HIF-1alpha Research Articles

Remote Ischemic Conditioning Mediates Cardio-protection After Myocardial Ischemia/Reperfusion Injury by Reducing 4-HNE Levels and Regulating Autophagy via the ALDH2/SIRT3/HIF1α Signaling Pathway.

Remote ischemic conditioning (RIC) can be effectively applied for cardio-protection. Here, to clarify whether RIC exerts myocardial protection via aldehyde dehydrogenase 2 (ALDH2), we established a myocardial ischemia/reperfusion (I/R) model in C57BL/6 and ALDH2 knockout (ALDH2-KO) mice and treated them with RIC. Echocardiography and single-cell contraction experiments showed that RIC significantly improved myocardial function and alleviated I/R injury in C57BL/6 mice but did not exhibit its cardioprotective effects in ALDH2-KO mice. TUNEL, Evan's blue/triphenyl tetrazolium chloride, and reactive oxygen species (ROS) assays showed that RIC's effect on reducing myocardial cell apoptosis, myocardial infarction area, and ROS levels was insignificant in ALDH2-KO mice. Our results showed that RIC could increase ALDH2 protein levels, activate sirtuin 3 (SIRT3)/hypoxia-inducible factor 1-alpha (HIF1α), inhibit autophagy, and exert myocardial protection. This study revealed that RIC could exert myocardial protection via the ALDH2/SIRT3/HIF1α signaling pathway by reducing 4-HNE secretion.

Stathmin1 promotes lymph node metastasis in hypopharyngeal squamous cell carcinoma via regulation of HIF‑1α/VEGF‑A axis and MTA1 expression.

Extensive neck lymph node metastasis (LNM) is an important clinical feature of hypopharyngeal squamous cell carcinoma (HSCC). Stathmin1 (STMN1) is closely associated with LNM in numerous human cancers. In the present study, the association between STMN1 and neck LNM in HSCC and the underlying molecular mechanisms were explored. First, postoperative samples of HSCC were screened and the association between STMN1 and neck LNM in HSCC was analyzed. Then, cell functional experiments were performed to assess the potential of STMN1 to promote invasion and migration. Subsequently, the potential target genes and pathways of STMN1 were predicted using bioinformatics analysis. Finally, the obtained target genes and pathways of STMN1 were validated by reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses to confirm the potential mechanisms by which STMN1 promotes LNM in HSCC. As a result, a total of 117 postoperative samples of HSCC were screened, and STMN1 was proven to be associated with neck LNM in HSCC. Further, cell functional experiments established that high expression of STMN1 could actually promote FaDu cell invasion and metastasis. Bioinformatics analysis revealed that high expression of STMN1 was associated with the activation of hypoxia inducible factor-1alpha (HIF-1α) pathway and increased expression of metastasis-associated protein 1 (MTA1). Finally, RT-qPCR and western blot analyses confirmed that STMN1 promotes the expression levels of HIF-1α/vascular endothelial growth factor (VEGF)-A and MTA1 in FaDu cell lines. In conclusion, it was found that high expression of STMN1 promoted neck LNM in HSCC and the potential mechanisms may be via regulation of the HIF-1α/VEGF-A axis and MTA1 expression.

Low expression of HIF1AN accompanied by less immune infiltration is associated with poor prognosis in breast cancer.

Hypoxia-inducible factor 1-alpha (HIF-1α) stability and transcriptional action are reduced by the hypoxia-inducible factor 1-alpha subunit suppressor (HIF1AN). Its inappropriate expression is associated with the development of cancer and immune control. It is yet unknown how HIF1AN, clinical outcomes, and immune involvement in breast cancer (BC) are related. Using the GEPIA, UALCAN, TIMER, Kaplan-Meier plotter, and TISIDB datasets, a thorough analysis of HIF1AN differential expression, medical prognosis, and the relationship between HIF1AN and tumor-infiltrating immune cells in BC was conducted. Quantitative real-time PCR (qRT-PCR) analysis of BC cells were used for external validation. The findings revealed that, as compared to standard specimens, BC cells had significantly lower levels of HIF1AN expression. Good overall survival (OS) for BC was associated with higher HIF1AN expression. Additionally, in BC, the expression of HIF1AN was closely associated with the chemokines and immune cell infiltration, including neutrophils, macrophages, T helper cells, B cells, Tregs, monocytes, dendritic cells, and NK cells. A high correlation between HIF1AN expression and several immunological indicators of T-cell exhaustion was particularly revealed by the bioinformatic study. HIF1AN is a predictive indicator for breast tumors, and it is useful for predicting survival rates.

Expression pattern of hypoxia-related genes in odontogenic cysts

ObjectiveThe aim of the present study was to reveal the effects of hypoxia-associated signaling in odontogenic cysts. DesignThe expression levels of genes involved in the hypoxia-associated signaling pathway were determined by quantitative Polymerase Chain Reaction (PCR) method. ResultsAs a result, it was found that phosphatase and tensin homolog (PTEN) expression was low (p = 0.037), and the expression levels of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (p = 0.0127), hypoxia inducible factor 1 alpha (HIF1A) (p < 0.001), and HIF1A antisense RNA 1 (HIF1A-AS1) (p = 0.0218) were higher in cyst tissue compared to normal tissue. HIF1A gene expression was found to be significantly altered according to the pathologic subtypes of odontogenic keratocyst, dentigerous cyst, and radicular cyst. ConclusionsOdontogenic cysts were found to have higher expression of HIF1A and HIF1A-AS1, which may be related to the increased hypoxia in these lesions. In addition, PI3K/Akt signaling may be stimulated by increased PIK3CA and decreased PTEN expression, which promote cell survival and support the mechanism of cyst formation.

Thrombospondin-1 induction and VEGF reduction by proteasome inhibition

The present study focuses on investigating the expression of thrombospondin-1 (TSP-1), a natural inhibitor of neovascularization. Immunofluorescent staining was used to detect the expression of TSP-1 in rabbit corneal tissue with vascularization induced by limbectomy. TSP-1 was detected in healthy and Cultured Autologous Oral Mucosal Epithelial Cell Sheet (CAOMECS) grafted rabbit corneas. TSP-1 was not detected in diseased corneas. Rabbit and human primary oral mucosal and corneal epithelial cells were cultured and treated with proteasome inhibitor (PI) in vitro. Changes in the expression of TSP-1, HIF-1 alpha and 2 alpha, VEGF-A, and VEGF receptor were analyzed by Western blotting. Neovascularization developed in rabbits’ corneas as early as 1 month after limbectomy and was stable for at least 3 months. HIF-1 alpha and VEGF-A expression was reduced in CAOMECS grafted corneas, as compared to sham corneas. While TSP-1 expression was decreased in injured corneas, it was expressed in CAOMECS grafted corneas, but still less expressed compared to healthy corneas. PI treatment, of human oral mucosal and corneal epithelial cells increased TSP-1 expression and reduced VEGF-A expression. The results showed that TSP-1 expression was lost in injured corneal surface and that CAOMECS grafting restored TSP-1 expression to certain extent. Proteasome inhibition treatment increased TSP-1 and decreased VEGF-A expression in human oral mucosal and corneal epithelial cells. The result suggests that corneal neovascularization could be managed with the inhibition of the proteasome after CAOMECS grafting and increase corneal transparency.

Isoproterenol-induced Upregulation of HPSE Accelerates Triple-negative Breast Cancer Cell Proliferation and Migration through Enhancing the Transcriptional Activity of HIF-1α.

Triple-negative breast cancer (TNBC) is considered to be the most malignant subtype of breast cancer (BC). Heparanase (HPSE) has been reported to contribute to tumor development, but its potential function in TNBC is not clear. The intention of this study was to investigate whether HPSE affects TNBC progression and to explore the possible mechanisms. Bioinformatics analyses were applied to analyze the expression of HPSE in TNBC samples and normal breast samples. The mRNA and protein levels of HPSE in TNBC cells were detected by RT-qPCR and western blot. Function assays, including CCK-8 assay, colony formation assay, transwell assay and wound healing assay, were conducted to validate the effects of HPSE silencing on TNBC cell proliferation and migration. Mechanism experiments were performed to explore the upstream molecular mechanism of HPSE in TNBC cells. Silencing of HPSE suppressed the proliferation and migration of TNBC cells. Moreover, hypoxia-inducible factor-1 alpha (HIF-1α) interacted with the HPSE promoter and promoted the transcription of HPSE. Isoproterenol (ISO), a pharmacological substitute for chronic stress-induced sympathetic activation, was proven to induce HIF-1α upregulation, so as to transcriptionally activate HPSE in TNBC cells. Furthermore, it manifested that ISO facilitated TNBC cell proliferation and migration in an HPSE-dependent way. HPSE activated by ISO-induced HIF-1α promoted TNBC cell proliferation and migration, which might offer a novel insight for TNBC treatment.

Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma.

Glioblastoma (GBM) is one of the most aggressive tumors in the adult central nervous system. We previously revealed that circadian regulation of glioma stem cells (GSCs) affects GBM hallmarks of immunosuppression and GSC maintenance in a paracrine and autocrine manner. Here, we expand the mechanism involved in angiogenesis, another critical GBM hallmark, as a potential basis underlying CLOCK's pro-tumor effect in GBM. Mechanistically, CLOCK-directed olfactomedin like 3 (OLFML3) expression results in hypoxia-inducible factor 1-alpha (HIF1α)-mediated transcriptional upregulation of periostin (POSTN). As a result, secreted POSTN promotes tumor angiogenesis via activation of the TANK-binding kinase 1 (TBK1) signaling in endothelial cells. In GBM mouse and patient-derived xenograft models, blockade of the CLOCK-directed POSTN-TBK1 axis inhibits tumor progression and angiogenesis. Thus, the CLOCK-POSTN-TBK1 circuit coordinates a key tumor-endothelial cell interaction and represents an actionable therapeutic target for GBM.

Effects of long-term tubular HIF-2α overexpression on progressive renal fibrosis in a chronic kidney disease model

Renal fibrosis is the final manifestation of chronic kidney disease (CKD) regardless of etiology. Hypoxia-inducible factor-2 alpha (HIF-2α) is an important regulator of chronic hypoxia, and the late-stage renal tubular HIF-2α activation exerts protective effects against renal fibrosis. However, its specific role in progressive renal fibrosis remains unclear. Here, we investigated the effects of the long-term tubular activation of HIF-2α on renal function and fibrosis, using in vivo and in vitro models of renal fibrosis. Progressive renal fibrosis was induced in renal tubular epithelial cells (TECs) of tetracycline-controlled HIF-2α transgenic (Tg) mice and wild-type (WT) controls through a 6-week adenine diet. Tg mice were maintained on doxycycline (DOX) for the diet period to induce Tg HIF-2α expression. Primary TECs isolated from Tg mice were treated with DOX (5 μg/ml), transforming growth factor-β1 (TGF-β1) (10 ng/ml), and a combination of both for 24, 48, and 72 hr. Blood was collected to analyze creatinine (Cr) and blood urea nitrogen (BUN) levels. Pathological changes in the kidney tissues were observed using hematoxylin and eosin, Masson's trichrome, and Sirius Red staining. Meanwhile, the expression of fibronectin, E-cadherin and α-smooth muscle actin (α-SMA) and the phosphorylation of p38 mitogenactivated protein kinase (MAPK) was observed using western blotting. Our data showed that serum Cr and BUN levels were significantly lower in Tg mice than in WT mice following the adenine diet. Moreover, the protein levels of fibronectin and E-cadherin and the phosphorylation of p38 MAPK were markedly reduced in the kidneys of adenine-fed Tg mice. These results were accompanied by attenuated fibrosis in Tg mice following adenine administration. Consistent with these findings, HIF-2α overexpression significantly decreased the expression of fibronectin in TECs, whereas an increase in α-SMA protein levels was observed after TGF-β1 stimulation for 72 hr. Taken together, these results indicate that long-term HIF-2α activation in CKD may inhibit the progression of renal fibrosis and improve renal function, suggesting that long-term renal HIF-2α activation may be used as a novel therapeutic strategy for the treatment of CKD. [BMB Reports 2023; 56(3): 196-201].

The evaluation of CD39, CD73, and HIF-1 α expression besides their related miRNAs in PBMCs of women with recurrent pregnancy loss

The molecular mechanisms involved in the pathogenesis of recurrent pregnancy loss (RPL) are not completely recognized. The present study aimed to assess the molecules associated with ATP catabolism and hypoxia besides their related miRNAs in patients with RPL. The frequency of Th17 and Treg cells in PBMCs of RPL women and healthy pregnant women were evaluated with Flow cytometry. The expression levels of CD39, CD73, and Hypoxia-inducible factor-alpha (HIF-1α), miR-18a, miR-30a, and miR-206 in PBMCs of two groups were measured with real-time PCR and western blotting. Then, serum levels of IGF-1, TGF-β, and HIF-1α were measured by ELISA. Our results indicated a higher (p = 0.0002) and lower (p < 0.0001) frequency of Th17 and Treg lymphocytes in RPL women, respectively. The expression level of CD39 decreased in PBMCs of RPL women whereas the level of CD73 and HIF-α increased (p = 0.0010, 0.0023, 0.0006 respectively). The results of CD39 and CD37 were also confirmed by protein analysis (p = 0.0047, 0.0364 respectively). Almost, the same results for CD39 and CD73 expression at mRNA and protein levels were observed in isolated Treg cells. Moreover, we found the higher expression of miR-206 and miRNA-30a (p = 0.0038, 0.0123), but the lower expression of miRNA-18a (p = 0.0101) in RPL. The concentration level of IGF-1, and TGF-β reduced (p = 0.0017, 0.0065 respectively) while the level of HIF-α elevated (p = 0.0235) in serum samples of RPL. In conclusion, we observed the dysregulation of molecules that are involved in ATP catabolism and hypoxia, including CD39, CD73, and HIF-1a which is related to miR-18a, miR-30a, and miR-206 change in RPL women. It may be potentially used for RPL prognosis by more comprehensive future studies.

Low Expression of Calcitriol Level and Interleukin-10 and Hypoxia-inducible Factor-1 Alpha Expression on Placenta

BACKGROUND: Preeclampsia (PE) is the disease of theories and the second leading cause of maternal and perinatal morbidities and mortalities worldwide. These pathological disturbances will induce inflammation process, oxidative stress, and poor subsequent growth on the fetus including 32% of intrauterine growth restriction, 22% of prematurity, and 24% of neonatal sepsis and asphyxia. There are many theories about the mechanism of PE. In the molecularly level, it is suspected that the low level of calcitriol and interleukin (IL)-10 expressions and high expression of hypoxia- inducible factor (HIF)-1α are the risk factors of PE. AIM: The aim of this study was to prove the low calcitriol level, IL-10, and high expression of HIF-1α in the placenta as the risk factors of PE. METHODS: A nested case–control study was conducted at the Department of Obstetrics-Gynecology Sanglah and Wangaya Hospital Denpasar, Bali, from November 2020 to February 2021. RESULTS: A total of 64 samples of 20–40 weeks gestation age were selected by purposive consecutive sampling, divided into two groups consist of 32 PE as the cases and 32 non-PE as the controls. The material examination, 3 × 3 cm was isolated from the maternal placental surface, was performed at Laboratorium Biomedik Terpadu, Faculty of Medicine, Udayana University. We performed an ELISA technique to find out the calcitriol level; in the other hand, we used immunohistochemistry for detected expression of IL-10 and HIF-1-α. The results revealed the risk of PE in low placental calcitriol levels about 13.8 times higher than in high calcitriol levels (odds ratio [OR] = 13,801, 95% confidence interval [CI] = 4.048–47,050, p = 0.001. The risk of PE in low placental IL-10 expression about 6.6 times higher than in high IL-10 expression (OR = 6600; 95% CI = 2208–19,728; p = 0.001). The risk of PE in high placental HIF-1-α expression about 5.6 times higher than in low placental HIF-1-α expression (OR = 5.622; 95% CI = 1.922–16.450; p = 0.001). CONCLUSION: Low calcitriol level, low IL-10, and high HIF-1-α expression on the placenta were proved as significant risk factors for the development of PE.

Expression of HIF-1α and markers of angiogenesis and metabolic adaptation in molecular subtypes of breast cancer

Hypoxic zones exist in solid tumors, where oxygen levels are significantly lower than in normal tissues. Hypoxia makes chemo-radiation therapeutics less effective and renders the metastatic potential more favorable. Emerging research has found that the transcriptional expression of hypoxia-inducible factor-1alpha (HIF-1α) promotes the transcription of vascular endothelial growth factor A (VEGF-A) and Hexokinase-I (HK-I), which are associated to cellular growth, angiogenesis, and metastatic invasion in many malignancies. However, it is still unclear whether VEGFA and HK-I expression has any influence on survival based on the intrinsic subtypes of breast cancer. Their prognostic significance remains a debatable topic. In the present study, quantitative Real-time polymerase chain reaction (qRT-PCR) was employed to check the relative expression of HIF-1α, VEGF-A and HK-I. The hazard ratios (HR) of breast cancer-specific and overall mortality were calculated using Cox proportional hazards model, which were adjusted for demographic, clinicopathological, and associated molecular variables, as well as the diagnosis year. The relative mRNA expression levels of HIF-1α (p = 0.0010) and VEGFA (p = 0.0119) were significantly higher in tumor tissues. The expression of both HIF-1α (p = 0.0111) and VEGFA (p = 0.0078) was higher in the TNBC group of breast cancers, while HK-I (p = 0.0106) was higher in ER/PR-positive, HER2-negative group. HIF-1α and HK-I overexpression were associated with a higher likelihood of survival, while overexpression of VEGFA was associated with a low survival rate, although it was not statistically significant.

Ubiquitin protein E3 ligase ASB9 suppresses proliferation and promotes apoptosis in human spermatogonial stem cell line by inducing HIF1AN degradation

BackgroundSpermatogonial stem cells (SSCs) are critical for sustaining spermatogenesis. Even though several regulators of SSC have been identified in rodents, the regulatory mechanism of SSC in humans has yet to be discovered.MethodsTo explore the regulatory mechanisms of human SSCs, we analyzed publicly available human testicular single-cell sequencing data and found that Ankyrin repeat and SOCS box protein 9 (ASB9) is highly expressed in SSCs. We examined the expression localization of ASB9 using immunohistochemistry and overexpressed ASB9 in human SSC lines to explore its role in SSC proliferation and apoptosis. Meanwhile, we used immunoprecipitation to find the target protein of ASB9 and verified its functions. In addition, we examined the changes in the distribution of ASB9 in non-obstructive azoospermia (NOA) patients using Western blot and immunofluorescence.ResultsThe results of uniform manifold approximation and projection (UMAP) clustering and pseudotime analysis showed that ASB9 was highly expressed in SSCs, and its expression gradually increased during development. The immunohistochemical and dual-color immunofluorescence results displayed that ASB9 was mainly expressed in nonproliferating SSCs. Overexpression of ASB9 in the SSC line revealed significant inhibition of cell proliferation and increased apoptosis. We predicted the target proteins of ASB9 and verified that hypoxia-inducible factor 1-alpha inhibitor (HIF1AN), but not creatine kinase B-type (CKB), has a direct interaction with ASB9 in human SSC line using protein immunoprecipitation experiments. Subsequently, we re-expressed HIF1AN in ASB9 overexpressing cells and found that HIF1AN reversed the proliferative and apoptotic changes induced by ASB9 overexpression. In addition, we found that ABS9 was significantly downregulated in some NOA patients, implying a correlation between ASB9 dysregulation and impaired spermatogenesis.ConclusionASB9 is predominantly expressed in human SSCs, it affects the proliferation and apoptotic process of the SSC line through HIF1AN, and its abnormal expression may be associated with NOA.

Linagliptin counteracts rotenone’s toxicity in non-diabetic rat model of Parkinson’s disease: Insights into the neuroprotective roles of DJ-1, SIRT-1/Nrf-2 and implications of HIF1-α

While all current therapies’ main focus is enhancing dopaminergic effects and remission of symptoms, delaying Parkinson’s disease (PD) progression remains a challenging mission. Linagliptin, a Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, exhibited neuroprotection in various neurodegenerative diseases. This study aims to evaluate the neuroprotective effects of Linagliptin in a rotenone-induced rat model of PD and investigate the possible underlying mechanisms of Linagliptin’s actions. The effects of two doses of Linagliptin (5 and 10 mg/kg) on spontaneous locomotion, catalepsy, coordination and balance, and histology were assessed. Then, after Linagliptin showed promising results, it was further tested for its potential anti-inflammatory, antiapoptotic effects, and different pathways for oxidative stress. Linagliptin prevented rotenone-induced motor deficits and histological damage. Besides, it significantly inhibited the rotenone-induced increase in pro-inflammatory cytokines: Tumor Necrosis Factor-α (TNF-α) and Interleukin-6 (IL-6) and decrease in caspase 3 levels. These effects were associated with induction in the levels of Protein deglycase also known as DJ-1, Hypoxia-inducible factor 1-alpha (HIF-1α), potentiation in the Sirtuin 1 (SIRT-1)/Nuclear factor erythroid-2-related factor 2 (Nrf-2)/Heme oxygenase-1 (HO-1) pathway, and an increase in the antioxidant activity of catalase which provided neuroprotection to the neurons from rotenone-induced PD. Collectively, these results suggest that Linagliptin might be a suitable candidate for the management of PD.

Targeting fatty acid synthase modulates sensitivity of hepatocellular carcinoma to sorafenib via ferroptosis

BackgroundSorafenib resistance is a key impediment to successful treatment of patients with advanced hepatocellular carcinoma (HCC) and recent studies have reported reversal of drug resistance by targeting ferroptosis. The present study aimed to explore the association of fatty acid synthase (FASN) with sorafenib resistance via regulation of ferroptosis and provide a novel treatment strategy to overcome the sorafenib resistance of HCC patients.MethodsIntracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Biological information analyses, immunofluorescence assays, western blot assays, and co-immunoprecipitation analyses were conducted to elucidate the functions of FASN in HCC. Both in vitro and in vivo studies were conducted to examine the antitumor effects of the combination of orlistat and sorafenib and CalcuSyn software was used to calculate the combination index.ResultsSolute carrier family 7 member 11 (SLC7A11) was found to play an important role in mediating sorafenib resistance. The up-regulation of FASN antagonize of SLC7A11-mediated ferroptosis and thereby promoted sorafenib resistance. Mechanistically, FASN enhanced sorafenib-induced ferroptosis resistance by binding to hypoxia-inducible factor 1-alpha (HIF1α), promoting HIF1α nuclear translocation, inhibiting ubiquitination and proteasomal degradation of HIF1α, and subsequently enhancing transcription of SLC7A11. Orlistat, an inhibitor of FASN, with sorafenib had significant synergistic antitumor effects and reversed sorafenib resistance both in vitro and in vivo.ConclusionTargeting the FASN/HIF1α/SLC7A11 pathway resensitized HCC cells to sorafenib. The combination of orlistat and sorafenib had superior synergistic antitumor effects in sorafenib-resistant HCC cells.

Association between iron metabolism and SARS-COV-2 infection, determined by ferritin, hephaestin and hypoxia-induced factor-1 alpha levels in COVID-19 patients.

Due to the growing evidence of the importance of iron status in immune responses, the biomarkers of iron metabolism are of interest in novel Coronavirus Disease 2019 (COVID-19). The present prospective study was carried out to compare iron status indicated by levels of ferritin with the levels of two novel biomarkers related to iron homeostasis, hephaestin and hypoxia-inducible factors-1 (HIF-1α) in the serum of patients with COVID-19 in comparison with a control group. Blood samples from 34 COVID-19 patients and from 43 healthy volunteers were collected and the levels of HEPH and HIF-1α were measured by ELISA and compared with levels of serum ferritin. COVID-19 patients had higher serum levels of ferritin than those levels in control group (P < 0.0001). Conversely levels of HIF-1α and HEPH in the COVID-19 group were significantly lower than those of control group (P < 0.0001 for both). An inverse correlation between hephaestin and ferritin as well as between HIF-1α and ferritin was found among all subjects (P < 0.0001), and among COVID-19 patients, but not to statistical significance. Levels of hephaestin and HIF-1α were found to be inversely related levels of ferritin across all participants in the study, and to our knowledge this is the first report of hephaestin and HIF-1α as potential markers of iron status. Further studies are needed to corroborate the findings, utilizing a broader range of markers to monitor inflammatory as well as iron status.

The endoplasmic reticulum stress sensor IRE1α modulates macrophage metabolic function during Brucella abortus infection.

Endoplasmic reticulum (ER) stress plays a major role in several inflammatory disorders. ER stress induces the unfolded protein response (UPR), a conserved response broadly associated with innate immunity and cell metabolic function in various scenarios. Brucella abortus, an intracellular pathogen, triggers the UPR via Stimulator of interferon genes (STING), an important regulator of macrophage metabolism during B. abortus infection. However, whether ER stress pathways underlie macrophage metabolic function during B. abortus infection remains to be elucidated. Here, we showed that the UPR sensor inositol-requiring enzyme 1α (IRE1α) is as an important component regulating macrophage immunometabolic function. In B. abortus infection, IRE1α supports the macrophage inflammatory profile, favoring M1-like macrophages. IRE1α drives the macrophage metabolic reprogramming in infected macrophages, contributing to the reduced oxidative phosphorylation and increased glycolysis. This metabolic reprogramming is probably associated with the IRE1α-dependent expression and stabilization of hypoxia-inducible factor-1 alpha (HIF-1α), an important molecule involved in cell metabolism that sustains the inflammatory profile in B. abortus-infected macrophages. Accordingly, we demonstrated that IRE1α favors the generation of mitochondrial reactive oxygen species (mROS) which has been described as an HIF-1α stabilizing factor. Furthermore, in infected macrophages, IRE1α drives the production of nitric oxide and the release of IL-1β. Collectively, these data unravel a key mechanism linking the UPR and the immunometabolic regulation of macrophages in Brucella infection and highlight IRE1α as a central pathway regulating macrophage metabolic function during infectious diseases.

Advances in Hypoxia-Inducible Factor 1-Alpha and Ischemic Heart Disease

Ischemic heart disease, resulting from ischemic and anoxic cardiomyocytes, can lead to the abnormal metabolic activity which is able to result in some serious diseases including cardiac failure, thrombus and other deadly disease and it is also the bad factor to the health of human. Besides, oxidative stress resulting from ischemic heart disease is one of the most serious factors of this disease which can destroy the healthy tissue, protein and so on. Hypoxia, as a signal, is able to launch hypoxia-inducible factor 1-alpha which lives in cytoplasm. It transfers to cell nucleus to achieve its aim, which means hypoxia-inducible factor 1-alpha is going to bind to hypoxia-inducible factor 1-beta first, then start some downstream promoters to facilitate several target genes such as vascular endothelial growth factor, inducible nitric oxide synthase, necessary enzyme of glycolysis and erythropoietin. Reactive oxygen species has also been proved that, it can start hypoxia-inducible factor 1-alpha as the second messenger. At the moment, hypoxia-inducible factor 1-alpha has been proved that, it is influential for ischemic heart disease through some pathways such as the increased angiogenesis, promoting glycolysis and the decreased reactive oxygen species. In this review, we discussed the advances in hypoxiainducible factor 1-alpha and ischemic heart disease.

Hypoxia inducible factors and hypoxia associated factor expression profiles and prognostic significance in renal cell carcinomas

Hypoxia Inducible Factor-1 alpha and Hypoxia Inducible Factor-2 alpha (HIF-1α and HIF-2α) are crucial in Renal Cell Carcinoma (RCC) formation. Hypoxia Associated Factor (HAF) prompts HIF-1α degradation regardless of oxygen levels, but no such link exists for HIF-2α. This study encompassed 239 cases, where tissue microarray (TMA) sections were exposed to HIF-1α, HIF-2α, and HAF antibodies. Staining intensity and tumor cell percentage determined scores for HIF-1α, HIF-2α, and HAF, with median histoscore establishing "high" or "low" cutoffs. Among the cases, 64.9% (155 cases) were negative for HIF-1α, 17.6% (42 cases) displayed low, and another 17.6% (42 cases) showed strong HIF-1α expression. HIF-1α expression correlated significantly with histological type and World Health Organization/International Society of Urological Pathology (WHO/ISUP) nuclear grade. Regarding HIF-2α, 15.5% (37 cases) were negative, 23.4% (56 cases) exhibited low, and 61.1% (146 cases) displayed high expression, with larger tumor size in the high HIF-2α group. Among 239 cases, 41.4% (99 cases) were negative for HAF, 36.8% (88 cases) showed low, and 21.8% (52 cases) displayed high HAF scores. HAF expression correlated with WHO/ISUP nuclear grade and metastasis presence. Notably, HIF-2α staining intensity directly correlated with increased HAF intensity (rho=0.146; p=0.024), while HIF-1α intensity decrease corresponded with heightened HAF intensity, showing a statistically significant negative correlation (rho=-0.180; p=0.005). In this rare examination of tumor tissue, a reverse connection between HIF-1α and HAF expression was uncovered, while a linear link emerged between HIF-2α and HAF expression. Overall, this study established that HIF-1α, HIF-2α, and HAF expression are associated with an unfavorable prognosis.

Serum hypoxia-inducible factor 1 alpha levels in stroke

Aim: In order to survive, human cells must adapt to changes in the oxygen level of their environment. Many endogenous mechanisms operate in hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional protein involved in the head of the cascade that regulates the response of brain and other tissues to hypoxia. HIF-1 alpha (HIF-1α) is the main molecule that responds to hypoxia and is an important marker of cerebral hypoperfusion. Materials and Methods: 39 acute stroke patients aged between 18-80 years and 38 control patients included in our study. We aimed to examine the serum HIF-1α levels in early period of acute ischemic stroke. We also aimed to evaluate its usefulness in determining tissue damage due to hypoxia and the prognosis of the disease. Results: Serum HIF-1α levels were higher in acute ischemic stroke patients compared to the control group (p= 0.000). There was no significant correlation between infarct volumes, NHISS scores, blood pressure and HIF-1α values of the stroke patients. Conclusion: HIF-1α could be an important biomarker in detecting cerebral hypoxia. It is possible to study this in human peripheral blood. Its usability in stroke may become widespread with studies on its therapeutic target.

Study on the mechanism of Zhimu in the treatment of ovarian cancer based on network pharmacology

We aimed to investigate the mechanism of action of Zhimu in the treatment of ovarian cancer (OC) using network pharmacology. OC targets were screened using the DisGeNET and Online Mendelian Inheritance in Man databases. Common OC and Zhimu targets were identified using the Traditional Chinese Medicine System Pharmacology, UniProt databases, and Venny 2.1.0. The protein-protein interaction (PPI) network in the Search Tool for the Retrieval of Interacting Genes/Proteins database was created using Zhimu/OC targets and a Zhimu active ingredient-target-pathway network in the Cytoscape 3.9.1 software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted using the Metascape database. And overall, 15 active ingredients in addition to 93 related targets were identified. The PPI network had 52 targets that overlapped with it, with the 10 most relevant targets being the tumour protein p53, tumour necrosis factor, serine/threonine kinase 1, vascular endothelial growth factor A, caspase-3, prostaglandin G/H synthase-2, hypoxia-inducible factor-1 alpha, interleukin-1 beta, heat-shock protein 90-alpha, and progesterone receptor. According to GO and KEGG analyses, Zhimu and OC had the nuclear factor NF-kappaB signalling pathway, oxidative stress, and the advanced glycation end product (AGE)/the receptor for the advanced glycation end product (RAGE) signalling pathway as common targets. This study highlighted the active ingredients in Zhimu and identified potential molecular therapeutic mechanisms for the treatment of OC. It also provided suggestions and directions for future research into molecular mechanisms.