER • MYCN • NLRP3

Aflatoxin B induces infertility, fetal deformities, and potential therapies. (PubMed, Open Med (Wars)) - "Substances such as esculin, selenium, gynandra extract, vitamins C and E, oltipraz, and CDDO-Im are potential therapies for AFB. Thus, this review elucidates the pivotal pathogenic roles of AFB in infertility, fetal deformities, and potential therapies because AFB toxicity is a key problem globally."

Journal • Review • CNS Disorders • Infertility • Oncology • Ophthalmology • Sexual Disorders • Ventriculomegaly

Activation of Nrf2 antioxidant signaling alleviates gout arthritis pain and inflammation. (PubMed, Biomed Pharmacother) - "Pharmacologically activating Nrf2 by activator oltipraz (50, 100 or 150 mg/kg, intraperitoneal) at 1 h before and 5, 23, 47 h after model establishment dose-dependently inhibited joint inflammation, mechanical and heat hypersensitivities in model mice...These results suggest pharmacologically activating Nrf2 alleviates gout pain, gait impairments, inflammation and peripheral sensitization via Nrf2-dependent antioxidant mechanism. Targeting Nrf2 may represent a novel treatment option for gout arthritis."

Journal • Gout • Immunology • Inflammation • Inflammatory Arthritis • Musculoskeletal Pain • Pain • Rheumatology

Mechanism of Nrf2/miR338-3p/TRAP-1 pathway involved in hyperactivation of synovial fibroblasts in patients with osteoarthritis. (PubMed, Heliyon) - "It was confirmed by in vitro assays that oltipraz (agonists of Nrf2) treatment effectively inhibited the hyperactivation of HFLS induced by TGF-β1, and the effects of oltipraz could be reversed by the exogenous TRAP-1. In short, our research has revealed for the first time that Nrf2/miR338-3p/TRAP-1 pathway was involved in hyperactivation of HFLS in OA patients, Nrf2 has the potential to be used as therapy and new drug target of OA."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • MIR338 • TGFB1

SIRT7 PROTECTS AGAINST OXALIPLATIN INDUCED LIVER INJURY VIA MAINTAINING NRF2 STABILIZATION AND ACTIVATION (AASLD 2023) - "Background: Oxaliplatin (Oxa) is the core therapeutic agents which widely used for treatment of advanced stage of colorectal cancer patients, but it occasionally causes hepatotoxicity characterized by sinusoidal dilatation, hepatic plate atrophy and venular obstruction. We identify previously unidentified protective role of SIRT7 in chemotherapy drugs induced liver injury via acting as a positive regulator of Nrf2 protein level and activation."

Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Liver Failure • Metabolic Disorders • Oncology • Solid Tumor • KEAP1 • SIRT7

NRF2 Deficiency Attenuates Diabetic Kidney Disease in Db/Db Mice via Down-Regulation of Angiotensinogen, SGLT2, CD36, and FABP4 Expression and Lipid Accumulation in Renal Proximal Tubular Cells. (PubMed, Antioxidants (Basel)) - "NRF2 KO attenuated the stimulatory effect of the Nrf2 activator, oltipraz, on AGT, SGLT2, and CD36 expression and high-glucose/free fatty acid (FFA)-stimulated lipid accumulation in HK2. Kidneys from T2D patients exhibited markedly higher levels of CD36 and FABP4 in RPTCs than kidneys from non-diabetic patients. These data suggest that NRF2 exacerbates DKD through the stimulation of AGT, SGLT2, CD36, and FABP4 expression and lipid accumulation in RPTCs of T2D."

Journal • Preclinical • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • CD36 • FABP4

Efficacy of oltipraz in preventing acetaminophen-induced liver injury in mice. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "This suggests that NQO1 is responsible for the enhanced GSH recovery and protection against APAP-induced liver injury seen in OPZ-treated mice. In summary, OPZ protects against APAP-induced liver injury by inducing NQO1 expression and resulting in improved GSH recovery."

Journal • Preclinical • Hepatology • Liver Failure • Oncology • CYP2E1 • NQO1

Effect of Oltipraz on urethral healing: An experimental study. (PubMed, Prog Urol) - "According to our results, we cannot suggest OPZ in the treatment of urethral injury. Future studies in this area are needed."

Journal • Anesthesia • Fibrosis • Immunology • Inflammation • Pediatrics • KDR • TGFB1

First non-covalent, druglike, and orally bioavailable inhibitors of thioredoxin glutathione reductase with schistosomicidal activity in vivo (ACS-Sp 2023) - "Both potassium antimonial tartrate and oltipraz inhibit TGR and were used clinically for schistosomiasis treatment but their use was discontinued due to unacceptable side effects. Most importantly, novel druglike and orally bioavailable TGR inhibitors demonstrated efficacy against schistosome infections in mice, meeting the criteria for lead progression indicated by WHO and significantly outperformed praziquantel against juvenile worms. These findings open a new avenue for the development of therapeutics for the treatment of schistosomiasis."

Preclinical • Infectious Disease

Dopamine inhibits group 2 innate lymphoid cell-driven allergic lung inflammation by dampening mitochondrial activity. (PubMed, Immunity) - "Augmentation of OXPHOS activity with oltipraz antagonized the inhibitory effect of dopamine. Local administration of dopamine alleviated allergen-induced ILC2 responses and airway inflammation. These findings demonstrate that dopamine represents an inhibitory regulator of ILC2 responses in allergic airway inflammation."

Journal • Immunology • Inflammation • Pneumonia • Respiratory Diseases • DRD1