Hypoxia-inducible Factor-1α Research Articles

Quinoa Ethanol Extract Ameliorates Cognitive Impairments Induced by Hypoxia in Mice: Insights into Antioxidant Defense and Gut Microbiome Modulation.

Quinoa, rich in pharmacologically active ingredients, possesses the potential benefit in preventing cognitive impairments induced by hypoxia. In this study, the efficacy of quinoa ethanol extracts (QEE) consumption (200 and 500 mg/kg/d, respectively) against hypobaric hypoxia (HH)-induced cognitive deficits in mice was investigated. QEE significantly ameliorated hypoxic stress induced by HH, as evidenced by improvements in baseline indices and reductions in hypoxia-inducible factor 1α levels. Furthermore, QEE enhanced antioxidant defense mechanisms, alleviated neuroinflammation in brain regions associated with memory, and improved HH-induced cognitive impairments by modulating the cyclic adenosine monophosphate response element-binding protein/brain-derived neurotrophic factor signaling pathway. Higher doses generally yielded more effective outcomes than lower doses. QEE also significantly reshaped the gut microbiome structure of HH mice, inhibited gut barrier damage, and reduced lipopolysaccharide migration, thereby increasing short-chain fatty acids (SCFAs) levels. Our findings suggest that QEE may be a promising strategy for preventing hypoxia-induced cognitive impairments by maintaining gut microbiome stability and increasing SCFAs levels.

Chewing-Activated TRPV4/PIEZO1-HIF-1α-Zn Axes in a Rat Periodontal Complex.

The upstream mechanobiological pathways that regulate the downstream mineralization rates in periodontal tissues are limitedly understood. Herein, we spatially colocalized and correlated compression and tension strain profiles with the expressions of mechanosensory ion channels (MS-ion) TRPV4 and PIEZO1, biometal zinc, mitochondrial function marker (MFN2), cell senescence indicator (p16), and oxygen status marker hypoxia-inducible factor-1α (HIF-1α) in rats fed hard and soft foods. The observed zinc and related cellular homeostasis in vivo were ascertained by TRPV4 and PIEZO1 agonists and antagonists on human periodontal ligament fibroblasts ex vivo. Four-week-old male Sprague-Dawley rats were fed hard (n = 3) or soft (n = 3) foods for 4 wk (in vivo). Significant changes in alveolar socket and root shapes with decreased periodontal ligament space and increased cementum volume fraction were observed in maxillae on reduced loads (soft food). Reduced loads impaired distally localized compression-stimulated PIEZO1 and mesially localized tension-stimulated TRPV4, decreased mitochondrial function (MFN2), and increased cell senescence in mesial and distal periodontal regions. The switch in HIF-1α from hard food-distal to soft food-mesial indicated a plausible effect of shear-regulated blood and oxygen flows in the periodontal complex. Blunting or activating TRPV4 or PIEZO1 MS-ion channels by channel-specific antagonists or agonists in human periodontal ligament fibroblast cultures (in vitro) indicated a positive correlation between zinc levels and zinc transporters but not with MS-ion channel expressions. The effects of reduced chewing loads in vivo were analogous to TRPV4 and PIEZO1 antagonists in vitro. Study results collectively illustrated that tension-induced TRPV4 and compression-induced PIEZO1 activations are necessary for cell metabolism. An increased hypoxic state with reduced functional loads can be a conducive environment for cementum growth. From a practical standpoint, dose rate-controlled loads can modulate tension and compression-specific MS-ion channel activation, cellular zinc, and HIF-1α transcription. These mechanobiochemical events indicate the plausible catalytic role of biometal zinc in mineralization, periodontal maintenance, and dentoalveolar joint function.

Mesenchymal Stem Cell-conditioned Medium Attenuated CoCl2-induced Injury of Renal Tubular Epithelial Cells by Inhibiting NCOA1, HIF-1α, and Sox9.

Renal interstitial fibrosis (RIF) constitutes the ultimate pathological alteration in nearly all chronic kidney diseases (CKD). Mesenchymal stem cell conditioned medium (MSC-CM) exhibits an alleviating impact on renal fibrosis; however, the underlying mechanism remains unclear. The objective of this study was to explore whether MSC-CM regulates the expression of α-smooth muscle actin (α-SMA), Transforming growth factor-β1 (TGF-β1), Hypoxia-inducible factor-1α (HIF-1α), Nuclear receptor coactivators (NCOA1), and SRY-related high mobility (Sox9). Rat renal tubular epithelial cells (RTECs), NRK-52E, were treated with diverse concentrations of Cobalt chloride (CoCl2) for 24 hours. The survival rate and protein expression of NRK-52E cells exposed to different concentrations of CoCl2 were determined to identify the final concentration. Three groups of NRK-52E cells were employed in the experiment: the normal control group, the 400 μM CoCl2 group, and the MSC-CM + 400 μM CoCl2 group. The cell morphology was observed by an inverted phase contrast microscope and scanning electron microscope, and the protein expressions of α-SMA, TGF-β1, HIF-1α, NCOA1, and Sox9 were detected. The microscopic findings demonstrated that MSC-CM was able to decrease the degree of cytochemical hypoxia damage in NRK-52E cells induced by CoCl2. Immunofluorescence and Western blot analyses also affirmed a similar tendency. The upregulation of α-SMA, TGF-β1, HIF-1α, NCOA1, and Sox9 triggered by CoCl2 could be inhibited following MSC-CM intervention. Our findings indicate that MSC-CM exerts a protective effect on RTECs by down-regulating α-SMA, TGF-β1, HIF-1α, NCOA1, and Sox9.

Bacopa monnieri Extract Diminish Hypoxia-Induced Anxiety by Regulating HIF-1α Signaling and Enhancing the Antioxidant Defense System in Hippocampus.

Hypoxia is a significant stressor, and stabilized hypoxia-inducible factor-1α (HIF-1α) regulates the expression of numerous genes, leading to various biochemical, molecular, physiological and genomic changes. The body's oxygen-sensing system activates gene expression to protect brain tissues from hypoxia. Gamma-aminobutyric acid, an inhibitory neurotransmitter, regulates brain excitability during hypoxia through the activation of HIF-1 α. Herbal medicines have been widely used for managing various toxicological effects and disorders including hypoxia; however, the data on safety, efficacy and the molecular mechanisms that increase vulnerability or lethality against hypoxia are still lacking and urgently need to be investigated. The Current study aims to investigate how Bacopa monnieri extract (BME), specially CDRI-08 affects the hippocampus of mice subjected to conditions that simulate hypoxia. The pre and co-treatment of mice involved administrating BME (200mg/kg BW) for 14days, followed by exposure to CoCl2 (40mg/kg BW). BME decreased the levels of reactive oxygen species (ROS) and lipid peroxidation, while it increased the Gamma-aminobutyric acid receptor subunit-ɑ1 (GABAAR-ɑ1) level as well as the activity of antioxidant enzymes superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx). Furthermore BME reduced the levels of HIF-1α and its downstream targets glucose transporter-1 (GLUT-1) and erythropoietin (EPO) in the DG, CA1, and CA3 regions of hippocampus. Additionally, results obtained from the open field, elevated zero maze and plus maze tests indicate that BME restores anxiety caused by hypoxia. Together, these findings suggested that BME mitigates the harmful effects of oxidative stress and altered hypoxia related signaling in hippocampus; and may provide a basis for its therapeutic use in the recovery from hypoxia-led anxiety.

Red and blue LED light increases the survival rate of random skin flaps in rats after MRSA infection.

Skin flap transplantation is a conventional wound repair method in plastic and reconstructive surgery, but infection and ischemia are common complications. Photobiomodulation (PBM) therapy has shown promise for various medical problems, including wound repair processes, due to its capability to accelerate angiogenesis and relieve inflammation. This study investigated the effect of red and blue light on the survival of random skin flaps in methicillin-resistant Staphylococcus aureus (MRSA)-infected Sprague Dawley (SD) rats. Forty male SD rats were divided into control and light-emitting diode-red and blue light-treated (LED-RBL) groups at a ratio of 1:1 and a McFarland flap procedure was performed, which was subsequently infected with MRSA strains. After 7 days, the appearance and survival of the flaps were evaluated. The microvascular density was determined by hematoxylin and eosin (HE) staining. The expression levels of vascular endothelial growth factor (VEGF), hypoxia inducible factor 1α (HIF-1α), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (normally expressed as AKT) were detected by immunohistochemistry. The flap survival rate and microvascular density in the LED-RBL group were significantly higher than those in the control group (P < 0.05). In addition, the VEGF, HIF1-α, PI3K, and AKT levels were significantly higher in the LED-RBL group compared to the control group (P < 0.05). Red and blue light increased the survival area of the infected flap in rats by promoting angiogenesis, relieving oxidative stress, and reducing bacterial loads, indicating that PBM therapy is a convenient, simple, analgesic, and safe treatment intervention in promoting the survival rate of transplanted flaps after wound repair surgery.

Circadian rhythm, hypoxia, and cellular senescence: From molecular mechanisms to targeted strategies.

Cellular senescence precipitates a decline in physiological activities and metabolic functions, often accompanied by heightened inflammatory responses, diminished immune function, and impaired tissue and organ performance. Despite extensive research, the mechanisms underpinning cellular senescence remain incompletely elucidated. Emerging evidence implicates circadian rhythm and hypoxia as pivotal factors in cellular senescence. Circadian proteins are central to the molecular mechanism governing circadian rhythm, which regulates homeostasis throughout the body. These proteins mediate responses to hypoxic stress and influence the progression of cellular senescence, with protein Brain and muscle arnt-like 1 (BMAL1 or Arntl) playing a prominent role. Hypoxia-inducible factor-1α (HIF-1α), a key regulator of oxygen homeostasis within the cellular microenvironment, orchestrates the transcription of genes involved in various physiological processes. HIF-1α not only impacts normal circadian rhythm functions but also can induce or inhibit cellular senescence. Notably, HIF-1α may aberrantly interact with BMAL1, forming the HIF-1α-BMAL1 heterodimer, which can instigate multiple physiological dysfunctions. This heterodimer is hypothesized to modulate cellular senescence by affecting the molecular mechanism of circadian rhythm and hypoxia signaling pathways. In this review, we elucidate the intricate relationships among circadian rhythm, hypoxia, and cellular senescence. We synthesize diverse evidence to discuss their underlying mechanisms and identify novel therapeutic targets to address cellular senescence. Additionally, we discuss current challenges and suggest potential directions for future research. This work aims to deepen our understanding of the interplay between circadian rhythm, hypoxia, and cellular senescence, ultimately facilitating the development of therapeutic strategies for aging and related diseases.

Concoctive principles of detoxification and retention of the main toxic hepatotoxicity of Tripterygium wilfordii and its anti-inflammatory efficacy by concocting with the medicinal excipient Spatholobi Caulis juice.

Tripterygium wilfordii (TW), which has severe hepatotoxicity, is commonly used as anti-rheumatism. Using the juice of auxiliary herbs in concocting poisonous herbs is a conventional method for toxicity reduction or efficacy enhancement. Traditional Chinese Pharmacy textbooks record that Spatholobi Caulis (SC) can alleviate the side effects caused by TW and also possesses excellent hepatoprotective effect. However, it is still unclear how the concoctive principles of hepatotoxicity reduction and anti-inflammatory efficacy retention of TW after being concocted with the medicinal excipient SC juice. Therefore, this study aimed to evaluate the hepatotoxicity and anti-inflammatory efficacy of concoction with SC juice on TW and preliminarily explored its detoxification mechanism. The attenuation effect of TW concocted with SC juice was determined by triptolide (TP) content, hepatic histological and serum biochemical indexes. The detoxification mechanism was predicted by network pharmacology and molecular docking, and confirmed by quantitative real-time PCR (qRT-PCR) and Western blot. Moreover, the anti-inflammatory efficacy was evaluated by paw edema test, and the major active ingredients in the SC juice introduced to TW concoction were detected. Concoction with SC juice significantly reduced TP content and serum biochemical indicator levels, alleviated liver pathological damage, introduced the main active ingredients, and inhibited the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF). Furthermore, the anti-inflammatory efficacy was retained. In summary, this study elucidated that concoction with SC juice alleviated the hepatotoxicity of TW by inhibiting HIF-1α/VEGFA signaling, decreasing TP content, and introducing the main active components. Moreover, the anti-inflammatory efficacy was retained.

P0141 Estrogen receptor β alleviates colitis in intestinal epithelial cells by activating HIF-1α and ATG-9a mediated autophagy

Abstract Background Ulcerative colitis (UC) manifests as excessive inflammation and compromised integrity of the intestinal epithelial barrier. Estrogen receptor β (ERβ) exerts anti-inflammatory effects in the colon. However, the mechanism remains unclear. This study aims to explore the role and mechanism of ERβ in alleviating colitis, and provide a novel therapeutic target for UC. Methods The level of ERβ and autophagy in the inflammatory and non-inflammatory colons of patients with UC were assessed. Mice with dextran sulfate sodium (DSS)-induced colitis were used to establish an in vivo model. The body weight change, colon length, disease activity index (DAI) and histological score of mice in each group were compared. In vitro, HT-29 cell inflammation was induced by lipopolysaccharide (LPS). ERB041, an ERβ specific agonist, was administered to DSS-induced mice and LPS-induced HT-29 cells. Autophagy in vivo and in vitro was evaluated by western blot, transmission electron microscope, and immunofluorescence. Co-immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assay were conducted to further delineate the mechanism between ERβ and autophagy. Results Compared with non-inflammatory mucosa, the expression of ERβ in the inflammatory mucosa in patients with UC was down-regulated, with autophagy inhibited significantly. ERβ activation attenuated the intestinal epithelial barrier disruption, decreased the level of pro-inflammatory cytokines, and significantly attenuated DSS-induced experimental colitis. Mechanically, ERB041 intervention activated autophagy, which was manifested as up-regulation of LC3BII expression, decreased p62 level and increased number of autolysosomes. ERβ interacted with hypoxia-inducible factor 1α (HIF-1α) and activated autophagy. Furthermore, HIF-1α bound to the promoter region of ATG- 9a, and positively regulates its transcription. Conclusion ERβ exerts anti-inflammatory effect by up-regulating HIF-1α and activating ATG-9a mediated autophagy in intestinal epithelial cells, and may be a promising therapeutic target for UC.

Differential effects of β-hydroxybutyrate and α-ketoglutarate on HCT-116colorectal cancer cell viability under normoxic and hypoxic low-glucose conditions: exploring the role of SRC, HIF1α, ACAT1, and SIRT2 genes.

Recent therapeutic strategies have highlighted the potential of β-hydroxybutyrate (BHB) and α-ketoglutarate (α-KG) as effective anticancer agents, particularly for colon cancer. These metabolites can modulate cellular metabolism and induce epigenetic changes, inhibiting tumor growth. Nonetheless, certain cancer cells may utilize ketone bodies, like BHB as nutrient sources under hypoxic conditions, potentially reducing treatment efficacy. Understanding these mechanisms is crucial for optimizing cancer therapies. This study evaluated the effects of BHB and α-KG on HCT-116 colorectal cancer cell viability under normoxic and low-glucose hypoxic conditions. HCT-116 cell lines were treated with different doses of BHB and α-KG in normoxic and low-glucose hypoxic conditions, and then cell viability was assessed by the MTT assay. Moreover, the mRNA expression levels of SRC, hypoxia-inducible factor 1α(HIF-1α), acetyl-CoA acetyltransferase 1 (ACAT1), and sirtuin 2 (SIRT2) genes were determined using quantitative reverse transcriptase-polymerase chain reaction (q RT-PCR). BHB significantly increased the proliferation of HCT-116 colon cancer cells under low-glucose hypoxic conditions, while α-KG maintained cell viability in normoxic conditions but not in hypoxia. BHB treatment reduced SIRT2 mRNA levels and increased ACAT1, SRC, and HIF-1α expression. Conversely, α-KG decreased ACAT1, SRC, and HIF-1α expression and increased SIRT2 levels in normoxia but could not reverse gene expression during hypoxia. Our study demonstrated that BHB and α-KG exhibited complex interactions with colon cancer cell viability under varying oxygen and glucose conditions. While BHB promoted cell proliferation in hypoxic environments, α-KG showed protective effects in normoxic conditions. This research contributed to the growing body of evidence supporting the role of metabolic modulators in cancer therapy and emphasized the importance of understanding tumor microenvironments to optimize treatment outcomes. However, the need for further research into the metabolic pathways is underscored to enhance therapeutic strategies for cancer treatment.

UBE2Q2 promotes tumor progression and glycolysis of hepatocellular carcinoma through NF-κB/HIF1α signal pathway.

Metabolic reprogramming, particularly the Warburg effect, plays a crucial role in the onset and progression of tumors. The ubiquitin-conjugating enzyme E2 Q2 (UBE2Q2) has been identified overexpressed in hepatocellular carcinoma (HCC). Our aim was to determine if UBE2Q2 plays a role in regulating glycolysis, contributing to the carcinogenesis of HCC. Bioinformatics analysis, western blot and qPCR were used to detect the expression of UBE2Q2. Functional experiments, proteomics analysis and subcutaneous tumors were constructed to find the biological function of UBE2Q2 in HCC. Co-immunoprecipitation, western blot and ubiquitination assays were used to identify the mechanisms involved. We found a significant association between high UBE2Q2 expression and poor prognosis in HCC patients. Functionally, UBE2Q2 was shown to advance tumor progression in HCC through both in vitro assays and in vivo assessments. Proteomics analysis and glycolysis stress tests corroborated an increase in glycolytic activity due to UBE2Q2. Our findings reveal that UBE2Q2 augments glycolysis by boosting the transcription levels of hypoxia-inducible factor 1α (HIF1α), primarily through the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. At the molecular level, UBE2Q2 interaction with baculoviral IAP repeat-containing 2 (cIAP1) orchestrates the K63-linked ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1), which in turn, activates the NF-κB signaling pathway. Our investigation reveals that UBE2Q2 regulates the glycolysis in HCC through modulation of the NF-κB/HIF1α signaling pathway, pinpointing UBE2Q2 as a promising therapeutic target for the disease.

A cRGD-modified liposome for targeted delivery of artesunate to inhibit angiogenesis in endometriosis.

Currently, hormonal therapy for endometriosis faces challenges in achieving a balance between treatment and preserving the chance of pregnancy. Therefore, the development of non-hormonal therapy holds significant clinical importance. Angiogenesis is a hallmark of endometriosis, and anti-angiogenic therapies targeting the hypoxia-inducible factor-1α (HIF-1α) pathway are considered potential approaches for endometriosis. However, angiogenesis is also involved in numerous physiological processes, including pregnancy, and systemic anti-angiogenesis may lead to severe adverse effects. To address this, a cRGD-modified liposome nanodrug (cRGD-LP-ART) is synthesized, which enhances drug efficacy while reducing adverse reactions. Artesunate (ART), a non-hormonal drug used to treat malaria, has shown anti-angiogenic effects beyond its original indications in various benign and malignant diseases. With cRGD modification, cRGD-LP-ART can target ectopic lesions and inhibit local angiogenesis by suppressing the HIF-1α/vascular endothelial growth factor (VEGF) pathway. Furthermore, cRGD-LP-ART exhibits better therapeutic effects than free ART, without affecting ovarian function or causing atrophy of the eutopic endometrium, making it a promising new option for non-hormonal therapy of endometriosis. As a combination of liposomes and a clinically approved drug, cRGD-LP-ART holds great potential and clinical prospects for the treatment of endometriosis.

Sustained Release of HIF-2α Inhibitors Using Biodegradable Porous Silicon Carriers for Enhanced Immunogenic Cell Death of Malignant Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer with limited treatment options, often associated with Merkel cell polyomavirus (MCPyV) and marked by hypoxic tumor microenvironments that promote resistance to therapies. Belzutifan, an FDA-approved hypoxia-inducible factor-2α (HIF-2α) inhibitor, has shown promise in inhibiting tumor growth; however, its clinical efficacy is hindered by its low solubility, rapid clearance, and limited bioavailability. In this study, we present a strategy using porous silicon (pSi) microparticles and nanoparticles as carriers for the sustained delivery of benzoate to MCC cells. The pSi carriers were engineered to securely encapsulate and gradually release belzutifan, overcoming the limitations of free drug administration. Microparticles provided sustained extracellular release, while nanoparticles enabled efficient intracellular delivery, enhancing HIF-2α inhibition. Moreover, the use of biodegradable silicon particles enables long-term consistent release of belzutifan over 10 days in vitro with a single dose administration in the tumor microenvironment, while free belzutifan is rapidly deactivated within 1 day postadministration. In vitro studies demonstrated significant immunogenic cell death (ICD) in MCC cells, marked by the cytosolic localization of HMGB1 and elevated expression of pro-inflammatory cytokines as well as strong upregulation of TLR9. Particularly, the increased TLR9 expression in both MCC cell lines with pSi carrier treatment reinforces immune activation through toll-like receptor signaling, enhancing both innate and adaptive immune responses within the tumor microenvironment. These findings indicate that pSi carriers not only enhance belzutifan's stability and release profile but also amplify antitumor immune responses within the tumor microenvironment. Our results suggest that belzutifan-loaded pSi carriers offer a potent and targeted therapeutic strategy for MCC, potentially addressing key challenges in cancer immunotherapy by combining HIF-2α inhibition with robust immune activation. This platform highlights the universal utility of pSi-based delivery systems to advance MCC treatment with implications for broader cancer therapies.

Head and Neck Paraganglioma in Pacak-Zhuang Syndrome.

Head and neck paragangliomas (HNPGLs) are typically slow-growing, hormonally inactive tumors of parasympathetic paraganglia. Inactivation of prolyl-hydroxylase domain-containing 2 protein causing indirect gain-of-function of hypoxia-inducible factor-2α (HIF-2α), encoded by EPAS1, was recently shown to cause carotid body hyperplasia. We previously described a syndrome with multiple sympathetic paragangliomas caused by direct gain-of-function variants in EPAS1 (Pacak-Zhuang syndrome, PZS) and developed a corresponding mouse model. We evaluated a cohort of patients with PZS (n = 9) for HNPGL by positron emission tomography, magnetic resonance imaging, and computed tomography and measured carotid body size compared to literature reference values. Three patients had imaging consistent with HNPGL, one of which warranted resection and was confirmed on histology. Three additional patients had carotid body enlargement (Z-score > 2.0), and three had carotid artery malformations. Using high resolution ex vivo imaging and histology, we found that nine of ten adult mutant mice had carotid body tumors and six of eight had a paraganglioma on the cranio-caval vein, the murine homologue of the superior vena cava; these were also found in four of five mutant mice at post-natal day 8. These tumors and the one resected from a patient were positive for tyrosine hydroxylase, synaptophysin, and chromogranin A. Brown fat in a resected patient tumor carried the EPAS1 pathogenic variant. These findings 1) suggest HNPGL as a feature of PZS and 2) show that these pathogenic variants are sufficient to cause the development of these tumors, which we believe represents a continuous spectrum of disease starting from hyperplasia.

Contribution of hypoxia-inducible factor 1alpha to pathogenesis of sarcomeric hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) caused by autosomal-dominant mutations in genes coding for structural sarcomeric proteins, is the most common inherited heart disease. HCM is associated with myocardial hypertrophy, fibrosis and ventricular dysfunction. Hypoxia-inducible transcription factor-1α (Hif-1α) is the central master regulators of cellular hypoxia response and associated with HCM. Yet its exact role remains to be elucidated. Therefore, the effect of a cardiomyocyte-specific Hif-1a knockout (cHif1aKO) was studied in an established α-MHC719/+ HCM mouse model that exhibits the classical features of human HCM. The results show that Hif-1α protein and HIF targets were upregulated in left ventricular tissue of α-MHC719/+ mice. Cardiomyocyte-specific abolishment of Hif-1a blunted the disease phenotype, as evidenced by decreased left ventricular wall thickness, reduced myocardial fibrosis, disordered SRX/DRX state and ROS production. cHif1aKO induced normalization of pro-hypertrophic and pro-fibrotic left ventricular remodeling signaling evidenced on whole transcriptome and proteomics analysis in α-MHC719/+ mice. Proteomics of serum samples from patients with early onset HCM revealed significant modulation of HIF. These results demonstrate that HIF signaling is involved in mouse and human HCM pathogenesis. Cardiomyocyte-specific knockout of Hif-1a attenuates disease phenotype in the mouse model. Targeting Hif-1α might serve as a therapeutic option to mitigate HCM disease progression.

Aryl Hydrocarbon Receptor Establishes a Delicate Balance between the Level of the Trace Amine Tryptamine and Monoamine Oxidase Activity in the Brain and Periphery in Health and Conditions such as Neurodegenerative, Neurodevelopmental, and Psychiatric Disorders.

The purpose of this review was to analyse the literature regarding the correlation between the level of tryptamine, aryl hydrocarbon receptor (AHR) signalling pathway activation, and monoamine oxidase (MAO)-A and MAO-B activity in health and conditions such as neurodegenerative, neurodevelopmental, and psychiatric disorders. Tryptamine is generated through the decarboxylation of tryptophan by aromatic amino acid decarboxylase (AADC) in the central nervous system (CNS), peripheral nervous system (PNS), endocrine system, and gut bacteria. Organ-specific metabolism of tryptamine, which is mediated by different MAO isoforms, causes this trace amine to have different pharmacokinetics between the brain and periphery. Reactive oxygen species (ROS) generated by MAO can influence miRNA-CYP enzyme regulatory network and affect mitochondrial function. Tryptamine regulates AHR function by acting as an endogenous ligand for AHR, initiating AHR activation and inhibiting the expression of the CYP1A1 and CYP1A2 genes. The dysregulation of AHR signalling, triggered by endogenous tryptamine binding, can disrupt the regulation of prolactin levels. Depending on the tryptamine concentration and context, tryptamine can be beneficial or harmful. By acting as an agonist of inhibitory serotonin receptors and trace-amine associated receptor 1 (TAAR1) and an antagonist of excitatory serotonin receptors, it can engage in diverse physiological interactions with serotonin. Increased tryptamine production is observed under hypoxic conditions and is associated with hypoxia-inducible factor 1α (HIF-1α) activation, leading to AHR activation. Dysregulation of the association between tryptamine levels, AHR signalling pathway activation, and MAO activity are observed in Alzheimer's disease (AD), Parkinson's Disease (PD), Autism Spectrum Disorder (ASD) and schizophrenia.

Reply to: Concerns on Potential Risk of Roxadustat in Promoting Tumor Progression: Double-Edged Sword of Hypoxia-Inducible Factor-1α Activation.

Reply to: Concerns on Potential Risk of Roxadustat in Promoting Tumor Progression: Double-Edged Sword of Hypoxia-Inducible Factor-1α Activation.

Effect of ultrasound combined with microbubbles therapy on tumor hypoxic microenvironment.

Tumor tissues exhibit significantly lower oxygen partial pressure compared to normal tissues, leading to hypoxia in the tumor microenvironment and result in resistance to tumor treatments. Strategies to mitigate hypoxia include enhancing blood perfusion and oxygen supply, for example,by decomposing hydrogen peroxide within the tumor. Improving hypoxia in the tumor microenvironment could potentially improve the efficacy of cancer treatments. Previous studies have demonstrated that ultrasound of appropriate intensity when combined with microbubbles, can improve tumor blood perfusion. However, its effects on tumor hypoxia remain unclear. This study aimed to assess the effects of low-frequency non-focused ultrasound combined with microbubbles at different intensities on tumor microenvironment hypoxia and to identify the optimal ultrasound parameters for alleviating tumor hypoxia. Rabbits with VX2 tumors received ultrasound and microbubble treatments at different acoustic pressures and pulse repetition frequencies. The changes in tumor tissue blood perfusion before and after treatment were observed by contrast enhanced ultrasound (CEUS). The changes in tumor tissue hypoxia before and after treatment were observed by measuring oxygen partial pressure directly with in tumor tissue and immunohistochemical staining for hypoxia-inducible factor-1α (HIF-1α). Results indicated that low frequency, non-focused ultrasound at 0.5MPa/20Hz and 0.5MPa/40Hz, when combined with microbubbles, could increase tumor tissue blood perfusion and improve the hypoxia in tumor tissues. This study provides a new method for improving hypoxia in the tumor microenvironment (TME) which could potentially improve the cancer treatments resistance.

Stereodivergent Synthesis of the Vicinal Difluorinated Tetralin of Casdatifan Enabled by Ru-Catalyzed Transfer Hydrogenation.

We disclose a stereodivergent strategy to prepare vicinal difluorinated tetralins from γ-substituted tetralones via a combination of catalyst-controlled transfer hydrogenation and substrate-controlled fluorinations. This process is easily scalable and amenable to highly functionalized substrates, as demonstrated here in the late-stage synthesis of casdatifan, a clinical-stage inhibitor of hypoxia-inducible factor-2α. Analysis of the physicochemical properties of casdatifan, which features a cis-vicinal difluoride, revealed a higher level of facial polarization compared to its trans-vicinal difluoride isomers.

Reply to: Concerns on Potential Risk of Roxadustat in Promoting Tumor Progression: Double-Edged Sword of Hypoxia-Inducible Factor-1α Activation.

Reply to: Concerns on Potential Risk of Roxadustat in Promoting Tumor Progression: Double-Edged Sword of Hypoxia-Inducible Factor-1α Activation.

A Study on Endometrial Polyps Recurrence Post-Hysteroscopic Resection: Identification of Influencing Factors and Development of a Predictive Model.

This study aimed to explore influencing factors and develop a predictive model of endometrial polyps (EP) recurrence after hysteroscopic resection. This retrospective study included 180 patients who underwent hysteroscopic resection for EP between January 2021 to December 2023. The patients were divided into a modeling group (n = 135) and a validation group (n = 45) in a 3:1 ratio. The patients in the modeling group were further divided into a recurrence group (n = 35) and a non-recurrence group (n = 100) based on whether their polyps recurred. General information on patients was compared between the two groups. Univariate and multiple logistic regression analyses were conducted to identify factors influencing EP recurrence post-hysteroscopic resection. A predictive model was developed, and the receiver operating characteristic (ROC) curve analysis was performed to determine the clinical utility of the model. Comparison of baseline characteristics between the modeling and validation groups showed no statistically significant differences (p > 0.05). However, 35 patients in the modeling group had recurrence, while 12 patients experienced recurrence in the validation group. Binary logistics regression analysis revealed matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1), hypoxia-inducible factor-1α (HIF-1α) and platelet-derived growth factor (PDGF) as independent predictors for polyp recurrence (p < 0.05). Furthermore, a model formula, p = eZ/1 + eZ, was developed. The slope of the calibration curve of this model in both groups were straight lines close to 1, indicating that the model's predicted recurrence risk strongly agreed with the actual risk. ROC analysis demonstrated that the area under the curve in the modeling group was 0.902, with standard error of 0.028 (95% confidence interval (CI): 0.885-0.954). The model yielded the Youden value of 0.79, with a sensitivity of 82.96% and a specificity of 95.66%. Moreover, the area under the curve in the validation group was 0.871, with a standard error of 0.040 (95% CI: 0.859-0.920). However, the model showed the Youden value of 0.59, with a sensitivity of 79.29% and a specificity of 79.96%. The Decision Curve Analysis (DCA) demonstrated significant clinical advantages of the model. This study identified the influencing factors of EP recurrence and successfully constructed a predictive model based on these factors. After validation, the model demonstrates significant clinical utility.