Hypoxia-inducible Factor Research Articles

Unraveling the influence of LncRNA in gastric cancer pathogenesis: a comprehensive review focus on signaling pathways interplay.

Gastric cancers (GCs) are among the most common and fatal malignancies in the world. Despite our increasing understanding of the molecular mechanisms underlying GC, further biomarkers are still needed for more in-depth examination, focused prognosis, and treatment. GC is one among the long non-coding RNAs, or lncRNAs, that have emerged as key regulators of the pathophysiology of cancer. This comprehensive review focuses on the diverse functions of long noncoding RNAs (lncRNAs) in the development of GC and their interactions with important intracellular signaling pathways. LncRNAs affect GC-related carcinogenic signaling cascades including pathways for EGFR, PI3K/AKT/mTOR, p53, Wnt/β-catenin, JAK/STAT, Hedgehog, NF-κB, and hypoxia-inducible factor. Dysregulated long non-coding RNA (lncRNA) expression has been associated with multiple characteristics of cancer, such as extended growth, apoptosis resistance, enhanced invasion and metastasis, angiogenesis, and therapy resistance. For instance, lncRNAs such as HOTAIR, MALAT1, and H19 promote the development of GC via altering these pathways. Beyond their main roles, GC lncRNAs exhibit potential as diagnostic and prognostic biomarkers. The overview discusses CRISPR/Cas9 genome-modifying methods, antisense oligonucleotides, small molecules, and RNA interference as potential therapeutic approaches to regulate the expression of long noncoding RNAs (lncRNAs). An in-depth discussion of the intricate functions that lncRNAs play in the development of the majority of stomach malignancies is provided in this review. It provides the groundwork for future translational research in lncRNA-based whole processes toward GC by highlighting their carcinogenic effects, regulatory roles in significant signaling cascades, and practical scientific uses as biomarkers and therapeutic targets.

The Relationship Between Expression of HIF-1α and Clinical Response in Cervical Cancer Patients with Neoadjuvant Chemotherapy at Dr. Soetomo Surabaya Hospital

This investigation aims to analyze the relationship between expression of Hypoxia Inducible factors-1 αlfa (HIF-1α) to assess the response to neoadjuvant chemotherapy in cervical cancer patients. This research is a Quast Experimental Non-Randomized Before and After with no control design with a sample size of 30 stage IIIB cervical cancer patients by inclusion and exclusion criteria, with pretest and posttest treatment, namely biopsy for immunohistochemical examination and abdominal ultrasound to evaluate lesion diameter cervix after three cycles of chemotherapy. This study showed a decrease in HIF-1α expression before and after chemotherapy (p=0,003) and a decrease in the diameter of cervical lesions before and after chemotherapy (p=0,000). Correlation between decreased HIF-1α expression and decreased diameter of cervical lesions (p=<0,05). Response to neoadjuvant chemotherapy: 25 patients (83,3 %) showed a negative response and 5 patients (16,7 %) showed a positive response. Strong HIF-1α expression before chemotherapy gave a negative response 23 and 25 subjects with a negative response after neoadjuvant chemotherapy. This study found a relationship between high HIF-α expression before chemotherapy with a negative chemotherapy response and low HIF-1α expression after neoadjuvant chemotherapy with a positive chemotherapy response in cervical cancer patients at Dr Soetomo Hospital, Surabaya

Abstract Tu136: HIF-1α a novel therapeutic target to reduce Cardiac Ischemia Reperfusion Injury during AMI

Acute myocardial infarction (AMI) is a major cause of mortality worldwide. In preclinical models of AMI, using a trans-valvular pump (TVP) to reduce left ventricular (LV) workload for 30 minutes before reperfusion reduces infarct size by 50%. The mechanisms underlying the cardioprotective effect of LV unloading remain poorly understood. Hypoxia inducible factor 1-alpha (HIF-1α) is an oxygen-sensitive transcription factor that activates cardioprotective signaling pathways, improves cell survival and mitochondrial function during myocardial ischemia. We hypothesized that LV unloading limits myocardial injury by activating hypoxia inducible factor 1-a (HIF-1α). To explore the effect of LV unloading on HIF-1α stabilization during ischemia, we performed left anterior descending artery (LAD) occlusion for a total of 120 minutes in adult swine in the presence and absence of LV unloading and further 180 minutes of reperfusion was performed following 120 minutes of LAD occlusion. Trans-valvular unloading activation significantly decreased infarct size both during ischemia (IS/AAR: 4.78±4 % vs 1.5±3%) and post reperfusion when compared ischemia alone and IR alone groups (36.04±8.39 % vs 16.02±3.52 %, p<0.0001) respectively. Interestingly, HIF-1α stabilization is significantly reduced with LV unloading during ischemia and significantly increased post reperfusion in the infarct zone of the swine model of AMI. To test whether HIF1a is necessary for cardioprotection with LV unloading, adult swine were treated with intracoronary delivery of the HIF-1α inhibitor (2-methoxyestradiol; 2ME) before reperfusion. Compared to TVP activation for 30 minutes before reperfusion, addition of 2ME abolished the cardioprotective effect of TVP resulting in increased infarct size (16.03% vs 35.86% p<0.03) and decreased HIF-1a stabilization. Stabilizing HIF-1α post-reperfusion by using a well know HIF-1a stabilizing agent Roxadustat, immediately before reperfusion significantly decreased infarct size in both with and without TVP groups compared to IRI alone. Treatment with Roxadustat also preserved mitochondrial function and increased RISK signaling. We report the novel finding that stabilizing HIF-1a activity before reperfusion plays a critical role in reducing Infarct size in preclinical model of AMI.

Abstract We060: Hypoxia Inducible Factor-2α Enhances Neutrophil Survival and Promotes Cardiac Injury Following Myocardial Infarction via cIAP-1 Signaling

Rationale: Heart failure is a major cause of mortality following myocardial infarction (MI). Neutrophils (PMNs) are among the first immune cells to accumulate in the infarcted region. While some long-term beneficial functions of PMN in heart injury are now appreciated, en mase PMN accumulation in injured hearts is still associated with worsened resolution of inflammation and disease outcomes. MI causes extensive hypoxic injury to heart tissue, where hypoxia-inducible factors (HIFs) play critical roles in cellular functions. While HIF1α regulation of cell survival, migration and metabolism have been well-studied, the role of HIF-2α in these processes is not well-understood. Even less is known of HIF-2α contributions to PMN effector functions, especially in the context of MI. Objectives: The current study aimed to 1. Mechanistically explore how HIF-2α regulates survival of tissue infiltrating PMNs post-MI and 2. Determine how HIF-2α activity in PMNs impacts heart injury resolution post-MI, and whether specific HIF-2α deletion in PMNs can alleviate MI-induced tissue injury. Methods & Results: Infarct size, cardiac functions monitored by echocardiography, and scar tissue formation after left anterior descending coronary ligation injury model were compared between littermate control and specific PMN HIF-2α depletion (Ly6G-cre +/- HIF-2α fl/fl ) mice. Myocardial infarction size, cardiac dysfunction, scare tissue deposit and survival of tissue infiltrating PMNs post-MI were substantially attenuated in mice with PMN HIF-2α deletion. A significantly reduced lifespan of HIF-2α knockout PMNs was further confirmed by fate-mapping EdU pulse chase experiments. Mechanistically, molecular studies revealed that HIF-2α transcriptionally regulates expression of the pro-survival factor cIAP1 in PMNs binding to an HRE located in the promoter region of BIRC2 , in a hypoxia-inducible manner. Ex-vivo pharmacological inhibition of cIAP1 expression in PMNs using Birinapant resulted in dramatic cell death, establishing the critical role of cIAP1 in PMN survival. Finally, our data demonstrate that the protective effect of HIF-2α deletion in PMNs on MI outcomes was due to elevated recruitment of reparative macrophages into infarcted hearts. Conclusion: HIF-2α, through cIAP1 regulation, promotes PMN survival and tissue retention post-MI, leading to worsen cardiac functions and scar formation.

Luoshi Neiyi Prescription inhibits estradiol synthesis and inflammation in endometriosis through the HIF1A/EZH2/SF-1 pathway

Ethnopharmacological relevanceEndometriosis (EMS) is a common gynecological disease that causes dysmenorrhea, chronic pelvic pain and infertility. Luoshi Neiyi Prescription (LSNYP), a traditional Chinese medicine (TCM) formula, is used to relieve EMS in the clinic. AimsThis study aimed to examine the active components of LSNYP and the possible mechanism involved in its treatment of EMS. Materials and methodsUltrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was used to identify the chemical components of LSNYP. Human primary ectopic endometrial stromal cells (ecESCs) and eutopic endometrial stromal cells (euESCs) were isolated, and the expression levels of hypoxia inducible factor 1A (HIF1A), enhancer of zeste homolog 2 (EZH2) and steroidogenic factor 1 (SF-1) were detected by immunofluorescence and qPCR. Cobalt chloride (CoCl2) was utilized to construct an in vitro hypoxic environment, and lentiviruses were engineered to downregulate HIF1A and EZH2 and upregulate EZH2. Subsequently, the expression levels of HIF1A, EZH2, and SF-1 were measured using qPCR or western blotting. The binding of EZH2 to the SF-1 locus in ESCs was examined via ChIP. Furthermore, the effects of LSNYP on the HIF1A/EZH2/SF-1 pathway were evaluated both in vitro and in vivo. ResultsA total of 185 components were identified in LSNYP. The protein and gene expression levels of HIF1A and SF-1 were increased, whereas those of EZH2 were decreased in ecESCs. After treating euESCs with 50 μmol L−1 CoCl2 for 24 h, cell viability and estradiol (E2) production were enhanced. Hypoxia decreased EZH2 protein expression, while si-HIF1A increased it. SF-1 was increased when EZH2 was downregulated in normal and hypoxic environments, whereas the overexpression of EZH2 led to a decrease in SF-1 expression. ChIP revealed that hypoxia reduced EZH2 binding to the SF-1 locus in euESCs. In vitro, LSNYP-containing serum decreased E2 and prostaglandin E2 (PGE2) production, inhibited cell proliferation and invasion, and reduced the expression of HIF1A, SF-1, steroidogenic acute regulatory protein (StAR), and aromatase cytochrome P450 (P450arom). In vivo, LSNYP suppressed inflammation and adhesion and inhibited the HIF1A/EZH2/SF-1 pathway in endometriotic tissues. ConclusionsLSNYP may exert pharmacological effects on EMS by inhibiting E2 synthesis and inflammation through regulation of the HIF1A/EZH2/SF-1 pathway. These results suggest that LSNYP may be a promising candidate for the treatment of EMS.

Panax notoginseng saponins promotes angiogenesis after cerebral ischemia-reperfusion injury

BackgroundIschemic stroke is a devastating disease that can result in permanent disability and death, and angiogenesis plays a critical role in the recovery and survival of patients and animal models of ischemic stroke. Panax notoginseng has been used as a key herb in the treatment of stroke diseases due to its effect in promoting blood circulation and removing blood stasis. However, the role of Panax notoginseng saponins, in promoting angiogenesis is unclear. PurposeThis study is aimed to investigate the effect of Xueshuantong (XST) injection, composed of Panax notoginseng saponins in post-stroke revascularization. MethodIn the present study, a middle cerebral artery occlusion/reperfusion model was established in Sprague-Dawley rats, with XST and the positive drug Dl-3-n-butylphthalide (NBP) administered via intraperitoneal injection to observe vascular changes after stroke. The protective and pro-angiogenic effects of XST after stroke were demonstrated by Triphenyltetrazolium chloride staining and optical coherence tomography angiography. Subsequently, network pharmacology and molecular docking techniques, as well as in vitro experimental validation, were used to further analyze the potential mechanism by which XST promotes angiogenesis. ResultsThe results showed that XST could reduce the cerebral infarction region in rats. And the neovascularization in the ischemic area of the rat brain significantly increased after 7 or 14 days of XST administration. Furthermore, XST could activate the vascular endothelial growth factor A (VEGFA)/vascular endothelial growth factor receptor 2 (VEGFR2), and hypoxia-inducible factor 1 (HIF-1) signaling pathways. ConclusionXST may promote post-stroke angiogenesis by affecting the HIF1-α/VEGFA/VEGFR2 signaling pathways.

Integration of serum pharmacochemistry with network pharmacology to reveal the potential mechanism of Yangqing Chenfei formula for the treatment of silicosis.

To explore the mechanisms of Yangqing Chenfei formula (, YCF) in the treatment of silicosis through a comprehensive strategy consisting of serum pharmacochemistry, network pharmacology analysis, and in vitro validation. An ultrahigh-performance liquid chroma-tography-tandem mass spectrometry method was used to confirm the active components in YCF-medicated serum. Then, we obtained targets for active components and genes for silicosis from multiple databases. Furthermore, a protein-protein interaction network was constructed, and Kyoto Encyclopedia of Genes and Genomes pathway and biological process analyses were conducted to elucidate the mechanisms of YCF for the treatment of silicosis. Finally, we validated the important components and mechanisms in vitro. Altogether, 19 active components were identified from rat serum after YCF administration. We identified 724 targets for 19 components, which were mainly related to inflammation [phosphatidy linositol 3 kinase/protein kinase B, forkhead box O, hypoxia inducible factor, and T-cell receptor signaling pathway, nitric oxide biosynthetic process], fibrotic processes [vascular endothelial growth factor signaling pathway, extracellular signal regulated kinase (ERK) 1 and ERK2 cascade, smooth muscle cell proliferation], and apoptosis (negative regulation of apoptotic process). In addition, 218 genes for silicosis were identified and were mainly associated with the inflammatory response and immune process [cytokine?cytokine receptor interaction, tumor necrosis factor alpha (TNF-α), toll-like receptor, and nucleotide binding oligomerization domain-like receptor signaling pathway]. Taking an intersection of active component targets and silicosis genes, we obtained 61 common genes that were mainly related to the inflammatory response and apoptosis, such as the phosphatidylinositol-3-kinase/protein kinase B signaling pathway, mitogen activated protein kinases signaling pathway, TNF signaling pathway, toll-like receptor signaling pathway, biosynthesis of nitric oxide, and apoptotic process. In the herb-component-gene-pathway network, paeoniflorin, rutin and nobiletin targeted the most genes. In vitro, paeoniflorin, rutin and nobiletin decreased the mRNA levels of inflammatory factors [interleukin (IL)-6, TNF-α, and IL-1β], suppressed p-AKT and cleaved caspase-3, and increased B cell lymphoma (Bcl)-2 protein expression in silica-induced macrophages in a concentration-dependent manner. YCF could significantly relieve the inflammatory response of silicosis via suppression of the AKT/Bcl-2/Caspase-3 pathway.

Integrated Network Pharmacology and Molecular Docking to Explore the Mechanisms of Ningshen Wendan Decoction in the Treatment of Schizophrenia.

Schizophrenia (SCZ) is a prevalent chronic mental disorder characterized by a high recurrence rate and significant disability. Currently, no satisfactory pharmacological treatments have been identified. Although Ningshen Wendan decoction (NSWDD) has shown promising results in improving cognitive function in patients with schizophrenia, its underlying mechanism of action remains unclear. This study systematically investigated the mechanisms of NSWDD in SCZ treatment using network pharmacology and molecular docking approaches. Analysis of the interaction genes revealed 307 common targets of NSWDD and SCZ. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated the involvement of multiple signaling pathways including interleukin 17 signaling pathway, multiple virus infections, Advanced glycosylation end products (AGEs) - receptor of AGEs (AGEs-RAGE) signaling pathway, tumor necrosis factor signaling pathway, and Hypoxia-inducible factor-1 (HIF-1) signaling pathway as key pathways influenced by NSWDD in treating SCZ. These pathways are associated with various biological processes such as transcriptional regulation, apoptosis regulation, gene expression regulation, and external stimulus-response. Molecular docking simulations indicated favorable binding interactions between components of NSWDD and target proteins via intermolecular forces. The study provided initial insights into the internal molecular mechanisms underlying the beneficial effect of NSWDD on SCZ through multi-target modulation across multiple pathways.

Pimitespib, a Novel Heat Shock Protein 90 Inhibitor, Is Effective in Treating Renal Cell Carcinoma by Anti-angiogenetic Signaling.

Most clear cell renal cell carcinomas (ccRCCs) have a dysfunctional von Hippel-Lindau tumor suppressor protein (VHL). Hypoxia-inducible factors 1 and 2 alpha (HIF1α and HIF2α) accumulate in ccRCC with dysfunctional VHL and up-regulate the vascular endothelial growth factor (VEGF) pathway and tumor angiogenesis. Recently, pimitespib (PIM), a potent ATP-competitive inhibitor of heat shock protein 90 (HSP90), was developed. PIM down-regulates the expression of HIF, a key protein in ccRCC progression, with anti-angiogenic effects. This study aimed to examine the effectiveness of PIM in ccRCC and the underlying mechanisms. The efficacy and mechanism of PIM against ccRCCs was evaluated using ccRCC cell lines. PIM inhibited the VEGFR pathway by down-regulating VEGFR 2, phosphorylated VEGFR 2, and protein levels in downstream signaling pathways. The growth of ccRCC cell lines was inhibited by PIM. Furthermore, PIM inhibits HIF1α, HIF2α, and VEGF expression, suggesting that PIM may suppress angiogenesis in addition to the VEGFR pathway. PIM provides a novel approach for treating ccRCC and holds promise for future clinical strategies. Further in vivo and clinical research is required to elucidate the detailed relationship between the effects of PIM and ccRCC.

Immune Clearance Mechanism for Hypoxia-Inducible Factor in Pelvic Peritonitis by Directly Targeting MiR-206a Using Magnetic Ferric Oxide Particles as a Carrier

miR-206a can directly target and regulate hypoxia-inducible factor, playing a role in inflammation and immune response. This study explored the effect of miR-206a using magnetic ferric oxide particles as a carrier to directly target and regulate HIF on immune clearance mechanism for pelvic peritonitis. A rat model of pelvic peritonitis was constructed and divided into NC group, NC group, Fe3O4 nanoparticle group, Fe3O4-miR-206a group, miR-206a gene knockout group, 740Y-P group, BKM120 group, Fe3O4-miR-206a+BKM120 group, PHD group, BAY 87-2243 group, Fe3O4-miR-206a+PHD group, 740Y-P+PHD group, BKM120+PHD group, and Fe3O4-miR-206a+BKM120+PHD group. We then detected serum C-Reactive protein (CRP), TNF-α and IL-6 levels, T lymphocyte, and miR-206a expression. HIF, TNF, IL-1, and IL-6 protein expressions were also detected. A rat model for pelvic peritonitis was also established, and magnetic ferric oxide particles carrying miR-206a nanocomplexes were successfully prepared. Levels of TNF-α, IL-6 and CRP were reduced under intervention by Fe3O4-miR-206a, and blood flow was reduced. All chemical indicators were reduced, and inflammatory response was significantly improved. After knocking out the miR-206a, the opposite results were observed. This study findings show that, miR-206a can directly target and regulate HIF to inhibit PI3K/Akt signaling pathway using magnetic ferric oxide particles as a carrier, thereby improving the immune clearance ability for patients with pelvic peritonitis, reducing inflammatory reactions, and thus improving prognosis. In addition, this research not only provides a new direction for management of inflammatory diseases, but also serves as a reference for treatment of immune diseases. Therefore, direct targeting and regulating HIF by miR-206a using magnetic ferric oxide particles as a carrier can become an effective strategy for the treatment of inflammatory and immune-related diseases.

Renal cancer: signaling pathways and advances in targeted therapies.

Renal cancer is a highlyheterogeneous malignancy characterized by rising global incidence and mortalityrates. The complex interplay and dysregulation of multiple signaling pathways,including von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), Hippo-yes-associated protein (YAP), Wnt/ß-catenin, cyclic adenosine monophosphate (cAMP), and hepatocyte growth factor (HGF)/c-Met, contribute to theinitiation and progression of renal cancer. Although surgical resection is thestandard treatment for localized renal cancer, recurrence and metastasiscontinue to pose significant challenges. Advanced renal cancer is associatedwith a poor prognosis, and current therapies, such as targeted agents andimmunotherapies, have limitations. This review presents a comprehensiveoverview of the molecular mechanisms underlying aberrant signaling pathways inrenal cancer, emphasizing their intricate crosstalk and synergisticinteractions. We discuss recent advancements in targeted therapies, includingtyrosine kinase inhibitors, and immunotherapies, such as checkpoint inhibitors.Moreover, we underscore the importance of multiomics approaches and networkanalysis in elucidating the complex regulatory networks governing renal cancerpathogenesis. By integrating cutting-edge research and clinical insights, this review contributesto the development of innovative diagnostic and therapeutic strategies, whichhave the potential to improve risk stratification, precision medicine, andultimately, patient outcomes in renal cancer.

Unraveling the intricacies of cold-inducible RNA-binding protein: A comprehensive review.

Cold-inducible RNA-binding protein (CIRP) is a versatile RNA-binding protein, pivotal in modulating cellular responses to diverse stress stimuli including cold shock, ultraviolet radiation, hypoxia, and infections, with a principal emphasis on cold stress. The temperature range of 32-34°C is most suitable for CIRP expression. The human CIRP is an 18-21kDa polypeptide containing 172 amino acids coded by a gene located on chromosome 19p13.3. CIRP has an RNA-recognition motif (RRM) and an arginine-rich motif (RGG), both of which have roles in coordinating numerous cellular activities. CIRP itself also undergoes conformational changes in response to diverse environmental stress. Transcription factors such as hypoxia-inducible factor 1 alpha and nuclear factor-kappa B have been implicated in coordinating CIRP transcription in response to specific stimuli. The potential of CIRP to relocate from the nucleus to the cytoplasm upon exposure to different stimuli enhances its varied functional roles across different cellular compartments. The different functions include decreasing nutritional demand, apoptosis suppression, modulation of translation, and preservation of cytoskeletal integrity at lower temperatures. This review explores the diverse functions and regulatory mechanisms of CIRP, shedding light on its involvement in various cellular processes and its implications for human health and disease.

Controlling Pericellular Oxygen Tension in Cell Culture Reveals Distinct Breast Cancer Responses to Low Oxygen Tensions.

In oxygen (O2)-controlled cell culture, an indispensable tool in biological research, it is presumed that the incubator setpoint equals the O2 tension experienced by cells (i.e., pericellular O2). However, it is discovered that physioxic (5% O2) and hypoxic (1% O2) setpoints regularly induce anoxic (0% O2) pericellular tensions in both adherent and suspension cell cultures. Electron transport chain inhibition ablates this effect, indicating that cellular O2 consumption is the driving factor. RNA-seq analysis revealed that primary human hepatocytes cultured in physioxia experience ischemia-reperfusion injury due to cellular O2 consumption. A reaction-diffusion model is developed to predict pericellular O2 tension a priori, demonstrating that the effect of cellular O2 consumption has the greatest impact in smaller volume culture vessels. By controlling pericellular O2 tension in cell culture, it is found that hypoxia vs. anoxia induce distinct breast cancer transcriptomic and translational responses, including modulation of the hypoxia-inducible factor (HIF) pathway and metabolic reprogramming. Collectively, these findings indicate that breast cancer cells respond non-monotonically to low O2, suggesting that anoxic cell culture is not suitable for modeling hypoxia. Furthermore, it is shown that controlling atmospheric O2 tension in cell culture incubators is insufficient to regulate O2 in cell culture, thus introducing the concept of pericellular O2-controlled cell culture.

HIF1 activation safeguards cortical bone formation against impaired oxidative phosphorylation.

Energy metabolism, through pathways such as oxidative phosphorylation (OxPhos) and glycolysis, plays a pivotal role in cellular differentiation and function. Our study investigates the impact of OxPhos disruption in cortical bone development by deleting mitochondrial transcription factor A (TFAM). TFAM controls OxPhos by regulating the transcription of mitochondrial genes. The cortical bone, constituting the long bones' rigid shell, is sheathed by the periosteum, a connective tissue layer populated with skeletal progenitors that spawn osteoblasts, the bone-forming cells. TFAM-deficient mice presented with thinner cortical bone, spontaneous midshaft fractures, and compromised periosteal cell bioenergetics, characterized by reduced ATP levels. Additionally, they exhibited an enlarged periosteal progenitor cell pool with impaired osteoblast differentiation. Increasing hypoxia-inducible factor 1a (HIF1) activity within periosteal cells substantially mitigated the detrimental effects induced by TFAM deletion. HIF1 is known to promote glycolysis in all cell types. Our findings underscore the indispensability of OxPhos for the proper accrual of cortical bone mass and indicate a compensatory mechanism between OxPhos and glycolysis in periosteal cells. The study opens new avenues for understanding the relationship between energy metabolism and skeletal health and suggests that modulating bioenergetic pathways may provide a therapeutic avenue for conditions characterized by bone fragility.

Cannabidiol as a possible treatment for endometriosis through suppression of inflammation and angiogenesis.

Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it. This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways. Among the pro-inflammatory cytokines, studies have shown solid roles for interleukin 1β (IL-β), IL-6, and tumor necrosis factor α (TNF-α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre-existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1α (HIF-1α), transforming growth factor β1 (TGF-β1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non-psychoactive member of cannabinoids which has well-known and notable anti-inflammatory and antiangiogenic properties. This agent has been shown to decrease IL-1β, IL-6, TNF-α, VEGF, TGFβ, and MMPs in different animal models of diseases. It seems that CBD could be a possible treatment for endometriosis due to its anti-inflammatory and antiangiogenic activity, however, further studies are needed.

HIF-1α–dependent regulation of angiogenic factor expression in Müller cells by mechanical stimulation

Mechanical stress regulates various biological processes in cells, tissues, and organs as well as contributes to the pathogenesis of various diseases. The retina is subjected to mechanical stress imposed by intraocular pressure as well as by retinal hemorrhage and edema. Responses to mechanical stress have been studied in retinal pigment epithelial cells and Müller cells of the retina, with the former cells having been found to undergo a stress-induced increase in the expression of vascular endothelial growth factor (VEGF), which plays a key role in physiological and pathological angiogenesis in the retina. We here examined the effects of stretch stimulation on the expression of angiogenic factors in cultured human Müller cells. Reverse transcription and quantitative PCR analysis revealed that expression of the VEGF-A gene was increased by such stimulation in Müller cells, whereas that of the angiopoietin 1 gene was decreased. An enzyme-linked immunosorbent assay showed that stretch stimulation also increased VEGF secretion from these cells. Expression of the transcription factor HIF-1α (hypoxia-inducible factor–1α) was increased at both mRNA and protein levels by stretch stimulation, and the HIF-1α inhibitor CAY10585 prevented the effects of mechanical stress on VEGF-A gene expression and VEGF secretion. Furthermore, RNA-sequencing analysis showed that the expression of angiogenesis-related pathway genes was upregulated by stretch stimulation. Our results thus suggest that mechanical stress induces VEGF production in Müller cells in a manner dependent on HIF-1α, and that HIF-1α is therefore a potential therapeutic target for conditions such as diabetic retinopathy, age-related macular degeneration, and retinal vein occlusion.

Expression of the HIF-1α/VEGF pathway is upregulated to protect alveolar bone density reduction in nasal-obstructed rats.

Hypoxia and mouth breathing are closely related to maxillofacial bone metabolism and are characteristic of obstructive sleep apnea-hypopnea syndrome (OSAHS). Being key factors in the hypoxia response, hypoxia-inducible factor 1α (HIF-1α) and HIF-responsive gene vascular endothelial growth factor (VEGF) are essential for bone remodeling. This study focuses on the role of the HIF-1α/VEGF pathway in alveolar bone metabolism during OSAHS. 36 three-week-old male Wistar rats were divided into three groups: twelve control rats, twelve bilateral nasal obstructed (BNO) rats, twelve BNO rats treated with intraperitoneal injection of Dimethyloxalylglycine (DMOG). After two weeks, the microstructure and bone mineral density (BMD) of alveolar bone were evaluated using micro-computed tomography (micro-CT). The expressions of HIF-1α and VEGF in the alveolar bone were then assessed via immunohistochemistry staining, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Alkaline phosphatase (ALP) staining and Alizarin red S staining were performed to evaluate osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). Significant reductions in alveolar bone density were noted in BNO rats. Bilateral nasal obstruction increased the expressions of HIF-1α and VEGF in alveolar bone. With upregulation of HIF-1α/VEGF via DMOG, alveolar bone density of BNO rats increased. Furthermore, DMOG promoted the osteogenic differentiation of BMSCs by stabilizing the HIF-1α protein and increasing the expression of VEGF. Bilateral nasal obstruction changes alveolar bone structure and leads to a reduction in alveolar bone density. Moreover, the expression of the HIF-1α/VEGF signaling pathway increases to protect alveolar bone density reduction in BNO rats.

IDENTIFICATION OF NEW CHEMICAL ENTITIES AS VHL INHIBITORS FOR DIABETIC WOUND HEALING

Diabetes is a kind of endocrine disease that impacts around 6% of the world's population. Globally, 68% of amputations were performed in persons with diabetes. Hypoxia-inducible factor 1-alpha (HIF-1) is a crucial regulator of wound healing in diabetic patients, which includes epithelialization, angiogenesis, granulation, tissue development, and wound contraction. Even though diabetic wounds are hypoxic, HIF-1 levels are decreased during diabetic conditions. Diabetic wound healing necessitates the modulation of hypoxia-induced responses by VHL–HIF-1 protein-protein inhibition (PPI). Our proposed hypothesis is to increase HIF-1 levels by inhibiting VHL and HIF-1 interactions by small bioactive molecules, accelerating diabetic wound healing. Three features (Two hydrogen bond acceptors and One hydrogen bond donor) pharmacophore model was generated from the existing VHL inhibitors. Virtual screening was done based on the generated pharmacophore, and a library of 700 compounds was selected using ZINCPharmer. Based on the docking analysis the Top 15 HITs were selected & after performing ADMET studies, the Top 2 HITs (ZINC04214700 and ZINC12529886) were identified as potential VHL inhibitors. From this finding, we demonstrated that inhibiting the VHL and HIF-1 connection is a promising strategy for treating diabetic wounds.

A Small-Molecule Inhibitor of Factor Inhibiting HIF Binding to a Tyrosine-Flip Pocket for the Treatment of Obesity.

In animals, limiting oxygen upregulates the hypoxia-inducible factor (HIF) and promotes a metabolic shift towards glycolysis. Factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that regulates HIF function by reducing its interaction with histone acetyl transferases. HIF levels are negatively regulated by the HIF prolyl hydroxylases (PHDs) which, like FIH, are 2-oxoglutarate (2OG) oxygenases. Genetic loss of FIH promotes both glycolysis and aerobic metabolism. FIH has multiple non-HIF substrates making it challenging to connect its biochemistry with physiology. A structure-mechanism guided approach identified a highly potent in vivo active FIH inhibitor, ZG-2291, the binding of which promotes a conformational flip of a catalytically important tyrosine, enabling the selective inhibition of FIH over other Jumonji C subfamily 2OG oxygenases. Consistent with genetic studies, ZG-2291 promotes thermogenesis and ameliorates symptoms of obesity and metabolic dysfunction in ob/ob mice. The results reveal ZG-2291 as a useful probe for the physiological functions of FIH and identify FIH inhibition as a promising strategy for obesity treatment.

A Small‐Molecule Inhibitor of Factor Inhibiting HIF Binding to a Tyrosine‐Flip Pocket for the Treatment of Obesity

AbstractIn animals, limiting oxygen upregulates the hypoxia‐inducible factor (HIF) and promotes a metabolic shift towards glycolysis. Factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that regulates HIF function by reducing its interaction with histone acetyl transferases. HIF levels are negatively regulated by the HIF prolyl hydroxylases (PHDs) which, like FIH, are 2‐oxoglutarate (2OG) oxygenases. Genetic loss of FIH promotes both glycolysis and aerobic metabolism. FIH has multiple non‐HIF substrates making it challenging to connect its biochemistry with physiology. A structure–mechanism guided approach identified a highly potent in vivo active FIH inhibitor, ZG‐2291, the binding of which promotes a conformational flip of a catalytically important tyrosine, enabling the selective inhibition of FIH over other Jumonji C subfamily 2OG oxygenases. Consistent with genetic studies, ZG‐2291 promotes thermogenesis and ameliorates symptoms of obesity and metabolic dysfunction in ob/ob mice. The results reveal ZG‐2291 as a useful probe for the physiological functions of FIH and identify FIH inhibition as a promising strategy for obesity treatment.