Panzem (2-methoxyestradiol) / CASI - LARVOL DELTA

BLCL-2ME-02: Multiple-Ascending Doses of 2-Methoxyestradiol in Healthy Non-Pregnant Female Participants. (clinicaltrialsregister.eu) - P1 | N=72 | Recruiting | Sponsor: Laboratorios Leon Farma S.A.

New P1 trial

Abatement of acrylonitrile-induced gastric injury by 2-Methoxyestradiol through inhibition of TLR4/MYD88/phospho-p38 MAPK axis. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Conclusively, 2ME ameliorates ACN-induced gastric injury. This protective effect may be associated with the antioxidant, anti-inflammatory, and anti-apoptotic properties of 2ME, in addition to a potential modulation of the TLR4/MYD88/phospho-p38 MAPK signaling pathway."

IO biomarker • Journal • B Cell Lymphoma • Lymphoma • Oncology • BCL2 • CAT • IL6 • MYD88 • TLR4 • TNFA

Taohong Siwu Decoction Regulates MSC-Mediated H-Type Angiogenesis to Accelerate Bone Fracture Healing Through VHL/HIF-1α Ubiquitination. (PubMed, Mediators Inflamm) - "Additionally, MSCs were treated with paeoniflorin and 2-methoxyestradiol (2-ME2) to explore the effects of paeoniflorin...In summary, TSD affects H-type angiogenesis and MSCs homing during the healing process of fractured mice through the HIF-1α axis. TSD regulated MSC-mediated H-type angiogenesis to accelerate fracture healing through VHL/HIF-1α ubiquitination."

Journal • Musculoskeletal Diseases • Orthopedics • Targeted Protein Degradation • Von Hippel-Lindau Syndrome • CD31 • EMCN • HIF1A • PECAM1 • THY1 • VHL

Hypoxia-Inducible-Factor mediates tissue-specific mitochondrial responses to acute hypoxia in mice but not in rats. (PubMed, Respir Physiol Neurobiol) - "To determine whether these effects were HIF-dependent, a group of animals were also treated with deferoxamine (a HIF stabilizer) under normoxia or with 2-methoxyestradiol (a HIF inhibitor) under hypoxia. In contrast, OCR remained unchanged in the cerebral cortex of mice and in both tissues of rats, indicating species- and tissue-specific regulation. These findings reveal that HIF activation under acute hypoxia selectively modulates liver mitochondrial function in mice but not in rats, supporting the view that interspecific differences in HIF-mediated metabolic regulation contribute to the superior hypoxic tolerance of mice."

Journal • Preclinical • HIF1A

Electroacupuncture improves hypoxic stress and energy metabolism to alleviate vascular cognitive impairment through activation of the HIF-1α/p53/NGB signaling pathway in rats. (PubMed, Iran J Basic Med Sci) - "Thirty minutes prior to EA, the hypoxia-inducible factor-1α (HIF-1α) inhibitor 2-methoxyestradiol (2ME2) was injected intraperitoneally...Notably, the beneficial effects of EA on cerebral energy metabolism were abolished by 2ME2 in VCI model rats. EA alleviated BCCAO-induced neurological impairment and cognitive dysfunction in rats, possibly by reducing hypoxic stress and enhancing energy metabolism in the cortex and hippocampus, potentially through modulation of the HIF-1α/p53/NGB signaling pathway."

Journal • Preclinical • Alzheimer's Disease • Cardiovascular • Cognitive Disorders • HIF1A • HMOX1

BMAL1 Downregulation Exacerbates Age-related Nonalcoholic Steatohepatitis by Promoting NLRP3 Inflammasome Activation via HIF-1ɑ-mediated Glycolysis. (PubMed, Free Radic Biol Med) - "This study revealed a novel mechanism in which BMAL1 downregulation under aging and HFD conditions promotes NASH progression by binding to HIF-1α and modulating the glycolysis-NLRP3 inflammasome axis."

Journal • Acute Myelogenous Leukemia • Fibrosis • Hepatitis B • Hepatology • Immunology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • ARNTL • BMAL1 • HIF1A • NLRP3

Hypoxic conditions confer chemoresistance to crizotinib but not to imatinib in chronic myeloid leukemia cells. (PubMed, Hematol Transfus Cell Ther) - "In summary, this study shows the critical role of selective targeting of components of the HIF1α signaling pathway for the complete eradication of chronic myeloid leukemia cells."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • HIF1A

Combined HIF-1α blockade and CHIR99021 treatment reverses pulmonary fibrosis via modulation endothelial-to-mesenchymal transition. (PubMed, iScience) - "We demonstrate that the dual inhibition of HIF-1α and GSK-3β with 2-methoxyestradiol (2-ME) and CHIR99021 reverses fibrotic alterations in endothelial cells and pulmonary fibroblasts, accompanied by reduced DNA damage foci...In fibroblasts from patients with idiopathic pulmonary fibrosis, the therapy reduced profibrotic gene expression, proliferation, and matrix remodeling. These findings highlight dual HIF-1α/GSK-3β targeting to reverse fibrosis through coordinated EndMT suppression, DNA repair, and chromatin remodeling."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • HIF1A

Mucinous cystic neoplasms of the pancreas demonstrate in situ production of estrogen. (PubMed, Front Cell Dev Biol) - "We identified that relative to histologically normal pancreas, and intraductal papillary mucinous neoplasm (IPMN), the stroma in MCN expresses significantly greater levels of estrone (E1), estradiol (E2), estriol (E3), 2-hydroxyestradiol (2-OHE2), 2-methoxyestrone (2-MeOE1), 2-methoxyestradiol (2-MeOE2) and 16α-hydroxyestrone (16α-OHE1), at levels similar to those seen in the stroma in the normal ovary. These findings establish the functional capability of the ova rian-type stroma in MCN tumors for endogenous hormone production and show that the levels of estrogen in the stroma of MCN tumors approach those of the ovary. These findings serve as a basis for future studies examining the systemic effects of estrogen and the effects of estrogen on tumor progression, both in MCN tumors and tumor metastatic to the ovary."

Journal • CNS Tumor • Oncology • Pancreatic Cancer • Solid Tumor

Hypoxia-induced USP13 expression drives ferroptosis resistance and tumor immune evasion in hepatocellular carcinoma through the stabilization of ACLY. (PubMed, Cell Death Discov) - "A USP13 inhibitor, 2-Methoxyestradiol (2-Met), was used to evaluate its therapeutic efficacy...Pharmacological inhibition or knockdown of USP13 impedes HCC progression, induces ferroptosis, and enhances T cell-mediated cytotoxic effects. These results highlight that USP13 could be a promising therapeutic target for HCC."

Journal • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • CD8 • HIF1A • USP13

2-Methoxyestradiol alleviates E. coli-induced endometritis in rats via inhibition of TLR-4/MyD88/NF-κB axis. (PubMed, Eur J Pharmacol) - "Finally, 2 ME significantly inhibited the expression of Toll-like receptor-4 (TLR-4), myeloid differentiation primary response 88 (MyD88), and nuclear factor-kappa B (NF-κB). In conclusion, 2 ME inhibits E. coli-induced endometritis in rats via modulation of the TLR-4/MyD88/NF-κB axis."

IO biomarker • Journal • Preclinical • B Cell Lymphoma • Endometriosis • Infectious Disease • Infertility • Inflammation • Lymphoma • Oncology • Sexual Disorders • CCL2 • IL6 • MPO • MYD88 • TLR4 • TNFA

Transcriptional profiling uncovers microglial HIF-1α signaling as a therapeutic target of radiation-induced brain injury. (PubMed, Free Radic Biol Med) - "Pharmacological inhibition of HIF-1α with 2-methoxyestradiol led to partial recovery of cognitive function and selectively suppressed the expression of Ccl2, a key HIF-1α-associated chemokine implicated in neuroinflammatory signaling. These findings highlight the subtype-specific vulnerability of microglia to radiation and underscore the central role of HIF-1α-mediated transcriptional changes in RIBI. Targeting the microglial HIF-1α-Ccl2 axis may thus offer a promising strategy to mitigate late-onset cognitive dysfunction following cranial irradiation."

Journal • Brain Cancer • CNS Disorders • Cognitive Disorders • Oncology • Solid Tumor • Vascular Neurology • CCL2 • HIF1A

Estradiol Downregulates MicroRNA-193a to Mediate Its Anti-Mitogenic Actions on Human Coronary Artery Smooth Muscle Cell Growth. (PubMed, Cells) - "Interestingly, the PDGF-BB-induced miR-193a formation in SMCs was also abrogated by 2-methoxyestradiol (2ME), an endogenous E2 metabolite that inhibits SMC growth via an ER-independent mechanism...Importantly, E2 prevents PDGF-BB-induced SMC growth by downregulating miR-193a formation in SMCs. Since, miR-193a antimir prevents SMC growth as well as cuff-induced vascular remodeling, it may represent a promising therapeutic molecule against cardiovascular disease."

Journal • Cardiovascular • Coronary Artery Disease • Eye Cancer • Oncology • Retinal Disorders • Solid Tumor • CCND1 • CDK4 • MIR193A • PCNA

2-Methoxyestradiol Treatment Prevents Graft-versus-Host Disease While Preserving Graft-versus-Leukemia Effect in Mice. (PubMed, bioRxiv) - "Furthermore, 2ME2 therapy is effective in preventing GVHD while preserving graft-versus leukemia (GVL) activity in mice. Our findings indicate that 2ME2 could be a novel and effective treatment for GVHD patients."

Journal • Preclinical • CNS Disorders • Graft versus Host Disease • Hematological Malignancies • Immunology • Inflammatory Arthritis • Leukemia • Multiple Sclerosis • Oncology • Rheumatoid Arthritis • Rheumatology • CD4 • CD8 • IFNG • IL2

Ramulus Mori (Sangzhi) Alkaloids Improve Pancreatic β-Cell Function Through Gut Microbial and Intra-Islet 2-Methoxyestradiol Biosynthesis. (PubMed, Biomedicines) - "In vitro, 2-ME suppressed HIF-1α signaling and promoted insulin secretion, indicating that 2-ME may act as a crucial mediator of the beneficial effects of SZ-A. SZ-A improve β-cell function by increasing 2-ME levels via gut microbiota modulation and islet production, ultimately suppressing HIF-1α signaling and restoring β-cell homeostasis."

Journal • Diabetes • Type 2 Diabetes Mellitus • COMT • HIF1A

Development of an HPLC-FLD Method for Estradiol and Metabolites: Application of Solid-Phase Microextraction. (PubMed, Int J Mol Sci) - "Good linearity was observed for estradiol, 2-hydroxyestradiol, and 2-methoxyestradiol (10-300 ng/mL; R2 = 0.9893-0.9995)...Solid-phase microextraction (SPME) offered advantages over liquid-liquid extraction. The method is suitable for quantifying estrogens in the 10 ng/mL-1 µg/mL range."

Journal

cJun-N-terminal kinase activity and mitosis perturbation drive the 2-methoxyestradiol-mediated enhancement of viral oncolysis by Epizootic Hemorrhagic Disease Virus-Tel Aviv University. (PubMed, Sci Rep) - "The findings suggest that combining OVs with MTAs, specifically EHDV-TAU and 2ME2, may exploit the enhanced susceptibility of cell-cycle-perturbed cancer cells to viral infection and cell death pathways. Such combinations may improve virus-based therapies for BC and potentially other cancers."

IO biomarker • Journal • Bladder Cancer • Genito-urinary Cancer • Hematological Disorders • Infectious Disease • Melanoma • Oncology • Solid Tumor • CALR • CDK1 • MAPK8

Redox-Responsive Dendritic Copolymer-Drug Conjugates Enhance Therapeutic Mitophagy Through Coordinated Microtubule Destabilization for Synergistic Triple-Negative Breast Cancer Therapy. (PubMed, Acta Biomater) - "Paclitaxel (PTX) and 2-methoxyestradiol (2ME) were conjugated to glutathione-stimuli responsive dendritic copolymers, resulting in DDS-PTX and DDS-2ME, respectively. Notably, the conjugates significantly reduced systemic toxicity compared to free drugs while maintaining hemocompatibility and organ safety. By integrating molecular-scale tumor microenvironment (TME) responsiveness with cytoskeletal-organelle crosstalk, this work establishes a mechanistically driven paradigm to amplify subcellular stress responses, offering a transformative strategy for refractory cancers with enhanced efficacy and safety."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Fucoxanthin Ameliorates Vascular Remodeling via Attenuating Oxidative Stress in Hypoxic Pulmonary Hypertension Rats. (PubMed, J Nutr Biochem) - "Notably, fucoxanthin exhibited effects similar to those of 2-methoxyestradiol (2ME2), an inhibitor of HIF-1α, on cell proliferation and ROS production in hypoxia-induced PASMCs...Collectively, fucoxanthin suppressed hypoxia-induced oxidative stress primarily by regulating the HIF-1α-ROS pathway, thereby alleviating pulmonary remodeling in HPH. Our findings represent a promising therapeutic strategy for HPH by improving pulmonary vascular remodeling."

Journal • Preclinical • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • HIF1A

Tea polyphenols and EGCG induce preeclampsia-like symptoms by reducing 2-methoxyestradiol. (PubMed, J Steroid Biochem Mol Biol) - "Furthermore, EGCG impaired the migration ability of HTR8/SVneo cells, which could be alleviated by 2-MeO-E2 supplementation. These findings indicate that tea polyphenols intake during pregnancy can cause PE-like symptoms by inhibiting COMT activity and production of 2-MeO-E2."

Journal • Cardiovascular • Gynecology • Hypertension • Renal Disease • COMT

2-Methoxyestradiol attenuates lung injury induced by chronic intermittent hypoxia via inhibiting the HIF1-α/SLC7A11 pathway. (PubMed, Sci Rep) - "The HIF-1α inhibitor, 2-ME2, effectively reverses CIH-induced lung tissue ferroptosis. The potential mechanism of 2-ME2 in inhibiting ferroptosis may involve suppressing the HIF-1α/SLC7A11 pathway."

Journal • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder • HIF1A • SLC7A11

2-Methoxyestradiol Inhibits the Oxygen-Sensing Pathway in Keloid Fibroblasts by Targeting HIF-1α/PHD. (PubMed, Int Wound J) - "In addition, the effects of 2-methoxyestradiol on the oxygen-sensing pathway in both hypoxic and normoxic keloid fibroblasts were evaluated. Our results suggest that 2-methoxyestradiol could be used to inhibit keloid fibroblast activity by inhibiting the oxygen-sensing pathway and its downstream effectors."

Journal • Fibrosis • Oncology • HIF1A • TNFA

Effects of an aryl hydrocarbon receptor ligand on human trophoblast cell development. (PubMed, Hum Reprod) - "The results suggest that AHR signaling activated by environmental pollutants could have a significant impact on placental development through mechanisms involving AHR activation. These findings may have broader implications for understanding how environmental factors affect fetal development."

Journal • CYP1A1 • CYP1B1

GLUT-Targeted Adhesive Nanoparticles Enhance the Oral Absorption and Anti-Tumor Effects of 2-Methoxyestradiol. (PubMed, Int J Nanomedicine) - "Compared with 2-ME-NPs, 2-ME-CMZ (1:1:9)-NPs significantly enhanced absorption through the mediation of multiple subtypes of GLUT, enhancing their original cellular uptake pathway and prolonging absorption time. These findings demonstrated that 2-ME-CMZ (1:1:9)-NPs are an extremely promising oral drug delivery system for 2-ME, and endowing GLUT-targeted drug-loaded nanoparticles with adhesion is an effective strategy for fully leveraging the role of GLUT in mediating oral absorption."

Journal • Oncology

Ubiquitin-specific protease 13 regulates FcεRI-mediated mast cell activation and allergic inflammation via SYK protein modulation. (PubMed, Int J Biol Macromol) - "Importantly, 2-methoxyestradiol (2-Meth) was identified as a potential inhibitor of USP13 and inhibited FcεRI-mediated MC activation effectively in vitro and in vivo. In conclusion, it elucidated the molecular mechanism by which USP13 regulated SYK stability in MCs. The USP13-SYK axis may serve as a therapeutic target for treating FcεRI-mediated activation of MCs and associated inflammatory responses."

Journal • Allergy • Inflammation • Targeted Protein Degradation • SYK • USP13