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Nucleophosmin1 (NPM1) mutated acute myeloid leukemia (AML) without FLT3-ITD mutation is classified as a favorable risk AML which responds well to cytarabine therapy. Hypoxia-inducible factor-1 alpha (HIF-1α) promotes leukemic cell survival and maintains leukemic stem cell quiescence possibly contributing to cytarabine resistance. This study evaluated HIF-1α expression using immunohistochemistry in bone marrow of 29 newly diagnosed NPM1+FLT3-ITD− normal karyotype AML patients and analyzed its correlation with survival. All patients achieved complete remission after standard induction chemotherapy and proceeded to cytarabine consolidations. Positive HIF-1α staining with golgi body pattern and strong cytoplasmic HIF-1α expression was identified in 34.5% and 58.6% of patients, respectively. The expression of golgi body or strong cytoplasmic HIF-1α expression was related to increased relapse (p = 0.048) with significantly inferior relapse-free survival (RFS, p = 0.042). Using multivariate analysis, extramedullary disease at diagnosis was revealed as an independent prognostic factor for adverse RFS (hazard ratio [HR] 3.82; 95% confidence interval [CI] 1.26–11.55, p = 0.018), while golgi body or strong cytoplasmic HIF-1α expression showed a trend toward poor RFS (HR 3.56; 95% CI 1.00–12.69, p = 0.050). In summary, high HIF-1α expression is potentially a baseline prognostic biomarker for poor RFS and cytarabine resistance in NPM1+FLT3-ITD− AML. Further studies with the large number of patients are warranted. [ABSTRACT FROM AUTHOR]

In order to evaluate the function of hypoxia-inducible factor-1 alpha (hif1α) and factor inhibiting hif1α (fih1) in response to thermal stress, we first conducted a functional analysis of A. sapidissima hif1α and fih1, and determined hif1α and fih1 expressions in different tissues in response to thermal stress based on identified housekeeping genes (HKGs). The results showed that hif1α and fih1 were mainly located in the nucleus and cytoplasm. The full length cDNA sequence of hif1α and fih1 was 4073 bp and 2759 bp, respectively. The cDNA sequence of hif1α includes 15 exons encoding 750 amino acid residues, and the full length cDNA sequence of fih1 contains 9 exons encoding 354 amino acid residues. During the acute thermal stress transferring from 16 ± 0.5 °C (control) to 20 ± 0.5 °C, 25 ± 0.5 °C, and 30 ± 0.5 °C for 15 min, it was found that the expression trends of hif1α and fih1 showed an inhibitory regulation in the heart, while they consistently expressed in brain, intestine, muscle, gill, kidney and liver. In conclusion, this is the first study to identify the tissue-specific HKGs in A. sapidissima and found that ef1α and β-actin are the most suitable HKGs. Hif1α and Fih1 are mainly the nuclear and cytoplasmic proteins, respectively, having high levels in the heart and brain. Alosa sapidissima countered a temperature increase from 16 to 25 ℃ by regulating the expressions of hif1α and fih1, but their physiological regulatory functions were unable to cope with acute thermal stress when the temperature difference was 14 ℃ (from 16 to 30 ℃). [ABSTRACT FROM AUTHOR]

Abstract Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa. It has therapeutic effects in different paradigms of brain injury, acting as a neuroprotectant. As oxidative stress is a primary risk factor for brain damage after neonatal hypoxia, we tested the effect of CBD on oxidative status and non-protein-bound iron accumulation in the immature brain after hypoxia. Moreover, we tested whether cannabidiol affects the accumulation of hypoxia-inducible factor-1 alpha (HIF-1α) which plays a key role in the regulation of cellular adaptation to hypoxia and oxidative stress. We used 7-day-old mice randomly assigned to hypoxic or control groups. Immediately after hypoxia or control exposure, pups were randomly assigned to a vehicle or CBD treatment. 24 h later, they were decapitated and the brains were immediately removed and stored for further biochemical analyses. We found that CBD reduced lipid peroxidation and prevented antioxidant depletion. For the first time, we also demonstrated that CBD upregulated HIF-1α protein level. This study indicates that CBD may effective agent in attenuating the detrimental consequences of perinatal asphyxia.

Cyclophilin A regulates the biological behavior of placental trophoblast cells in severe preeclampsia by regulating oxygen inducible factor (hypoxia-inducible factor-1 alpha) signal pathway. JEG3 cell line was selected and randomly divided into control group (minimum essential medium 1 l containing 10 % fetal bovine serum) (group A), low dose group (cyclophilin A protein concentration was 1 pg/ml) (group B) and high dose group (cyclophilin A protein concentration was 3 pg/ml) (group C). The apoptosis of JEG3 cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling method, the expression of tumor necrosis factor-alpha, interleukin-6 and interleukin-1 beta messenger ribonucleic acid in JEG3 cells was detected by quantitative read-time polymerase chain reaction method, and the expression of cleaved caspase-3, caspase-3, cleaved poly (ADP-ribose) polymerase 1, poly (ADP-ribose) polymerase 1, p53 and hypoxia-inducible factor-1 alpha protein was detected by Western bolting. Quantitative polymerase chain reaction assay showed that the expression levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-1 beta in group B and group C were raised than those in group A, and the expression levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-1 beta increased with the increase of cyclophilin A concentration. Western blotting detection showed that the cleaved caspase-3 expression level of JEG3 cells in group B and C was raised than that in group A, and increased with the increase of concentration, while the expression of cleaved poly (ADP-ribose) polymerase 1 in group C was raised than that in group A. The levels of hypoxia-inducible factor-1 alpha in JEG3 cells were higher in both the group B and C compared to the group A, and they further increased with the rise in concentration. Cyclophilin A can promote inflammation by increasing the expression of tumor necrosis factor-alpha, interleukin-6 and interleukin-1 beta in trophoblasts, and accelerate the apoptosis of trophoblasts by activating caspase-3 pathway, which is an important pathogenic factor of preeclampsia. This mechanism may be related to the regulation of hypoxia-inducible factor-1 alpha signal pathway. [ABSTRACT FROM AUTHOR]

BackgroundThe exposure to diesel particulate matter (DPM) and its polycyclic aromatic hydrocarbons (PAH) is closely related to the morbidity and mortality of ischemic heart disease (IHD). However, it is unclear what key components and targets of DPM exposure involve in myocardial ischemia-hypoxia injury and associated mechanisms.ObjectiveTo identify key PAH components of DPM that act on myocardial hypoxic injury, andclarify the role of oxygen sensors-regulated anaerobic metabolism in DPM and key components-induced hypoxic injury and the targets of the key PAH components.MethodsHuman cardiomyocyte cell line AC16 cells were exposed to 0, 1, 5, and 10 μg·mL−1 DPM in a high glucose DMEM medium with 10% fetal bovine serum (FBS) (HGM) or low FBS (0.5%) in high glucose DMEM medium (LFM), for 12 h under 2% O2, and expression of hypoxia-inducible factor-1α (HIF-1α), Bax, and Cleaved-caspase3 was determined by Western blotting. Under normal condition, the cell viability was detected after PAH exposure for 12 h. Under the condition of ischemia-hypoxia model, cells were exposed to 0, 0.005, 0.5, and 5 µg·mL−1 PAH for 12 h, and the protein expression of HIF-1α, Bax, and Cleaved-caspase3 was determined. After exposure to DPM or PAH for 12 h, the contents of pyruvate and lactate in cells were detected. Pretreatment with glycolysis inhibitor GSK2837808A was used to explore the role of glycolysis in DPM and benzo[a]pyrene (BaP)-induced hypoxia injury. A molecular docking technique was used to analyze the binding affinity between PAH and oxygen sensors (prolyl hydroxylase domain-containing protein 2, PHD2, and factor-inhibiting hypoxia-inducible factor 1, FIH1), and the protein levels of PHD2, FIH1, and hydroxyl-HIF-1-alpha (OH-HIF-1α) after the DPM or BaP treatment were further determined.ResultsUnder hypoxia, DPM exposure in the LFM induced the expression of HIF-1α, Bax, and Cleaved-caspase3 (P0.05), other PAH decreased cell viability when the concentration was above 1 μg·mL−1 (P

Aging is one of the hottest topics in biomedical research. Advances in research and medicine have helped to preserve human health, leading to an extension of life expectancy. However, the extension of life is an irreversible process that is accompanied by the development of aging-related conditions such as weakness, slower metabolism, and stiffness of vessels. It also debated that aging can be considered an actual disease with aging-derived comorbidities, including cancer or cardiovascular disease. Currently, cardiovascular disorders, including atherosclerosis, are considered as premature aging and represent the first causes of death in developed countries, accounting for 31% of annual deaths globally. Emerging evidence has identified hypoxia-inducible factor-1α as a critical transcription factor with an essential role in aging-related pathology, in particular, regulating cellular senescence associated with cardiovascular aging. In this review, we will focus on the regulation of senescence mediated by hypoxia-inducible factor-1α in age-related pathologies, with particular emphasis on the crosstalk between endothelial and vascular cells in age-associated atherosclerotic lesions. More specifically, we will focus on the characteristics and mechanisms by which cells within the vascular wall, including endothelial and vascular cells, achieve a senescent phenotype.

Treatment of oral tongue squamous cell carcinoma (OTSCC) frequently includes surgery with postoperative radiotherapy (RT) or chemoradiotherapy (CRT). Resistance to RT or CRT remains a major clinical challenge and highlights the need to identify predictive markers for it. We included 71 OTSCC patients treated with surgery combined with RT or CRT. We evaluated the association between tumor budding, tumor–stroma ratio (TSR), depth of invasion (DOI), tumor‐infiltrating lymphocytes (TILs), hypoxia‐inducible factor‐1alpha (HIF‐1alpha) expression, octamer‐binding transcription factor 4 (OCT4) expression, high‐endothelial venules (HEVs), and disease‐free survival (DFS) using uni‐ and multivariate analyses. No significant association was observed between the different histological and molecular markers (TSR, DOI, TILs, HEV, HIF‐1alph, OCT4) and DFS. However, an associative trend between DOI, budding, and DFS was noted. Further studies with larger cohorts are needed to explore the prognostic value of DOI and budding for OTSCC patients treated with postoperative RT or CRT. [ABSTRACT FROM AUTHOR]

• Paeoniae radix alba (PRA) improved ulcerative colitis induced by DSS (dextran sodium sulfate). • PRA improved intestinal mucosal microcirculation disturbance. • PRA inhibited inflammation and improved mucosal microcirculation disturbance by down-regulating lncRNA MALAT1/HIF-1α signaling pathway. Microcirculatory problems in the intestinal mucosa are the primary cause of ulcerative colitis (UC). Although UC is commonly treated with paeoniae radix alba (PRA), its exact mechanism of action is unclear. To examine how PRA affects UC induced by dextran sulfate sodium (DSS) and the mechanism of its effects. The primary active components of PRA were identified using high-performance liquid chromatography (HPLC), and network pharmacology techniques were used to predict the possible targets of action and signaling pathways in treatment for UC. A model of UC was established in vivo using rats, and a PRA intervention was performed. The amounts of cytokines in the colonic tissues and serum were measured using enzyme-linked immunosorbent assay (ELISA). The permeability of the intestinal mucosa was measured using a fluorescein isothiocyanate (FITC)-dextran assay and western blot. A PeriCam PSI system was used to view the microcirculation of the intestinal mucosa, and immunohistochemistry and immunofluorescence stains were used to detect angiogenesis. An electron microscope was used to observe the damage to the endothelium of the colon. Western blot and immunohistochemistry analyses were used to evaluate the protein expression of hypoxia-inducible factor-1 alpha (HIF-1α) in colon tissues, and qRT-PCR was used to assess the lncRNA expression of MALAT1. HPLC identified 10 main active components of PRA, and the network pharmacology results showed that the treatment of UC with PRA was associated with the HIF-1 signaling pathway. The results of animal experiments revealed that PRA significantly improved the pathological damage to the colon and the microcirculatory issues in the intestinal mucosa. PRA also inhibited colonic endothelial cell damage and angiogenesis, which may be related to the inhibition of the increased expression of lncRNA MALAT1 and HIF-1α in colon tissues. The anti-UC effect of PRA by improving intestinal mucosal microcirculatory disorders was first reported in this study. PRA deactivated the lncRNA MALAT1/HIF-1α pathway, inhibited endothelial angiogenesis, restored intestinal mucosal microvascular homeostasis, improved microcirculatory disorders, and alleviated the symptoms of DSS-induced UC in rats. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Immune thrombocytopenia (ITP) is characterized by immune-mediated platelet destruction and impaired megakaryocyte maturation. Hypoxia-inducible factor-1 alpha (HIF-1α), pivotal in the development of megakaryocytes and immune regulation, is downregulated in ITP. Roxadustat, which stabilizes HIF-1α, has emerged as a potential therapeutic drug for ITP that acts by enhancing HIF-1α-mediated megakaryocyte development and modulating immune responses., Objectives: This study evaluates the safety profile of roxadustat and its therapeutic efficacy for ITP treatment using Mendelian randomization (MR) analysis., Methods: We used expression Quantitative Trait Loci (eQTLs) data for roxadustat's target genes (EGLN1, EGLN2, EGLN3) and genetic associations with ITP, and adverse outcomes from the Open Genome-Wide Association Study (OpenGWAS) project. MR analysis included IVW, MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods to evaluate pleiotropy. Heterogeneity was assessed using Cochran's Q statistic and I 2 measure, with sensitivity analyses. A meta-analysis was performed to integrate effect sizes from multiple literature sources., Results: MR analysis revealed a significant association between roxadustat and reduced ITP risk (odds ratio [OR] 0.79, 95% confidence interval [CI] 0.66-0.95, P=0.01) with no evidence of horizontal pleiotropy. Meta-analysis confirmed the protective effect of roxadustat on ITP. Utilizing eQTLs of roxadustat's target gene EGLN1 as instrumental variables, an MR analysis of 39 potential adverse reactions revealed no significant increase, suggesting a favorable safety profile for roxadustat., Conclusion: Roxadustat demonstrates a potential protective effect against ITP without increasing the risk of adverse outcomes, suggesting its promise as a therapeutic option for ITP and warranting further investigation., (Copyright © 2024. Published by Elsevier Inc.)

MicroRNA-491-5p (miR-491-5p) plays an important role in regulating cell proliferation and migration; however, the effect of miR-491-5p on neovascularization after traumatic brain injury remains poorly understood. In this study, a controlled cortical injury model in C57BL/6 mice and an oxygen-glucose deprivation model in microvascular endothelial cells derived from mouse brain were established to simulate traumatic brain injury in vivo and in vitro, respectively. In the in vivo model, quantitative real-time-polymerase chain reaction results showed that the expression of miR-491-5p increased or decreased following the intracerebroventricular injection of an miR-491-5p agomir or antagomir, respectively, and the expression of miR-491-5p decreased slightly after traumatic brain injury. To detect the neuroprotective effects of miR-491-p, neurological severity scores, Morris water maze test, laser speckle techniques, and immunofluorescence staining were assessed, and the results revealed that miR-491-5p downregulation alleviated neurological dysfunction, promoted the recovery of regional cerebral blood flow, increased the number of lectin-stained microvessels, and increased the survival of neurons after traumatic brain injury. During the in vitro experiments, the potential mechanism of miR-491-5p on neovascularization was explored through quantitative real-time-polymerase chain reaction, which showed that miR-491-5p expression increased or decreased in brain microvascular endothelial cells after transfection with an miR-491-5p mimic or inhibitor, respectively. Dual-luciferase reporter and western blot assays verified that metallothionein-2 was a target gene for miR-491-5p. Cell counting kit 8 (CCK-8) assay, flow cytometry, and 2?,7?-dichlorofluorescein diacetate (DCFH-DA) assay results confirmed that the downregulation of miR-491-5p increased brain microvascular endothelial cell viability, reduced cell apoptosis, and alleviated oxidative stress under oxygen-glucose deprivation conditions. Cell scratch assay, Transwell assay, tube formation assay, and western blot assay results demonstrated that miR-491-5p downregulation promoted the migration, proliferation, and tube formation of brain microvascular endothelial cells through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor pathway. These findings confirmed that miR-491-5p downregulation promotes neovascularization, restores cerebral blood flow, and improves the recovery of neurological function after traumatic brain injury. The mechanism may be mediated through a metallothionein-2-dependent hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway and the alleviation of oxidative stress. All procedures were approved by Ethics Committee of the First Affiliated Hospital of Chongqing Medical University, China (approval No. 2020-304) on June 22, 2020.

Abstract Background Endothelial cell (EC) injury accelerates the progression of diabetic macrovascular complications. Hypoxia is an important cause of EC injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is an important hypoxia regulatory protein. Our previous studies showed that high-glucose and hypoxic conditions could upregulate HIF-1α expression and enhance EC inflammatory injury, independently of the nuclear factor kappa-B (NF-κB) pathway. However, it is not clear whether HIF-1α plays a role in vascular disease through epigenetic-related mechanisms. Methods We conducted gene expression analysis and molecular mechanistic studies in human umbilical vein endothelial cells (HUVECs) induced by hyperglycemia and hypoxia using RNA sequencing (RNA-seq) and small interfering HIF-1α (si-HIF-1α). We determined HIF-1α and Jumonji domain-containing protein 1 A (JMJD1A) expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, analyzed inflammatory protein secretion in the cell supernatant by enzymelinked immunosorbent assay (ELISA), and assessed protein interaction between HIF-1α and JMJD1A by chromatin immunoprecipitation (Ch-IP). We used the Cell Counting Kit8 (CCK-8) assay to analyze cell viability, and assessed oxidative stress indicators by using a detection kit and flow cytometry. Results High glucose and hypoxia up-regulated HIF-1α expression, and down-regulated HIF-1α decreased the level of inflammation and oxidative stress in HUVECs. To determine the downstream pathways, we observed histone demethylases genes and related pathway by RNA-sEq. Among these, JMJD1A was the most upregulated gene in histone demethylases. Moreover, we observed that HIF-1α bound to the promoter of JMJD1A, and the ameliorative effects of si-HIF-1α on oxidative stress and inflammatory cytokines in high-glucose and hypoxia-induced HUVECs were reversed by JMJD1A overexpression. Furthermore, knockdown of JMJD1A decreased inflammatory and oxidative stress injury. To determine the JMJD1A-related factors, we conducted gene expression analysis on JMJD1A-knockdown HUVECs. We observed that downregulation of inflammation and the oxidative stress pathway were enriched and FOS and FOSB might be important protective transcription factors. Conclusions These findings provide novel evidence that the HIF-1α/JMJD1A signaling pathway is involved in inflammation and oxidative stress in HUVECs induced by high glucose and hypoxia. Also, this pathway might act as a novel regulator of oxidative stress and inflammatory-related events in response to diabetic vascular injury and thus contribute to the pathological progression of diabetes and vascular disease.

Excessive alcohol use increases the risk of developing respiratory infections partially due to impaired alveolar macrophage (AM) phagocytic capacity. Previously, we showed that chronic ethanol (EtOH) exposure led to mitochondrial derangements and diminished oxidative phosphorylation in AM. Since oxidative phosphorylation is needed to meet the energy demands of phagocytosis, EtOH mediated decreases in oxidative phosphorylation likely contribute to impaired AM phagocytosis. Treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) ligand, pioglitazone (PIO), improved EtOH-mediated decreases in oxidative phosphorylation. In other models, hypoxia-inducible factor-1 alpha (HIF-1α) has been shown to mediate the switch from oxidative phosphorylation to glycolysis; however, the role of HIF-1α in chronic EtOH mediated derangements in AM has not been explored. We hypothesize that AM undergo a metabolic shift from oxidative phosphorylation to a glycolytic phenotype in response to chronic EtOH exposure. Further, we speculate that HIF-1α is a critical mediator of this metabolic switch. To test these hypotheses, primary mouse AM (mAM) were isolated from a mouse model of chronic EtOH consumption and a mouse AM cell line (MH-S) were exposed to EtOH in vitro. Expression of HIF-1α, glucose transporters (Glut1 and 4), and components of the glycolytic pathway (Pfkfb3 and PKM2), were measured by qRT-PCR and western blot. Lactate levels (lactate assay), cell energy phenotype (extracellular flux analyzer), glycolysis stress tests (extracellular flux analyzer), and phagocytic function (fluorescent microscopy) were conducted. EtOH exposure increased expression of HIF-1α, Glut1, Glut4, Pfkfb3, and PKM2 and shifted AM to a glycolytic phenotype. Pharmacological stabilization of HIF-1α via cobalt chloride treatment in vitro mimicked EtOH-induced AM derangements (increased glycolysis and diminished phagocytic capacity). Further, PIO treatment diminished HIF-1α levels and reversed glycolytic shift following EtOH exposure. These studies support a critical role for HIF-1α in mediating the glycolytic shift in energy metabolism of AM during excessive alcohol use. [ABSTRACT FROM AUTHOR]

Excessive alcohol use increases the risk of developing respiratory infections partially due to impaired alveolar macrophage (AM) phagocytic capacity. Previously, we showed that chronic ethanol (EtOH) exposure led to mitochondrial derangements and diminished oxidative phosphorylation in AM. Since oxidative phosphorylation is needed to meet the energy demands of phagocytosis, EtOH mediated decreases in oxidative phosphorylation likely contribute to impaired AM phagocytosis. Treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) ligand, pioglitazone (PIO), improved EtOH-mediated decreases in oxidative phosphorylation. In other models, hypoxia-inducible factor-1 alpha (HIF-1α) has been shown to mediate the switch from oxidative phosphorylation to glycolysis; however, the role of HIF-1α in chronic EtOH mediated derangements in AM has not been explored. We hypothesize that AM undergo a metabolic shift from oxidative phosphorylation to a glycolytic phenotype in response to chronic EtOH exposure. Further, we speculate that HIF-1α is a critical mediator of this metabolic switch. To test these hypotheses, primary mouse AM (mAM) were isolated from a mouse model of chronic EtOH consumption and a mouse AM cell line (MH-S) were exposed to EtOH in vitro. Expression of HIF-1α, glucose transporters (Glut1 and 4), and components of the glycolytic pathway (Pfkfb3 and PKM2), were measured by qRT-PCR and western blot. Lactate levels (lactate assay), cell energy phenotype (extracellular flux analyzer), glycolysis stress tests (extracellular flux analyzer), and phagocytic function (fluorescent microscopy) were conducted. EtOH exposure increased expression of HIF-1α, Glut1, Glut4, Pfkfb3, and PKM2 and shifted AM to a glycolytic phenotype. Pharmacological stabilization of HIF-1α via cobalt chloride treatment in vitro mimicked EtOH-induced AM derangements (increased glycolysis and diminished phagocytic capacity). Further, PIO treatment diminished HIF-1α levels and reversed glycolytic shift following EtOH exposure. These studies support a critical role for HIF-1α in mediating the glycolytic shift in energy metabolism of AM during excessive alcohol use.

Objective: The goal of this research was to determine the influence of 4 weeks aerobic training on gene expression of tumor necrosis factor alpha (TNF-α), hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in the cardiac tissue of diabetic rats. Materials and Methods: In an experimental study, 30 male wistar rats were partitioned into three groups (n=10), diabetic aerobic training, diabetic control and healthy control (n=10). Induction of type 2diabetes (T2DM) was done by intraperitoneal infusion of streptozotocin. The progressive aerobic training protocol entailed 4 weeks, 5 sessions per week running on treadmill at velocity of 20 m/min for 60 min. The gene expression of TNF-α, VEGF and HIF-1α were measured by real time & PCR. One way analysis of variance and bonferroni test were applied to analysis the data. The significant level was set at P-value< 0.05. Results: The results indicated that the aerobic training induced significant decrease in TNF-α mRNA (P-value< 0.001) and significant increase in HIF-1α mRNA (P-value< 0.001) and VEGF mRNA (P-value< 0.001) compared to diabetic control group. Conclusion: It appears that aerobic training with reduction of TNF-α issues an affirmative effect on angiogenesis, as a result, it improves diabetic cardiac.

• A modulator for cancer cell proliferation related with lipid metabolism is needed to be figure out. • It is revealed by informatics that FABP5 levels are upregulated in colon cancer tissues. • The enhanced FABP5 levels are correlated with the enriched-HIF-1 target gene levels. • The 3D culture mimicking in vivo revealed that tumor growth is reinforced by FABP5. • FABP5 regulates HIF-1 signaling pathway positively. • The FABP5/HIF-1α axis is a promising target for reversing colon cancer progression. Dysfunctional lipid metabolism is a known cause of cancer development and progression, yet little is known about the underlying molecular mechanisms that contribute to cancer progression. In this study, we demonstrate that fatty acid binding protein 5 (FABP5) is elevated in colon cancer tissue and this increased expression is linked to upregulation of the hypoxia-inducible factor-1 (HIF-1) signaling pathway. Under physiologically in vivo mimicked conditions via a polydimethylsiloxane (PDMS)-based three-dimensional (3D) culture chip, FABP5-knockdown colon cancer cells exhibited attenuated cell growth throughout the culture period. FABP5 was found to regulate HIF-1α protein levels and gene expression levels within the HIF-1α signaling pathway under hypoxic conditions. Our results provide evidence that supports the use of FABP5 as a prognostic factor in colon cancer. The FABP5/HIF-1α axis is a promising target for ameliorating fatty acid-triggered cancer progression. [ABSTRACT FROM AUTHOR]

Background: Endothelial cell (EC) injury accelerates the progression of diabetic macrovascular complications. Hypoxia is an important cause of EC injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is an important hypoxia regulatory protein. Our previous studies showed that high-glucose and hypoxic conditions could upregulate HIF-1α expression and enhance EC inflammatory injury, independently of the nuclear factor kappa-B (NF-κB) pathway. However, it is not clear whether HIF-1α plays a role in vascular disease through epigenetic-related mechanisms. Methods: We conducted gene expression analysis and molecular mechanistic studies in human umbilical vein endothelial cells (HUVECs) induced by hyperglycemia and hypoxia using RNA sequencing (RNA-seq) and small interfering HIF-1α (si-HIF-1α). We determined HIF-1α and Jumonji domain-containing protein 1 A (JMJD1A) expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, analyzed inflammatory protein secretion in the cell supernatant by enzymelinked immunosorbent assay (ELISA), and assessed protein interaction between HIF-1α and JMJD1A by chromatin immunoprecipitation (Ch-IP). We used the Cell Counting Kit8 (CCK-8) assay to analyze cell viability, and assessed oxidative stress indicators by using a detection kit and flow cytometry. Results: High glucose and hypoxia up-regulated HIF-1α expression, and down-regulated HIF-1α decreased the level of inflammation and oxidative stress in HUVECs. To determine the downstream pathways, we observed histone demethylases genes and related pathway by RNA-sEq. Among these, JMJD1A was the most upregulated gene in histone demethylases. Moreover, we observed that HIF-1α bound to the promoter of JMJD1A, and the ameliorative effects of si-HIF-1α on oxidative stress and inflammatory cytokines in high-glucose and hypoxia-induced HUVECs were reversed by JMJD1A overexpression. Furthermore, knockdown of JMJD1A decreased inflammatory and oxidative stress injury. To determine the JMJD1A-related factors, we conducted gene expression analysis on JMJD1A-knockdown HUVECs. We observed that downregulation of inflammation and the oxidative stress pathway were enriched and FOS and FOSB might be important protective transcription factors. Conclusions: These findings provide novel evidence that the HIF-1α/JMJD1A signaling pathway is involved in inflammation and oxidative stress in HUVECs induced by high glucose and hypoxia. Also, this pathway might act as a novel regulator of oxidative stress and inflammatory-related events in response to diabetic vascular injury and thus contribute to the pathological progression of diabetes and vascular disease. [ABSTRACT FROM AUTHOR]

The recurrence of rectal cancer or its resistance to neoadjuvant treatment develops due to the adaptation to hypoxia, apoptosis or autophagy. Survivin, one of the inhibitors of apoptosis; Beclin 1, which is a positive regulator in the autophagy pathway; and hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase-9 (CA9), which are associated with tumor tissue hypoxia, may be related to resistance to treatment. Our aim was to evaluate the potential tumor markers that may help to monitor the response to neoadjuvant treatment in locally advanced rectal cancer (RC). Twenty-five patients with locally advanced RC were included in the study. Gene expression and protein levels of Beclin 1, Survivin, HIF-1α, and CA9 were analyzed in fresh tissue specimens and blood samples. The relationships of these markers to tumor staging and regression grade were evaluated. Higher blood CA9 gene expression levels and lower blood HIF-1α protein levels were found in the response group according to tumor regression grade. After neoadjuvant treatment, tissue Beclin 1 and blood Survivin gene expressions and tissue CA9, blood Beclin 1 and blood HIF-1α protein levels decreased significantly. Beclin 1, Survivin, HIF-1α ve CA9 may help to predict the effects of the applied treatment approach. [ABSTRACT FROM AUTHOR]

Clinical Trial Id: NCT04206631.Background: Acne vulgaris is a polymorphic skin condition comprising inflamed and noninflamed lesions. In addition to topical retinoids, systemic antibiotics play a role as a main therapy for acne with inflamed papules and cysts. However, due to the increasing tendency for bacterial resistance, alternatives to antibiotics are needed.Objective: The aim of this study was to evaluate the effectiveness of acne lesion extraction compared to oral doxycycline for moderate acne vulgaris and to explore the impact of both treatments on Hypoxia-inducible factor (HIF)-1 alpha.Methods: This randomized clinical trial was conducted in two teaching hospitals in 2016. Subjects with moderate acne vulgaris (N=140) were divided into two groups. Each subject in both groups received 0.05% tretinoin cream, applied to the entire face each night, and 2.5% benzoyl peroxide gel, applied to the acne lesions in the morning and afternoon. One group was also treated with oral doxycycline 100mg once daily and the other was treated with acne lesion extraction performed on all facial lesions every two weeks; the patients were evaluated via patient-reported self-assessment and lesion counts every two weeks for six weeks. HIF-1 alpha expression of the biopsied lessions was examined via immunohistochemistry.Results: 128 subjects completed the study. Among these 128 subjects there was a prominent decrease in inflamed lesions at Week 6 in the lesion extraction group compared to the oral doxycycline group (p<0.05). HIF-1 alpha expression of the biopsied lesions was found in 7 of 9 samples taken from the oral doxycycline group, while 3 of 4 samples in the lesion extraction group were found negative.Conclusion: According to our results, acne lesion extraction appeared to be more effective than oral doxycycline in treating this sample of patients with moderate acne vulgaris. Additionally, HIF-1 alpha expression appeared to be decreased after acne lesion extraction. [ABSTRACT FROM AUTHOR]

Osimertinib (OSI) resistance commonly occurs during the treatment of non-small-cell lung cancer (NSCLC). This study aims to investigate whether the thermal effects of radiofrequency ablation (RFA) can increase the sensitivity of OSI-resistant NSCLC to OSI treatment and whether OSI effectively inhibits the recurrence of OSI-resistant NSCLC following RFA treatment and improve survival of NSCLC patients. In vitro, OSI-resistant NCI-H1975 (NCI-H1975/OSIR) cells and thermotolerant NCI-H1975/OSIR (NCI-H1975/OSIR-a-h) cells were established using human NSCLC cell line NCI-H1975. Cell viability, apoptosis, sensitivity to OSI, threonine-methionine amino acid substitution at position 790 (T790M) mutation levels, and protein expression of epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), hypoxia-inducible factor-1 alpha (HIF-1a) were detected using different methods. In vivo, a nude mouse model of metastatic human lung cancer was developed and subjected to RFA treatment. The tumor growth, apoptosis, sensitivity to OSI, expression of EGFR/PI3K/AKT/HIF-1a, and CD34 levels were detected in the micrometastases of the transition zone (TZ) around the central ablation zone, and the reference zone (RZ) far from central ablation zone. NCI-H1975/OSIR and thermotolerant NCI-H1975/OSIR cell models were successfully established. Thermotolerant NCI-H1975/OSIR cells show higher sensitivity to OSI than NCI-H1975/OSIR cells and NCI-H1975 cells. OSI treatment can inhibit the EGFR/PI3K/AKT pathway and induce apoptosis in both NCI-H1975 cells and thermotolerant NCI-H1975/OSIR cells, but not in NCI-H1975/OSIR cells. In vivo, RFA treatment increases sensitivity to OSI in NCI-H1975/OSIR cell micrometastases in the TZ but not in the RZ. OSI intervention effectively inhibits the over-proliferation of micrometastases and activation of the EGFR/PI3K/AKT pathway, and induces apoptosis of micrometastases in the TZ, but shows little effects on the micrometastases in the RZ. The thermal effects can increase the sensitivity of OSI-resistant NSCLC cells to OSI through the EGFR/PI3K/AKT/HIF-1a signaling pathway, indicating that RFA combined with OSI might be a clinically effective and comprehensive therapy for the treatment of OSI-resistant NSCLC. [ABSTRACT FROM AUTHOR]

BackgroundThe combination of antiapoptotic and angiogenic actions may represent a pharmacotherapeutic strategy for the treatment of myocardial infarction. Fibroblast growth factor (FGF) is expressed in various cell types including endothelial and muscle cells and promotes their survival, migration, and proliferation.Methods and ResultsMyocardial microvascular endothelial cells were divided into four treatment groups, the sham, hypoxia, basic FGF (bFGF), and bFGF plus 2-methoxyestradiol groups, and subjected to in vitro apoptotic analysis and Matrigel assays. An in vivo model of myocardial infarction was established by ligaturing the left coronary artery of mice in the four treatment groups. Cardiac performance, myocardial injury, endothelial cell angiogenesis, and myocardial apoptosis were assessed. bFGF administration after myocardial infarction improved cardiac function and cell viability, attenuated myocardial injury and apoptosis, and enhanced angiogenesis. Western blotting of HIF-1α, p-AKT, VEGF, p53, BAX, and Bcl-2 showed that bFGF increased HIF-1α, p-AKT, VEGF, and Bcl-2 and decreased BAX protein levels.ConclusionThe results of the present study indicated that bFGF attenuates myocardial injury by inhibiting apoptosis and promoting angiogenesis via a novel HIF-1α-mediated mechanism and a potential utility of bFGF in protecting against myocardial infarction.

Introduction:Hypoxia-inducible factor-1 (HIF-1) is the protein product of the gene with the same name that is induced by hypoxia and induces a series of reactions that act in the adaptive response of the cell. HIF-1 activation is a primary defense mechanism against the hypoxia of the tissue. In general, it is activated when tissue oxygenation is disrupted. Tissue hypoxia in kidney disease provides adaptation to the current situation by activating the HIF-1 alpha level. In this report, it was aimed to measure HIF-1 alpha levels in early stage renal failure patients, compare them with healthy volunteers, and evaluate the relationship between HIF-1 alpha and other biochemical and inflammatory parameters.Methods:This study included 22 healthy subjects (male/ female; 8/14) as the control group and 25 patients (male/ female; 11/14) who are followed up in the outpatient clinic with the diagnosis of early stage renal failure (glomerular filtration rate 60-90 mL/min/1.73m²). HIF-1 alpha level, biochemical parameters [glucose, creatinine, uric acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT)], hemoglobin and inflammatory parameters [C-reactive protein (CRP), neutrophil/lymphocyte ratio], platelet count (PLT), platelet parameters [mean platelet volume (MPV), plateletcrit (PCT) and platelet distribution width (PDW)] were viewed in venous blood samples in both groups, and results were compared using descriptive statistical methods as well as Mann-Whitney U, chi-square, student t-test.Results:HIF-1 alpha, glucose, AST, ALT, gamma-glutamyl transpeptidase (GGT), PLT, MPV, PCT and PDW values were not statistically significantly different (p>0.05) among the case and control groups. There was no statistically significant correlation (p>0.05) between HIF-1 alpha and glucose, urea, creatinine, AST, GGT, CRP, neutrophile/lymphocyte ratio, PLT, MPV, PCT, PDW values.Conclusion:It is known that chronic hypoxia is an important factor in the progression of chronic renal diseases regardless of the underlying cause. It was assumed that the factors including normotension, normal hemoglobin level and the presence of medical therapy reducing oxidative stress (angiotensin converting enzyme inhibitors and angiotensin receptor blockers) in the patientsimproved renal hypoxia and therefore affected the results of this study.

Background: Tumor cells that have the ability to express vascular endothelial growth factor (VEGF) are more competent to growth and metastasize by the adequate amount of blood and oxygen supply by the blood vessels to the growing mass of cells. Hypoxic tumors are known for its aggressiveness and resistance to the treatment. Targeting VEGF and hypoxia‑inducible factor‑1 alpha (HIF‑1α) is an attractive strategy to interrupt the multiple pathways crucial for tumor growth. In the present study, two thiazole acetamide derivative’s anticancer property, anti VEGF and HIF‑1α inhibitory property were investigated. Methodology: Two thiazole acetamide compounds were synthesized, TA1 and TA2 and its anticancer property was studied in Erlich’s ascites cancer cells. To evaluate the anticancer property the assays such as 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assay, DNA diffusion assay for apoptosis, and lactate dehydrogenase leakage assay were carried out. The cell culture media was used to assess the secreted VEGF level. Molecular docking studies were performed to analyze the binding efficiency of the study compounds to the kinase insert domain‑containing receptor (KDR) and fms‑like tyrosine kinase (FLT)‑binding domains of VEGF protein. HIF‑1α inhibitory study was performed by flow cytometry analysis using HUVEC cell line. Results: The study compounds inhibited HIF‑1α and VEGF secretion, these data shown positive prop up for the anticancer property of the derivatives. The docking studies showed moderate binding of study compounds to KDR and FLT‑binding domains of VEGF protein. Conclusion: These results conclude the anticancer and anti‑angiogenic property of the synthesized thiazole‑acetamide derivatives. [ABSTRACT FROM AUTHOR]

Background: Tumor cells that have the ability to express vascular endothelial growth factor (VEGF) are more competent to growth and metastasize by the adequate amount of blood and oxygen supply by the blood vessels to the growing mass of cells. Hypoxic tumors are known for its aggressiveness and resistance to the treatment. Targeting VEGF and hypoxia-inducible factor-1 alpha (HIF-1α) is an attractive strategy to interrupt the multiple pathways crucial for tumor growth. In the present study, two thiazole acetamide derivative's anticancer property, anti VEGF and HIF-1α inhibitory property were investigated.Methodology: Two thiazole acetamide compounds were synthesized, TA1 and TA2 and its anticancer property was studied in Erlich's ascites cancer cells. To evaluate the anticancer property the assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, DNA diffusion assay for apoptosis, and lactate dehydrogenase leakage assay were carried out. The cell culture media was used to assess the secreted VEGF level. Molecular docking studies were performed to analyze the binding efficiency of the study compounds to the kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase (FLT)-binding domains of VEGF protein. HIF-1α inhibitory study was performed by flow cytometry analysis using HUVEC cell line.Results: The study compounds inhibited HIF-1α and VEGF secretion, these data shown positive prop up for the anticancer property of the derivatives. The docking studies showed moderate binding of study compounds to KDR and FLT-binding domains of VEGF protein.Conclusion: These results conclude the anticancer and anti-angiogenic property of the synthesized thiazole-acetamide derivatives. [ABSTRACT FROM AUTHOR]

The high prevalence of the risk factors for Non-Alcoholic Fatty Liver Disease (NAFLD) made it one of the most common noncommunicable diseases with high morbidity, nationally and worldwide. Early pathogenic implication of cellular hypoxia in Asymptomatic Simple Non-Alcoholic Isolated Hepatosteatosis (ANIHS) was investigated in this cross-sectional study and correlated changes in systemic hypoxia biomarkers with body mass index (BMI) in apparently healthy ANIHS participants with normal liver enzymes and size. We enrolled 180 adult consented volunteering Saudi participants in the period from January 1 to June 1, 2019. They comprised of normal lean healthy controls (n = 40; BMI = 18.5-25) and ANIHS participants (n 140) that were subdivided as overweight (n = 64; BMI = 25.1 - 30) and obese (n = 76; BMI >30 - <40). Male/female ratio was 1:1 and age range was 24 - 50 years (37.0 ± 7.85) without significant differences among groups. The cellular hypoxia biomarkers; lactate, pyruvate, lactate: pyruvate (L/P) ratio & hypoxia inducible factor (HIF)-1α were estimated in fasting plasma. Lactate was significantly higher in obese ANIHS compared to each of overweight ANSHS participants and controls. Pyruvate was significantly lowest in overweight ANIHS followed by obese ANIHS participants - compared to highest level in controls. L/P ratio was highest in obese ANIHS followed by overweight ANIHS participants, compared to controls. HIF-1α was more than 3-folds higher in obese ANIHS participants compared to healthy controls, with a mild increase in overweight ANIHS participants. Pyruvate and the ratio were significantly connected to steatosis, whereas lactate and HIF-1α were significantly connected to both BMI and hepatosteatosis. Cellular hypoxic changes may be implicated in pathogenesis of ANIHS. Plasma HIF-1α level reflects the correlation between BMI and occurrence/progression of ANIHS. Cellular hypoxia with responsive increases in HIF-1α could be prognostically good provided that it correlates a cytoprotective functional transcriptional response. [ABSTRACT FROM AUTHOR]

Background: The combination of antiapoptotic and angiogenic actions may represent a pharmacotherapeutic strategy for the treatment of myocardial infarction. Fibroblast growth factor (FGF) is expressed in various cell types including endothelial and muscle cells and promotes their survival, migration, and proliferation. Methods and Results: Myocardial microvascular endothelial cells were divided into four treatment groups, the sham, hypoxia, basic FGF (bFGF), and bFGF plus 2-methoxyestradiol groups, and subjected to in vitro apoptotic analysis and Matrigel assays. An in vivo model of myocardial infarction was established by ligaturing the left coronary artery of mice in the four treatment groups. Cardiac performance, myocardial injury, endothelial cell angiogenesis, and myocardial apoptosis were assessed. bFGF administration after myocardial infarction improved cardiac function and cell viability, attenuated myocardial injury and apoptosis, and enhanced angiogenesis. Western blotting of HIF-1α, p-AKT, VEGF, p53, BAX, and Bcl-2 showed that bFGF increased HIF-1α, p-AKT, VEGF, and Bcl-2 and decreased BAX protein levels. Conclusion: The results of the present study indicated that bFGF attenuates myocardial injury by inhibiting apoptosis and promoting angiogenesis via a novel HIF-1α-mediated mechanism and a potential utility of bFGF in protecting against myocardial infarction. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) is the most advanced stage of peripheral artery disease, associated with significant risk of limb loss, morbidity and mortality; however, there remains unmet therapeutic needs for arterial revascularization and ischemic tissue repair. Stem cell therapies have emerged as compelling candidates due to beneficial proangiogenic and immunosuppressive function. Nevertheless, in vivo efficacy was insufficient in proliferation, differentiation and survival/engraftment rate. Cardiac stem cells (CSCs) was firstly attempted for CLI as a novel therapeutic modality to provide superior angiogenic potency to bone marrow-derived stem cells (BMSCs). It was noted that CSCs demonstrated 3.2-fold in HGF, 2.9-fold in VEGF and 8.7-fold in PDGF-B higher gene expressions compared to BMSCs. To enhance the hypoxia-induced proangiogenic effect, CSCs were transfected with hypoxia-inducible factor-1 alpha (HIF-1α) by using electroporation method, specifically optimized for CSCs yielding 45.77% of transfection efficiency and 89.75% of viability. HIF-1α overexpression significantly increased CSC survival in hypoxia, proangiogenic factors production and endothelial differentiation. In mouse hind limb ischemia model, local intramuscular delivery of CSC overexpressing HIF-1α (HIF-CSC) significantly improved the blood flow recovery. Histological analysis revealed that muscle degeneration and fibrosis in the ischemic limb were attenuated. Local delivery of HIF-CSC might be a promising option for ischemic tissue restoration. Unlabelled Image • Cardiac stem cells (CSC) show better proangiogenic potential than BMSCs. • HIF-1α gene is transfected into CSC by electroporation. • Overexpression of HIF-1α augments migration and endothelial differentiation of CSC. • The injection of HIF-CSC with fibrin gel improves blood perfusion in limb ischemia. [ABSTRACT FROM AUTHOR]

Objective: The goal of this research was to determine the influence of 4 weeks aerobic training on gene expression of tumor necrosis factor alpha (TNF-α), hypoxia-inducible factor-1 alpha (HIF-1a) and vascular endothelial growth factor (VEGF) in the cardiac tissue of diabetic rats. Materials and Methods: In an experimental study, 30 male wistar rats were partitioned into three groups (n=10), diabetic aerobic training, diabetic control and healthy control (n=10). Induction of type 2diabetes (T2DM) was done by intraperitoneal infusion of streptozotocin. The progressive aerobic training protocol entailed 4 weeks, 5 sessions per week running on treadmill at velocity of 20 m/min for 60 min. The gene expression of TNF-α, VEGF and HIF-1α were measured by real time & PCR. One way analysis of variance and bonferroni test were applied to analysis the data. The significant level was set at P-value< 0.05. Results: The results indicated that the aerobic training induced significant decrease in TNF-α mRNA (P-value< 0.001) and significant increase in HIF-1α mRNA (P-value< 0.001) and VEGF mRNA (P-value< 0.001) compared to diabetic control group. Conclusion: It appears that aerobic training with reduction of TNF-α issues an affirmative effect on angiogenesis, as a result, it improves diabetic cardiac. [ABSTRACT FROM AUTHOR]

CONTEXT: Glioblastoma is a malignant brain tumor with limited treatment modalities due to its nature. SB365, Pulsatilla saponin D, is known to induce apoptosis and inhibit the growth of many cancer cells. AIM: We elucidated the anticancer effects of SB365 in glioblastoma cells. METHODS: We examined the antiproliferative activity of SB365 in human glioblastoma cell lines. Apoptosis was evaluated using the Hoechst assay, TUNEL assay, DAPI nuclear staining, and Western blotting analysis. To test the antimetastatic capacity of SB365, cell migration assay was conducted, and hypoxia-inducible factor-1 alpha (HIF-1a) expression and vascular endothelial growth factor (VEGF) level were determined under hypoxic conditions. STATICAL ANALYSIS: Significance of the results was confirmed by a one-way analysis of variance analysis. RESULTS: SB365 treatment suppressed the growth of glioblastoma cells and resulted in apoptotic morphological features such as nuclear condensation and fragmentation, enhancing the expression of cleaved poly (ADP-ribose) polymerase and caspase-3. It also significantly delayed cell migration and decreased the HIF-1a expression and VEGF secretion. CONCLUSION: Our findings thus demonstrate that SB365 induced apoptosis and delayed the growth and migration of human glioblastoma cells. It is considered that SB365 would be a promising therapeutic option for glioblastoma. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD)-related brain deterioration is linked to the type 2 diabetes mellitus (T2DM) features hyperglycemia, hyperinsulinemia, and insulin resistance. Hypoxia as a common risk factor for both AD and T2DM. Hypoxia-inducible factor-1 alpha (HIF-1α) acts as the main regulator of the hypoxia response and may be a key target in the comorbidity of AD and T2DM. HIF-1α expression is closely related to hyperglycemia, insulin resistance, and inflammation. Tissue oxygen consumption disrupts HIF-1α homeostasis, leading to increased reactive oxygen species levels and the inhibition of insulin receptor pathway activity, causing neuroinflammation, insulin resistance, abnormal Aβ deposition, and tau hyperphosphorylation. HIF-1α activation also leads to the deposition of Aβ by promoting the abnormal shearing of amyloid precursor protein and inhibiting the degradation of Aβ, and it promotes tau hyperphosphorylation by activating oxidative stress and the activation of astrocytes, which further exasperates AD. Therefore, we believe that HIF-α has great potential as a target for the treatment of AD. Importantly, the intracellular homeostasis of HIF-1α is a more crucial factor than its expression level. [Display omitted] [ABSTRACT FROM AUTHOR]

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Skeletal muscle is able to modify its size, and its metabolic/contractile properties in response to a variety of stimuli, such as mechanical stress, neuronal activity, metabolic and hormonal influences, and environmental factors. A reduced oxygen availability, called hypoxia, has been proposed to induce metabolic adaptations and loss of mass in skeletal muscle. In addition, several evidences indicate that muscle fiber-type composition could be affected by hypoxia. The main purpose of this review is to explore the adaptation of skeletal muscle fiber-type composition to exposure to high altitude (ambient hypoxia) and under conditions of pathological hypoxia, including chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF) and obstructive sleep apnea syndrome (OSAS). The muscle fiber-type composition of both adult animals and humans is not markedly altered during chronic exposure to high altitude. However, the fast-to-slow fiber-type transition observed in hind limb muscles during post-natal development is impaired in growing rats exposed to severe altitude. A slow-to-fast transition in fiber type is commonly found in lower limb muscles from patients with COPD and CHF, whereas a transition toward a slower fiber-type profile is often found in the diaphragm muscle in these two pathologies. A slow-to-fast transformation in fiber type is generally observed in the upper airway muscles in rodent models of OSAS. The factors potentially responsible for the adaptation of fiber type under these hypoxic conditions are also discussed in this review. The impaired locomotor activity most likely explains the changes in fiber type composition in growing rats exposed to severe altitude. Furthermore, chronic inactivity and muscle deconditioning could result in the slow-to-fast fiber-type conversion in lower limb muscles during COPD and CHF, while the factors responsible for the adaptation of muscle fiber type during OSAS remain hypothetical. Finally, the role played by cellular hypoxia, hypoxia-inducible factor-1 alpha (HIF-1α), and other molecular regulators in the adaptation of muscle fiber-type composition is described in response to high altitude exposure and conditions of pathological hypoxia.

Bone marrow-derived mesenchymal stem cells (MSCs) have therapeutic effects in experimental models of lung injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is a transcriptional regulator that influences cellular metabolism, energetics, and survival under hypoxic conditions. The current study investigated the effects of stabilizing HIF-1α on the therapeutic capacity of MSCs in an experimental mouse model of bacterial pneumonia. HIF-1α stabilization was achieved by the small molecule prolyl-hydroxlase inhibitor, AKB-4924 (Aerpio Therapeutics, Inc.), which blocks the pathway for HIF-1α degradation in the proteosome. In vitro, pre-treatment with AKB-4924 increased HIF-1α levels in MSCs, reduced the kinetics of their cell death when exposed to cytotoxic stimuli, and increased their antibacterial capacity. In vivo, AKB-4924 enhanced MSC therapeutic capacity in experimental pneumonia as quantified by a sustainable survival benefit, greater bacterial clearance from the lung, decreased lung injury, and reduced inflammatory indices. These results suggest that HIF-1α stabilization in MSCs, achieved ex vivo, may represent a promising approach to augment the therapeutic benefit of these cells in severe pneumonia complicated by acute lung injury.

AIM: To silent hypoxia inducible factor-1α(HIF-1α)gene in malignant melanoma of the choroid cell by small interference RNA(siRNA)and investigate its effect on the expression of matrix metalloproteinase-2(MMP-2)in the choroid cell line human uveal melanoma cell(OCM-1)in hypoxia environment. METHODS: OCM-1 cells cultured on culture flask were divided into normal group and hypoxia group. Hypoxia group were divided into five groups: simple hypoxic group, and interference group, and negative control group, and positive control group, and liposome group. Normal group cells were cultured on DMEM culture flask with 10% FBS, 100U/mL penicillin, 100μg/mL streptomycin as well as high concentration of glucose. The cells were maintained at 37℃ in a humidified 5% CO2 incubator. Cells in good condition were selected for experiment. For hypoxia group, chemical hypoxia inducer CoCl2 was added into nutrient medium at the concentration of 100μmol/L to simulate hypoxia microenvironment. We designed and synthesised siRNA(siRNA+negative control+positive control), the target sequences of the HIF-1α to transfect hypoxic malignant melanoma of the choroid cell. SiRNA including HIF-1α siRNA, β-actin siRNA and negative control group synthesized in vitro transfected hypoxic OCM-1 cell through Lipofectamine2000. The expression of HIF-1α, MMP-2 gene and the protein were detected by RT-PCR and Western blot.RESULTS: Compared with the normal group, the expression of HIF-1α mRNA was not obviously changed(P>0.05), but the expression of HIF-1α protein and MMP-2 mRNA protein was significantly higher(PPPP>0.05).CONCLUSION: Hypoxia status may upregulate the HIF-1α in OCM-1 cells by increasing the expression of protein. Hypoxia can also inactivate MMP-2, resulting in upregulation of MMP-2 RNA and the expression of its protein. The expression of HIF-1α and MMP-2 mRNA can be down-upregulated by transfecting OCM-1 with HIF-1α siRNA.

Aim of Study: Association between hypoxia-inducible factor-1 alpha (HIF-1α) gene polymorphism and renal cell carcinoma (RCC) susceptibility is still being conflicting. This meta-analysis was performed to assess the relationship between HIF-1α C1772T (rs11549465)/G1790A (rs11549467) gene polymorphism and RCC risk. Materials and Methods: Association studies were identified from the databases of PubMed and CBM-disc (China Biological Medicine Database) as of July 1, 2015, and eligible investigations were included and synthesized using meta-analysis method. Results: Five investigations were identified, and the meta-analysis was conducted to assess the association between HIF-1α gene polymorphism and RCC risk. There was a marked association between HIF-1α C1772T TT genotype and RCC susceptibility, and the association between HIF-1α C1772T T allele/CC genotype and RCC risk was not found in overall populations (T: odds ratios [OR] =1.04, 95% confidence interval [CI]: 0.70–1.54, P = 0.84; TT: OR = 0.13, 95% CI: 1.60–2.34, P = 0.01; CC: OR = 1.18, 95% CI: 0.68–2.07, P = 0.55). Furthermore, a marked association between HIF-1α G1790A AA genotype and RCC susceptibility was found, and the association between HIF-1α G1790A A allele/GG genotype and RCC risk was not found in overall populations (A: OR = 1.53, 95% CI: 0.60–3.92, P = 0.38; AA: OR = 3.09, 95% CI: 1.38–6.92, P = 0.006; GG: OR = 0.63, 95% CI: 0.20–2.03, P = 0.44). Conclusion: HIF-1α C1772T TT genotype and HIF-1α G1790A AA genotype were associated with RCC susceptibility. However, more investigations are required to further clarify the association. [ABSTRACT FROM AUTHOR]

Aim Of Study: Association between hypoxia-inducible factor-1 alpha (HIF-1α) gene polymorphism and renal cell carcinoma (RCC) susceptibility is still being conflicting. This meta-analysis was performed to assess the relationship between HIF-1α C1772T (rs11549465)/G1790A (rs11549467) gene polymorphism and RCC risk.Materials and Methods: Association studies were identified from the databases of PubMed and CBM-disc (China Biological Medicine Database) as of July 1, 2015, and eligible investigations were included and synthesized using meta-analysis method.Results: Five investigations were identified, and the meta-analysis was conducted to assess the association between HIF-1α gene polymorphism and RCC risk. There was a marked association between HIF-1α C1772T TT genotype and RCC susceptibility, and the association between HIF-1α C1772T T allele/CC genotype and RCC risk was not found in overall populations (T: odds ratios [OR] =1.04, 95% confidence interval [CI]: 0.70-1.54, P = 0.84; TT: OR = 0.13, 95% CI: 1.60-2.34, P = 0.01; CC: OR = 1.18, 95% CI: 0.68-2.07, P = 0.55). Furthermore, a marked association between HIF-1α G1790A AA genotype and RCC susceptibility was found, and the association between HIF-1α G1790A A allele/GG genotype and RCC risk was not found in overall populations (A: OR = 1.53, 95% CI: 0.60-3.92, P = 0.38; AA: OR = 3.09, 95% CI: 1.38-6.92, P = 0.006; GG: OR = 0.63, 95% CI: 0.20-2.03, P = 0.44).Conclusion: HIF-1α C1772T TT genotype and HIF-1α G1790A AA genotype were associated with RCC susceptibility. However, more investigations are required to further clarify the association. [ABSTRACT FROM AUTHOR]

Skeletal muscle is able to modify its size, and its metabolic/contractile properties in response to a variety of stimuli, such as mechanical stress, neuronal activity, metabolic and hormonal influences, and environmental factors. A reduced oxygen availability, called hypoxia, has been proposed to induce metabolic adaptations and loss of mass in skeletal muscle. In addition, several evidences indicate that muscle fiber-type composition could be affected by hypoxia. The main purpose of this review is to explore the adaptation of skeletal muscle fiber-type composition to exposure to high altitude (ambient hypoxia) and under conditions of pathological hypoxia, including chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF) and obstructive sleep apnea syndrome (OSAS). The muscle fiber-type composition of both adult animals and humans is not markedly altered during chronic exposure to high altitude. However, the fast-to-slow fiber-type transition observed in hind limb muscles during post-natal development is impaired in growing rats exposed to severe altitude. A slow-to-fast transition in fiber type is commonly found in lower limb muscles from patients with COPD and CHF, whereas a transition toward a slower fiber-type profile is often found in the diaphragm muscle in these two pathologies. A slow-to-fast transformation in fiber type is generally observed in the upper airway muscles in rodent models of OSAS. The factors potentially responsible for the adaptation of fiber type under these hypoxic conditions are also discussed in this review. The impaired locomotor activity most likely explains the changes in fiber type composition in growing rats exposed to severe altitude. Furthermore, chronic inactivity and muscle deconditioning could result in the slow-to-fast fiber-type conversion in lower limb muscles during COPD and CHF, while the factors responsible for the adaptation of muscle fiber type during OSAS remain hypothetical. Finally, the role played by cellular hypoxia, hypoxia-inducible factor-1 alpha (HIF-1α), and other molecular regulators in the adaptation of muscle fiber-type composition is described in response to high altitude exposure and conditions of pathological hypoxia. [ABSTRACT FROM AUTHOR]

Background The prognostic predict biomarkers are important in oral squamous cell carcinoma (OSCC). We investigated the expression patterns and quantitation of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) in OSCC patients. Among OSCC patients with recurrence and metastasis, the expression percentages of HIF-1α and VEGF also were analyzed. Methods Thirty-eight patients (8 hyperkeratosis, 30 oral squamous cell carcinoma) were included in this study. In the follow-up period, 5 OSCC patients had metastasis and 12 OSCC patients had local recurrence. We used computer-assisted image processing to analyze immunohistochemistry (IHC). The quantitative analysis of IHC slides, including upper-layer epithelium (U) and lower-layer epithelium (L), was calculated. Results We found homogeneous expression of VEGF in the epithelium. However, two patterns of HIF-1α expression were observed: homogeneous and heterogeneous. The highest U + L layer percentage in HIF-1α and VEF expression had significant association in tumor metastasis and recurrence ( p < 0.001 in HIF-1α and p < 0.001 in VEGF). U + L layer HIF-1α expression percentage was >156.4%, and the survival rate was poor ( p < 0.001). Conclusion HIF-1α expression was not only influenced by tumor hypoxia, it also reflected tumor cell characteristics. High concentrations of VEGF and HIF-1α may have value as prognostic markers of tumor metastasis and recurrence. [ABSTRACT FROM AUTHOR]

AIM: To investigate the morphological changes and the expression of hypoxia-inducible factor-1 alpha(HIF-1α)subunit during embryonic development of rat lens and explore the role of HIF-1α in lens development process. METHODS: Thirty clean pregnant Wistar rats were divided into 6 embryon groups,10-d, 12-d, 14-d, 16-d, 18-d and 20-d embryo. Two embryons were randomized obtained from every pregnant rat. One of the eyeball samples that were parallel to sagittal axis of optic nerve were cut into serial sections, used HE staining and examined by light microscope. Expression of HIF-1α protein in lens was detected by immunohistochemistry. The positive expression of HIF-1α mRNA of the other eyeball samples was detected by real-time PCR.RESULTS:In the 10th d of embryo(E10), the formation of lens vesicle were recognized under the light microscope. In the 12th d of embryo(E12), the anteriorly situated cells and posteriorly situated cells have already differentiated. The anteriorly situated cells were epithelium. In the 14th d of embryo(E14), primary fibers which came from posteriorly situated cells were examined. In the 16th d of embryo(E16), the lens epithelium undergoes extensive proliferation, and enlongate into the secondary fibers. In the 20th d of embryo(E20), the lens was maturation. By immunohistochemistry staining, the HIF-1α was highly expressed in the lens embryonic development. The expression was gradually promoting from E10 to E16, then reducing. The lens epithelium expressed more HIF-1α than fibers. The highest mean density was at E16, the lowest at E20. The difference was significant among of the 6 groups(PP>0.05). The other groups were compared with each other, finding significant difference(PPP>0.05). The other groups were compared with each other, finding significant difference(P<0.05). CONCLUSION:The lens of Wistar rats differentiate from the E10 when the vesicle formed through the embryo phase. The lens is basic mature before birth. The HIF-1α in the lens embryonic development is highly expressed and changeful. The varies of HIF-1α expression is depend upon rat embryo development indicating that HIF-1α might participate in the process of development of rat lens.

AIM:To investigate the effect of specific silencing hypoxia inducible factor-1 alpha(HIF-1α)by small interference RNA(siRNA)on expression of vimentin in human uveal melanoma cell lines(OCM-1)under hypoxia, in order to discuss the role of HIF-1α on epithelial-mesenchymal transition(EMT)in uveal melanoma.METHODS: OCM-1 cells were cultured under normoxia and hypoxia in vitro. We added chemical hypoxia inducer cobalt chloride(CoCl2)into nutrient medium at the concentration of 100μmol/L to simulate hypoxia microenvironment inside tumor to culture cells of hypoxic group. And hypoxic group cells were divided into five groups: simple hypoxic group, interference group, positive control group, negative control group and liposome group. SiRNA(including HIF-1α-siRNA, β-actin-siRNA and negative control)were designed and synthetized in vitro. LipofectamineTM 2000 was taken to transfect siRNA into OCM-1 cells under hypoxia. RT-PCR and Western blot were used to check the expression status of HIF-1α and vimentin on mRNA and protein levels before and after hypoxia culture and cell transfection.RESULTS: Compared with normoxia group, there was no obvious change on the expression level of mRNA of HIF-1α in simple hypoxia group(P>0.05), while the expression level of its protein increased obviously(PPPPP>0.05). CONCLUSION: Hypoxia can up-regulate the expression of HIF-1α on protein level in OCM-1 cells, and activate the transcription of vimentin as the downstream gene of HIF-1α, up-regulate the expression of vimentin both on mRNA and protein levels. This hints that HIF-1α can regulate the EMT in uveal melanoma and plays an important role in the process of tumor invasion and metastasis. We successfully down-regulate the expression of HIF-1α and vimentin by transfecting OCM-1 with HIF-1α-siRNA. This suggests that suppression the expression of HIF-1α at the molecular level maybe can shut down the process of tumor invasion and metastasis and offer new directions for cancer treatment.

The histopathological growth pattern (HGP) is a morphological reflection of interactions between cancer cells and the surrounding tissue, and has been identified with a remarkably predictive value in liver metastases. However, there is still a lack of studies on HGP of primary liver cancer even furtherly on HGP evolution. We employed VX2 tumor-bearing rabbits as the primary liver cancer model of which tumor size and distant metastasis were investigated. HGP assessment and computed tomography scanning was performed in four cohorts of different time points to map the HGP evolution. Additionally, Fibrin deposition and neovascularization were evaluated by Masson staining and immunohistochemical analysis of CD31, hypoxia-inducible factor-1 alpha (HIF1A) and vascular endothelial growth factor (VEGF). Tumors displayed exponential growth in the VX2 liver cancer model, but these tumor-bearing animals did not show any visible metastasis until they reached a specific stage of development. Correspondingly, the components of HGPs changed along with the tumor growth. The proportion of desmoplastic HGP (dHGP) decreased initially and then grew, but in contrast, the level of replacement HGP (rHGP) rose from the 7th day, reached a peak at around the 21st day, and then appeared drop. Importantly, the collagen deposition and expression of HIF1A and VEGF correlated with dHGP, while CD31 did not. HGP evolution presents a two-way switch including dHGP to rHGP and rHGP to dHGP, in which the emergence of rHGP may be linked to metastases. HIF1A-VEGF partially participates in the HGP evolution and presumably plays a key role in the formation of dHGP. [ABSTRACT FROM AUTHOR]

A water-soluble polysaccharide (STPC2) was isolated from the boiling-water extract of Sargassum thunbergii , purified by CaCl 2 precipitation and chromatography on DEAE-cellulose and Sephacryl S-300 column. It was found that STPC2, with a molecular weight of 57 kD, was composed of fucose, xylose, galactose and glucuronic acid, in a ratio of 8.1: 3.8: 2.1: 1.0. Additionally, we found that STPC2 significantly inhibited endothelial cell migration and tube formation without toxicity. Moreover, STPC2 significantly inhibited lung cancer cell A549 migration and proliferation. It was found that STPC2 treatment suppressed MMP-2 gene expression at transcriptional level and enzymatic activity. Furthermore, STPC2 reduced the mRNA and protein expression of vascular endothelial growth factor-A (VEGF-A) and hypoxia-inducible factor (HIF)-1 alpha in the endothelial cells. Taken together, our findings indicated that STPC2 was a potent bioactive polysaccharide with distinct anti-angiogenesis activity against tumor migration via down-regulation of MMP-2 activity and VEGF/HIF-1α signaling pathway. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-1 alpha (HIF-1α) plays a vital role in the initiation, evaluation and prognosis in lung cancer. The prognostic value of HIF-1α reported in diverse study remains disputable. Accordingly, a meta-analysis was implemented to further understand the prognostic role of HIF-1α in lung cancer. The relationship between HIF-1α and the clinicopathological characteristics and prognosis of lung cancer were investigated by a meta-analysis. PubMed and Embase were searched from their inception to January 2015 for observational studies. Fixed-effects or random-effects meta-analyses were used to calculate odds ratios and 95% confidence intervals of different comparisons. A total of 20 studies met the criteria. The results showed that HIF-1α expression in lung cancer tissues was significantly higher than that in normal lung tissues. Expression of HIF-1α in patients with squamous cell carcinoma was significantly higher than that of patients with adenocarcinomas. Similarly, non-small cell lung cancer (NSCLC) patients had higher HIF-1α expression than small cell lung cancer (SCLC) patients. Moreover, lymph node metastasized tissues had higher HIF-1α expression than non-lymph node metastasized tissues. A high level HIF-1α expression was well correlated with the expression of vascular endothelial growth factor and epidermal growth factor receptor in the NSCLC. Notably, NSCLC or SCLC patients with positive HIF-1α expression in tumor tissues had lower overall survival rate than patients with negative HIF-1α expression. It was suggested that HIF-1α expression may be a prognostic biomarker and a potential therapeutic target for lung cancer. [ABSTRACT FROM AUTHOR]