BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes...BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.展开更多
BACKGROUND Hypoxia-inducible factor 1α(HIF-1α)plays a crucial role in the prognosis of breast cancer,but the current evidence remains inconclusive.AIM To provide comprehensive evidence about the correlation of alter...BACKGROUND Hypoxia-inducible factor 1α(HIF-1α)plays a crucial role in the prognosis of breast cancer,but the current evidence remains inconclusive.AIM To provide comprehensive evidence about the correlation of altered HIF-1αexpression with overall survival(OS)and disease-free survival(DFS)in breast cancer patients.METHODS A systematic search was conducted in PubMed,Embase,and Web of Science databases to collect relevant articles that were published before April 8,2024.A meta-analysis was used to assess the impact of altered HIF-1αexpression on the OS and DFS of breast cancer patients.Subgroup and sensitivity analyses were also performed in this meta-analysis.RESULTS This meta-analysis included 40 studies.The average percentage of breast cancer patients with high HIF-1αexpression was 39.6%.The overall meta-analysis results demonstrated that high HIF-1αexpression is strongly linked to poor outcomes in patients of breast cancer.Compared with low HIF-1αexpression,the overall hazard ratio for OS in patients with high HIF-1αexpression was 1.47[95%confidence interval(CI):1.29-1.69],and the overall hazard ratio for DFS was 1.82(95%CI:1.56-2.12).Furthermore,both OS[1.18(95%CI:1.01-1.38)]and DFS[1.79(95%CI:1.03-3.11)]were markedly shorter in triple-negative breast cancer cases with high HIF-1αexpression.Subgroup analysis revealed that the antibody used to detect HIF-1αexpression affected only the correlation linking HIF-1αexpression to DFS in breast cancer patients(P=0.0004).Furthermore,the sensitivity analysis demonstrates that the overall conclusions of the meta-analysis were unaffected by the removal of individual studies.CONCLUSION Compared to patients with low HIF-1αexpression,those with high expression level had shorter OS and DFS.However,the prognostic significance of high HIF-1αexpression varies across molecularly stratified breast cancer cohorts needs to be further elucidated.展开更多
Background:Adenoid hypertrophy(AH)is a common pediatric disease that signifi-cantly impacts the growth and quality of life of children.However,there is no replica-ble and valid model for AH.Methods:An AH rat model was...Background:Adenoid hypertrophy(AH)is a common pediatric disease that signifi-cantly impacts the growth and quality of life of children.However,there is no replica-ble and valid model for AH.Methods:An AH rat model was developed via comprehensive allergic sensitization,chronic inflammation induction,and chronic intermittent hypoxia(CIH).The modeling process involved three steps:female Sprague-Dawley rats(aged 4-5 weeks)were used for modeling.Allergen sensitization was induced via intraperitoneal administra-tion and intranasal provocation using ovalbumin(OVA);chronic nasal inflammation was induced through intranasal lipopolysaccharide(LPS)administration for sustained nasal irritation;CIH akin to obstructive sleep apnea/hypopnea syndrome was induced using an animal hypoxia chamber.Postmodel establishment,behaviors,and histologi-cal changes in nasopharynx-associated lymphoid tissue(NALT)and nasal mucosa were assessed.Arterial blood gas analysis and quantification of serum and tissue levels of(interleukin)IL-4 and IL-13,OVA-specific immunoglobulin E(sIgE),eosinophil cationic protein(ECP),tumor necrosis factor(TNF-α),IL-17,and transforming growth factor(TGF)-βwere conducted for assessment.The treatment group received a combination of mometasone furoate and montelukast sodium for a week and then was evaluated.Results:Rats exhibited notable nasal symptoms and hypoxia after modeling.Histopathological analysis revealed NALT follicle hypertrophy and nasal mucosa in-flammatory cell infiltration.Elevated IL-4,IL-13,IL-17,OVA-sIgE,ECP,and TNF-αlev-els and reduced TGF-βlevels were observed in the serum and tissue of model-group rats.After a week of treatment,the treatment group exhibited symptom and inflam-matory factor improvement.Conclusion:The model effectively simulates AH symptoms and pathological changes.But it should be further validated for genetic,immunological,and hormonal back-grounds in the currently used and other strains and species.展开更多
Objective To explore the sequential effects of hypoxic exercising on miR-27/PPARγand lipid metabolism targetgene and protein expression levels in the obesity rats’liver.Methods 13-week-old male diet-induced obesity ...Objective To explore the sequential effects of hypoxic exercising on miR-27/PPARγand lipid metabolism targetgene and protein expression levels in the obesity rats’liver.Methods 13-week-old male diet-induced obesity rats were randomlydivided into three groups(n=10):normal oxygen concentration quiet group(N),hypoxia quiet group(H),hypoxic exercise group(HE).Exercise training on the horizontal animal treadmill for 1 h/d,5 d/week for a total of 4 week,and the intensity of horizontaltreadmill training was 20 m/min(hypoxic concentration was 13.6%).Comparison of the weights of perirenal fat and epididymal fat in rats across different groups and calculation of Lee’s index based on body weight and body length of rats in each group were done.And the serum concentrations of total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C),high-densitylipoprotein cholesterol(HDL-C)levels were detected.RT-PCR and Western Blot were used to detect the levels of miR-27,PPARγ,CYP7A1 and CD36.Results Hypoxic exercise decreased the expression levels of miR-27 in the obese rats’liver,however,theexpression level of PPARγwas gradually increased.The expression levels of miR-27 in HE group were significantly lower than Ngroup(P<0.05).The expression levels of PPARγmRNA in N group were significantly lower than H group(P<0.05),especially lowerthan HE group(P<0.01).The protein expression of PPARγprotein in N group was significantly lower than that other groups(P<0.01).The expression of lipid metabolism-related genes and proteins increased in the obese rats’liver.The expression of CYP7A1mRNA in N group was significantly lower than H group(P<0.05),especially lower than HE group(P<0.01).The expression ofCYP7A1 protein in the obese rats’liver in N group was extremely lower than H group and HE group(P<0.01).The proteinexpression of CD36 in N group was significantly lower than that in HE group(P<0.05).Hypoxia exercise improved the relatedphysiological and biochemical indexes of lipid metabolism disorder.The perirenal fat weight of obese rats in HE group wasextremely lower than N group and H group(P<0.01),and the perirenal fat weight in N group was significantly higher than H group(P<0.05).The epididymal fat weight in N group was significantly higher than H group(P<0.05),and extremely higher than HEgroup(P<0.01).The Lee’s index in HE group was extremely lower than N group and H group(P<0.01).The serum concentration ofTC in obese rats in HE group was extremely lower than N group and H group(P<0.01).The serum concentration of TG in HE groupwas extremely lower than N group and H group(P<0.01).The serum concentration of LDL-C in N group was extremely higher thanHE group(P<0.01).The serum concentration of HDL-C in N group was extremely lower than H group(P<0.01).Conclusion Hypoxiaand hypoxia exercise may negatively regulate the levels of PPARγby inhibiting miR-27 in the obese rats’liver,thereby affecting theexpression of downstream target genes CYP7A1 and CD36,and promoting cholesterol,fatty acid oxidation and HDL-C transport inthe liver,and ultimately the lipid levels in obese rats were improved.The effect of hypoxia exercise on improving blood lipid isbetter than simple hypoxia intervention.展开更多
Objective: To investigate the specific mechanism of hypoxia-inducible factor 1 alpha (HIF-1α) in the regulation of human sperm apoptosis, and to provide a new theoretical reference and scientific basis for the diagno...Objective: To investigate the specific mechanism of hypoxia-inducible factor 1 alpha (HIF-1α) in the regulation of human sperm apoptosis, and to provide a new theoretical reference and scientific basis for the diagnosis and treatment of asthenospermia and other related conditions. Methods: Semen samples were categorized into the normal group and asthenospermia group based on sperm motility criteria. HIF-1α interfering agent cobalt chloride (CoCl2) and guanylate cyclase activator (Lificiguat, YC-1) were added respectively, with a control group established accordingly. Sperm motility (using anterior viability rate as an index), apoptosis level, ATP level, mitochondrial membrane potential, and reactive oxygen species (ROS) level were measured. The expression levels of HIF-1α, p-PI3K, and Bcl-2 in the samples were analyzed using Western blotting. Results: Following CoCl2 treatment, there was a significant increase in sperm apoptosis compared to the normal control group (12.51% ± 2.50% VS 11.15% ± 2.42%);additionally, sperm motility (45.34% ± 3.37% VS 51.36% ± 11.68%), ATP production (11.51 ± 2.87 nM/µL VS 14.99 ± 2.83 nM/µL), ROS levels, and mitochondrial membrane potential all decreased significantly (all P α and p-PI3K increased significantly while Bcl-2 expression decreased (all P α in the YC-1 treatment group were decreased, and the expression level of Bcl-2 was increased (all P α can influence human sperm apoptosis and motility through the PI3K signaling pathway.展开更多
Objective Hypoxia plays a critical role in the pathophysiology of cardiomyopathy,myocardial infarction,and heart failure.Promoting ketone metabolism has been shown to be beneficial for myocardial cells under hypoxic c...Objective Hypoxia plays a critical role in the pathophysiology of cardiomyopathy,myocardial infarction,and heart failure.Promoting ketone metabolism has been shown to be beneficial for myocardial cells under hypoxic conditions.However,the expression and regulatory mechanisms of key enzymes in the ketone pathway under hypoxic conditions are still unclear.This study aimed to investigate the effects of hypoxia on the expression of key enzymes in the ketone metabolic pathway and the underlying regulatory mechanisms involved.Methods H9C2 myocardial cells were cultured for 6 h in an oxygen-glucose-deprived state,and the expression of various genes was detected by quantitative real-time PCR.ELISA and lactate dehydrogenase(LDH)cytotoxicity assay were used to measure CoAs,itaconic acid,and LDH levels,respectively,and the dependence of gene expression on hypoxia-inducible factor-1 alpha(HIF-1α)was evaluated using the inhibitor LW6.Results H9C2 cardiomyocytes exhibited increased ketone body metabolism in response to hypoxia.Hypoxia induced the expression of the ketone body enzymes succinyl-CoA:3-oxoacid CoA transferase(SCOT/OXCT1),3-hydroxybutyrate dehy-drogenase 2(BDH2),and acyl-CoA:cholesterol acyltransferase 1(ACAT1)in cardiomyocytes,with a concomitant increase in the level of acyl-CoA and a decrease in the level of succinyl-CoA.The HIF-1αinhibitor LW6 could partially reverse the expression of BDH2 and ACAT1,as well as the levels of succinyl-CoA.Interestingly,however,hypoxia-induced SCOT/OXCT1 expression was not regulated by the HIF-1αinhibitor.In addition,hypoxia promoted the expression of inflamma-tory factors.Conclusion These data confirm the critical role of ketone metabolism in myocardial hypoxia and help to elucidate the patho-physiology of cardiomyopathy,myocardial infarction and heart failure.展开更多
Innovative anti-cancer therapies that activate the immune system show promise in combating cancers resistant to conventional treatments.Photodynamic therapy(PDT)is one such treatment,which not only directly eliminates...Innovative anti-cancer therapies that activate the immune system show promise in combating cancers resistant to conventional treatments.Photodynamic therapy(PDT)is one such treatment,which not only directly eliminates tumor cells but also functions as an in situ tumor vaccine by enhancing tumor immunogenicity and triggering anti-tumor immune responses through immunogenic cell death(ICD).However,the effectiveness of PDT in enhancing immune responses is influenced by factors,such as photosensitizers and the tumor microenvironment,particularly hypoxia.Current clinically used PDT heavily relies on oxygen(O_(2))availability and can be limited by tumor hypoxia.Additionally,the tumor immunosuppressive microenvironment induced by hypoxia affects the anti-tumor immunity of tumor-infiltrating effector T cells.Meanwhile,the immunosuppressive myeloid-lineage cells are recruited to the hypoxic tumor tissue and exhibit higher immunosuppressive capabilities under hypoxia conditions.Consequently,numerous strategies have been developed to modulate tumor hypoxia or to create hypoxia-compatible PDT,aiming to reduce the effects of tumor hypoxia on PDT-driven immunotherapy.This review investigates these strategies,including approaches to alleviate,exploit,and disregard tumor hypoxia within the context of PDT/immunotherapy.It also emphasizes the role of advanced nanomedicine and its benefits in these strategies,while outlining current challenges and future prospects in the field.展开更多
Background Ochratoxin A(OTA)is a toxin widely found in aquafeed ingredients,and hypoxia is a common prob-lem in fish farming.In practice,aquatic animals tend to be more sensitive to hypoxia while feeds are contaminate...Background Ochratoxin A(OTA)is a toxin widely found in aquafeed ingredients,and hypoxia is a common prob-lem in fish farming.In practice,aquatic animals tend to be more sensitive to hypoxia while feeds are contaminated with OTA,but no studies exist in this area.This research investigated the multiple biotoxicities of OTA and hypoxia combined on the liver of grass carp and explored the mitigating effect of curcumin(CUR).Methods A total of 720 healthy juvenile grass carp(11.06±0.05 g)were selected and assigned randomly to 4 experi-mental groups:control group(without OTA and CUR),1.2 mg/kg OTA group,400 mg/kg CUR group,and 1.2 mg/kg OTA+400 mg/kg CUR group with three replicates each for 60 d.Subsequently,32 fish were selected,divided into nor-moxia(18 fish)and hypoxia(18 fish)groups,and subjected to hypoxia stress for 96 h.Results CUR can attenuate histopathological damage caused by coming to OTA and hypoxia by reducing vacu-olation and nuclear excursion.The alleviation of this damage was associated with the attenuation of apoptosis in the mitochondrial pathway by decreasing the expression of the pro-apoptotic proteins Caspase 3,8,9,Bax,and Apaf1 while increasing the expression of the anti-apoptotic protein Bcl-2,and attenuation of endoplasmic reticulum stress(ERS)by reducing Grp78 expression and chop levels.This may be attributed to the fact that the addi-tion of CUR increased the levels of catalase(CAT)and glutathione reductase(GSH),increased antioxidant capacity,and ensured the proper functioning of respiratory chain complexes I and II,which in turn reduced the high produc-tion of reactive oxygen species(ROS),thus alleviating apoptosis and ERS.Conclusions In conclusion,our data demonstrate the effectiveness of CUR in attenuating liver injury caused by the combination of OTA and hypoxia.This study confirms the feasibility and efficacy of adding natural products to mitigate toxic damage to aquatic animals.展开更多
BACKGROUND Hypobaric hypoxia exposure(HHE)often causes neuropsychiatric disorders.Due to its complex mechanism,efficient strategies for alleviating HHE-induced anxiety-and depression-like behaviors remain limited.AIM ...BACKGROUND Hypobaric hypoxia exposure(HHE)often causes neuropsychiatric disorders.Due to its complex mechanism,efficient strategies for alleviating HHE-induced anxiety-and depression-like behaviors remain limited.AIM To characterize alterations in the oral and gut microbiota following HHE and to explore a potential microbiota-based intervention to mitigate associated psychiatric symptoms.METHODS C57BL/6J mice were exposed to simulated high-altitude hypoxia(5000 m)for 1,3,5,or 7 days.Behavioral assessments,including the open field test,elevated plus maze,and forced swim test,were conducted to evaluate anxiety-and depressionlike behaviors.Oral and fecal microbiota were analyzed using 16S rRNA sequencing to assess changes in microbial composition and diversity.Immunofluorescence staining was performed to examine c-Fos expression in brain nuclei.A probiotic formulation containing Lactobacillus rhamnosus(L.rhamnosus)DSM17648,Lactobacillus acidophilus DDS-1,and L.rhamnosus UALR-06 was administered to mice subjected to one day of HHE(HH1)to evaluate its therapeutic efficacy.RESULTS Behavioral tests revealed that HHE caused anxiety-and depression-like behaviors,which were most pronounced after 1 day of exposure.The IF data revealed significantly increased expression of c-Fos in various brain nuclei after HHE,including the anterior cingulate cortex,paraventricular thalamic nucleus,lateral habenula nucleus,paraventricular hypothalamic nucleus,lateral hypothalamus,and periaqueductal gray.The 16S rRNA sequencing results demonstrated a sharp decline in the abundance of Lactobacillus in the oral microbiota of mice exposed to HH1 and a marked decrease in the abundance of Lactobacillus and Bifidobacterium in the fecal microbiota of mice exposed to three days of HHE.Finally,oral administration and gavage of Lactobacillus significantly alleviated anxiety-and depression-like behaviors in HH1 mice.CONCLUSION HHE caused significant variations in the oral and fecal microbiota of mice.Lactobacillus supplementation alleviated anxiety-and depression-like behaviors in mice.Improving oral flora may relieve HHE-induced psychiatric disorders.展开更多
The published article titled“MicroRNA-33b Inhibits the Proliferation andMigration of Osteosarcoma Cells via TargetingHypoxia-Inducible Factor-1α”has been retracted from Oncology Research,Vol.25,No.3,2017,pp.397–405.
Macrobenthos can serve as an indicator of hypoxia in the estuarine ecosystem.This comparative study surveyed macrobenthos from hypoxic and non-hypoxic areas of the Zhujiang(Pearl)River Estuary(PRE),and explores the ef...Macrobenthos can serve as an indicator of hypoxia in the estuarine ecosystem.This comparative study surveyed macrobenthos from hypoxic and non-hypoxic areas of the Zhujiang(Pearl)River Estuary(PRE),and explores the effects of environmental factor on the macrobenthos community structure.In July 2020,49 macrobenthos species were collected from the hypoxic area,contrasting with 91 species found in the non-hypoxic area.July 2021 recorded 51 species in the hypoxic area and 76 in the non-hypoxic area.Analysis of similarities(ANOSIM)and non-metric multidimentional scaling(NMDS)showed no significant difference in the macrobenthos community structure between the two areas.However,Polychaeta displays higher species richness,abundance,and biomass in the hypoxic zone,negatively correlating to dissolved oxygen(DO).Canonical correspondence analysis(CCA)also showed that the abundance of Polychaeta was negatively correlated with that of Crustacea.Interestingly,despite the differences in Polychaeta,macrobenthos community structure remains stable between hypoxic and non-hypoxic samples.This study suggests Polychaeta’s potential adaptation to hypoxic conditions in the PRE’s hypoxic area.Finally,Spearman correlation analysis showed that DO have a significant negative correlation with total phosphorus(TP),total nitrogen(TN)and total organic carbon(TOC)in the PRE,indicating that water eutrophication would exacerbate the occurrence of hypoxia.展开更多
The Pacific oyster(Crassostrea gigas)is a primary shellfish species for aquaculture around the world.However,the industry of Pacific oyster has been impaired by the mass summer mortality caused by environmental pertur...The Pacific oyster(Crassostrea gigas)is a primary shellfish species for aquaculture around the world.However,the industry of Pacific oyster has been impaired by the mass summer mortality caused by environmental perturbations,including hypoxia.Selective breeding of oysters with high hypoxia tolerance is a sustainable approach to prevent economic loss caused by hypoxia.In this study,we constructed 36 C.gigas families and executed the hypoxia stress experiment to estimate genetic parameters for hypoxia tolerance.The survival rate among 36 C.gigas families ranged from 0 to 53.33%,suggesting that high levels of phenotypic variation existed in the trait of hypoxia tolerance.Genetic parameters of hypoxia tolerance estimated by six statistical models showed a low to moderate heritability,ranging from 0.167 to 0.291.The Pearson and Spearman correlation coefficients among families estimated breeding values(EBVs)were high and positive,indicating that different models resulted in similar results in the estimation of breeding values.The phenotypic correlation between growth traits and hypoxia tolerance ranged from-0.030 to 0.061,while genetic correlation ranged from 0.110 to 0.285,implying that growth and hypoxia tolerance were independent traits.This work reported the first estimation of genetic parameters for hypoxia tolerance in C.gigas,and provided valuable information for the genetic improvement of hypoxia tolerance.展开更多
Objective High-altitude hypoxia exposure often damages hippocampus-dependent learning and memory.Nogo-A is an important axonal growth inhibitory factor.However,its function in high-altitude hypoxia and its mechanism o...Objective High-altitude hypoxia exposure often damages hippocampus-dependent learning and memory.Nogo-A is an important axonal growth inhibitory factor.However,its function in high-altitude hypoxia and its mechanism of action remain unclear.Methods In an in vivo study,a low-pressure oxygen chamber was used to simulate high-altitude hypoxia,and genetic or pharmacological intervention was used to block the Nogo-A/NgR1 signaling pathway.Contextual fear conditioning and Morris water maze behavioral tests were used to assess learning and memory in rats,and synaptic damage in the hippocampus and changes in oxidative stress levels were observed.In vitro,SH-SY5Y cells were used to assess oxidative stress and mitochondrial function with or without Nogo-A knockdown in Oxygen Glucose-Deprivation/Reperfusion(OGD/R)models.Results Exposure to acute high-altitude hypoxia for 3 or 7 days impaired learning and memory in rats,triggered oxidative stress in the hippocampal tissue,and reduced the dendritic spine density of hippocampal neurons.Blocking the Nogo-A/NgR1 pathway ameliorated oxidative stress,synaptic damage,and the learning and memory impairment induced by high-altitude exposure.Conclusion Our results demonstrate the detrimental role of Nogo-A protein in mediating learning and memory impairment under high-altitude hypoxia and suggest the potential of the Nogo-A/NgR1 signaling pathway as a crucial therapeutic target for alleviating learning and memory dysfunction induced by high-altitude exposure.展开更多
Objective:A complex relationship exists between obstructive sleep apnea syndrome and diabetes mellitus(DM).Chronic intermittent hypoxia(CIH),which is a core pathological feature of obstructive sleep apnea syndrome,may...Objective:A complex relationship exists between obstructive sleep apnea syndrome and diabetes mellitus(DM).Chronic intermittent hypoxia(CIH),which is a core pathological feature of obstructive sleep apnea syndrome,may play an important role in the onset and development of DM-related atherosclerosis(DM-AS).This study aimed to investigate the mechanism of action of tetramethylpyrazine(TMP)in CIH-associated DM-AS.Methods:In vivo,a DM-AS mouse model was established by intraperitoneal injection of streptozotocin combined with a high-fat diet.They were exposed to CIH or normoxic conditions for 8 weeks and received different doses of TMP,rosuvastatin,toyocamycin,and purified water.Glycolipid metabolism,inflammation levels,degree of aortic AS,and expression levels of endoplasmic reticulum stress(ERS)and autophagy proteins were examined in mice.In vitro,human umbilical vein endothelial cells(HUVECs)were treated with high glucose and fat in combination with insulin to establish an insulin-resistant cell model(HUVEC-IR).After pretreatment with 4μ8C(IRE1 inhibitor)and different doses of TMP,intermittent hypoxic intervention was performed.Changes in cell morphology,proliferative activity,glucose consumption,and ability to migrate were observed,and the expression levels of ERS and autophagy proteins were detected.Results:In vivo experiments showed that CIH significantly increased blood glucose levels and Homeostasis Model Assessment of Insulin Resistance(HOMA-IR)(P<0.001 or P<0.05),low-density lipoprotein cholesterol(LDL-C)content(P<0.001),and the levels of three inflammatory factors[interleukin-1 beta(IL-1β),IL-6,and tumor necrosis factor-alpha(TNF-α)]in the mice(P<0.001)compared with those of the mice with DM alone;moreover,the aortic atherosclerotic(AS)plaque area in CIH mice was significantly enlarged(P<0.001).Western blotting results showed that the expressions of aortic IRE1α,XBP1s,Beclin1,and LC3A proteins were significantly increased in CIH mice compared with DM mice(P<0.05).After treatment with different doses of TMP,rosuvastatin calcium,and toyocamycin,serum inflammation and lipid levels and plaque area were significantly reduced in mice(P<0.001 and P<0.001,respectively).The expression levels of aortic XBP1s,Beclin1,and LC3A were reduced in TMP-and toyocamycin-treated mice(P<0.05).In the in vitro experiments,compared with normoxic cells,the cells treated with intermittent hypoxia(IH)showed a significant decrease in cell migration distance(P<0.05),a significant increase in apoptosis rate(P<0.001),a substantial increase in proliferation inhibition rate(P<0.001),a significant increase in the levels of XBP1s and LC3A proteins(P<0.05),and an increase in the number of autophagic vesicles/lysosomes,as observed under transmission electron microscopy.After treatment with different doses of TMP and 4μ8C,cell morphology was significantly restored,apoptosis rate significantly reduced(P<0.001),and XBP1s,Beclin1,and LC3A expressions significantly inhibited(P<0.05).Conclusion:CIH promoted the onset of DM-AS,whereas TMP attenuated ERS and excessive autophagy by modulating the IRE1α-XBP1 signaling pathway and inhibiting XBP1 splicing,thereby ameliorating DM-AS exacerbated by CIH.展开更多
The development of efficient aggregation-induced emission(AIE)active probes is crucial for disease diagnosis,particularly for tumors and cardiovascular diseases.Current AIE-active probes primarily focus on improving t...The development of efficient aggregation-induced emission(AIE)active probes is crucial for disease diagnosis,particularly for tumors and cardiovascular diseases.Current AIE-active probes primarily focus on improving their water solubility to resist aggregation,thereby achieving an initial fluorescence-off state.However,the complex biological environment can cause undesirable aggregation,resulting in false signals.To address this issue,we have ingeniously introduced an azo group into the AIE luminogen(AIEgen),developing a reductase-activated AIE probe,Azo-quinoline-malononitrile(QM)-PN,for imaging hypoxic environments.In this probe,the azo group promotes intramolecular motion through rapid E/Z isomerization,causing the excited state energy to dissipate via non-radiative decay,thus turning off the initial fluorescence.In the presence of reductase,Azo-QM-PN is reduced and cleaved to produce the hydrophobic AIEgen NH_(2)-QM-PN,which subsequently aggregates and generates an in situ AIE signal,thereby imaging the hypoxic environment with reductase.Encapsulation of Azo-QM-PN with DSPEPEG2000 results in the formation of the nanoprobe Azo-QM-PN NPs,which can effectively penetrate cell membranes,specifically illuminate tumor cells,monitor fluctuations in azo reductase levels,and deeply penetrate and image multicellular tumor spheroids,demonstrating potential for hypoxic tumor imaging.Additionally,the nanoprobe Azo-QM-PN NPs can selectively image hypoxic atherosclerotic plaque tissues,showing potential for detecting atherosclerosis.Therefore,in this study,we successfully developed an enzyme-activated AIE probe for imaging hypoxic environments,laying the foundation for further clinical applications.展开更多
BACKGROUND While acute exposure to high-altitude hypoxic environments can lead to increased thrombosis risk,preventive measures are currently limited.Recently,human umbilical cord mesenchymal stem cell(hUC-MSC)transpl...BACKGROUND While acute exposure to high-altitude hypoxic environments can lead to increased thrombosis risk,preventive measures are currently limited.Recently,human umbilical cord mesenchymal stem cell(hUC-MSC)transplantation has been found effective in preventing and treating various clinical conditions,including thro-mbotic diseases.Platelets are crucial for thrombus formation,and theirα-granules are key determinants of platelet function.However,little is known about the influence of hUC-MSCs on plateletα-granules.METHODS Rats were assigned to three groups,namely,low-altitude,high-altitude,and hUC-MSC-treated groups.The low-altitude group was pretreated with normal saline and housed at an altitude of 1500 m.Rats in the high-altitude group received similar pretreatment and were housed in a simulated hypobaric hypoxia chamber with an altitude of 6500 m and oxygen partial pressure of 7.7 kPa.hUC-MSC-treated rats were pretreated with hUC-MSCs and exposed to hypoxic conditions.Aortic blood was collected after three days to assess platelet counts and mor-phology andα-granule release.RESULTS Compared to the low-altitude group,the high-altitude group exhibited significantly higher platelet counts,plasma levels of von Willebrand factor,platelet factor 4,beta-thromboglobulin,as well as surface P-selectin(CD62p)and p-protein kinase B,p-mitogen-activated protein kinase,and p-extracellular-signal regulated kinase expression in platelets.Platelet morphology in the high-altitude group was irregular,with extended pseudopodia and increasedα-granule densities.However,these changes were not apparent in the hUC-MSC-treated group.CONCLUSION Acute exposure to high-altitude hypoxia increased platelet counts,altered platelet morphology,and increasedα-granule density and release.These effects were mitigated by hUC-MSC treatment,mediated by the protein kinase B/mitogen-activated protein kinase/extracellular-signal regulated kinase pathway.The results indicate that hUC-MSCs may represent a promising and effective approach for the prevention and treatment of acute high-altitude-associated thrombosis,providing an experimental foundation for the development of clinical applications.展开更多
Intestinal inflammation is a common challenge in intensive aquaculture,yet its pathogenesis remains unclear.While interleukin 22(IL-22)is recognized as a critical regulator of cellular homeostasis during inflammation ...Intestinal inflammation is a common challenge in intensive aquaculture,yet its pathogenesis remains unclear.While interleukin 22(IL-22)is recognized as a critical regulator of cellular homeostasis during inflammation in higher vertebrates,its roles in fish are not well understood.This study established hypoxia-induced models in intestinal tissues and primary intestinal epithelial cells of yellow catfish to investigate the involvement of IL-22 in maintaining intestinal homeostasis.Results revealed that Pelteobagrus fulvidraco IL-22(Pf_IL-22)was abundantly expressed in mucosal tissues,with the highest levels in the gill and intestine.Hypoxia induced pronounced intestinal injury,characterized by loosening of the lamina propria and extensive vacuolization,while activating hypoxia-inducible factor(HIF)signaling and markedly up-regulating IL-22 expression.IL-22 levels peaked at 24 h post-hypoxia,suggesting a role in early immune responses.Recombinant Pf_IL-22 also induced transcription of pro-inflammatory mediators,including IL-1βand tumor necrosis factorα(TNF-α),in primary intestinal epithelial cells,indicating a dual regulatory function in balancing protection and inflammation.Mechanistic analyses revealed that HIF-1αdirectly interacted with a hypoxia response element within the IL-22 promoter to drive transcription,as confirmed by dual-luciferase assays,electrophoretic mobility-shift assays,and HIF-1αknockdown.Silencing Pf_IL-22 significantly suppressed Th17 cell differentiation pathways,demonstrating its role in shaping downstream immune responses.These findings establish the HIF-1α/IL-22 axis as a key regulatory pathway modulating immune responses and alleviating intestinal inflammation,providing a basis for developing IL-22-targeted immunotherapies and selective breeding strategies in aquaculture.展开更多
Background:Glioblastoma(GBM)is one of the most malignant types of central nervous system tumors.Oxygen deprivation in the tumor microenvironment is thought to be an important factor in promoting GBM progression.Howeve...Background:Glioblastoma(GBM)is one of the most malignant types of central nervous system tumors.Oxygen deprivation in the tumor microenvironment is thought to be an important factor in promoting GBM progression.However,the mechanisms of hypoxia-promoted tumor progression remain elusive.Methods:Alternative splicing of diacylglycerol kinase gamma(DGKG)-Δexon13 was amplified and verified by PCR-Sanger sequencing.The functions of DGKG and DGKG-Δexon13 were analyzed by Cell counting kit-8(CCK-8),Transwell,Matrigeltranswell experiments,and in vivo orthotropic GBM animal models.Transcriptome analyses were done to find out the regulated genes.Results:In this study,we found that a new transcript DGKG-Δexon13 was generated in GBM under hypoxia via alternative splicing.Moreover,the results of CCK-8,Transwell,and Matrigel-transwell experiments showed that the proliferation,migration,and invasion abilities of U87-MG and T98G were decreased after DGKG knockdown.Compared to wild-type DGKG,DGKG-Δexon13 overexpression significantly promoted cellular proliferation,migration,and invasion abilities in GBM.Furthermore,in vivo,orthotropic GBM animal models analysis showed that the tumor volumes were much smaller in the DGKG knockdown group.However,the tumor sizes in the DGKG and DGKG-Δexon13 rescue groups were restored,especially in the DGKG-Δexon13 group.Transcriptome analysis revealed that MORC1,KLHDC7B,ATP1A2,INHBE,TMEM119,and FGD3 were altered significantly when DGKG was knocked down.IL-16,CCN2,and EFNB3 were specifically regulated by DGKG-Δexon13.Conclusions:Our study found that hypoxia-induced alternative splicing transcript DGKG-Δexon13 promotes GBM proliferation and infiltration,which might provide a new potential target for the clinical treatment and diagnosis of GBM.展开更多
Hypoxemia is a common pathological state characterized by low oxygen saturation in the blood.This condition compromises mucosal barrier integrity particularly in the gut and oral cavity.However,the mechanisms underlyi...Hypoxemia is a common pathological state characterized by low oxygen saturation in the blood.This condition compromises mucosal barrier integrity particularly in the gut and oral cavity.However,the mechanisms underlying this association remain unclear.This study used periodontitis as a model to investigate the role of platelet activation in oral mucosal immunopathology under hypoxic conditions.Hypoxia upregulated methyltransferase-like protein 4(METTL4)expression in platelets,resulting in N6-methyladenine modification of mitochondrial DNA(mtDNA).This modification impaired mitochondrial transcriptional factor A-dependent cytosolic mtDNA degradation,leading to cytosolic mtDNA accumulation.Excess cytosolic mt-DNA aberrantly activated the cGAS-STING pathway in platelets.This resulted in excessive platelet activation and neutrophil extracellular trap formation that ultimately exacerbated periodontitis.Targeting platelet METTL4 and its downstream pathways offers a potential strategy for managing oral mucosa immunopathology.Further research is needed to examine its broader implications for mucosal inflammation under hypoxic conditions.展开更多
The cornea is an avascular,transparent tissue that is essential for visual function.Any disturbance to the corneal transparency will result in a severe vision loss.Due to the avascular nature,the cornea acquires most ...The cornea is an avascular,transparent tissue that is essential for visual function.Any disturbance to the corneal transparency will result in a severe vision loss.Due to the avascular nature,the cornea acquires most of the oxygen supply directly or indirectly from the atmosphere.Corneal tissue hypoxia has been noticed to influence the structure and function of the cornea for decades.The etiology of hypoxia of the cornea is distinct from the rest of the body,mainly due to the separation of cornea from the atmosphere,such as prolonged contact lens wearing or closed eyes.Corneal hypoxia can also be found in corneal inflammation and injury when a higher oxygen requirement exceeds the oxygen supply.Systemic hypoxic state during lung diseases or high altitude also leads to corneal hypoxia when a second oxygen consumption route from aqueous humor gets blocked.Hypoxia affects the cornea in multiple aspects,including disturbance of the epithelium barrier function,corneal edema due to endothelial dysfunction and metabolism changes in the stroma,and thinning of corneal stroma.Cornea has also evolved mechanisms to adapt to the hypoxic state initiated by the activation of hypoxia inducible factor(HIF).The aim of this review is to introduce the pathology of cornea under hypoxia and the mechanism of hypoxia adaptation,to discuss the current animal models used in this field,and future research directions.展开更多
文摘BACKGROUNDCancer stem cells(CSCs)drive recurrence and therapeutic resistance in triplenegativebreast cancer(TNBC),a highly aggressive breast cancer subtype.Intratumoralhypoxia,a common feature of solid tumors,promotes CSCs enrichment,yet the mechanisms sustaining CSCs stemness remain poorly understood.Hypoxia-induced reactive oxygen species can oxidatively activate ataxia telangiectasiamutated(ATM)kinase(oxidized ATM,p-ATM)independently of DNA breaks.AIMTo investigate the role of hypoxia-induced oxidized ATM in sustaining TNBCCSCstemness through c-Myc-mediated regulation of one-carbon metabolism.METHODSHs578T and MDA-MB-231 TNBC cells were cultured under normoxia or hypoxia.CSC stemness was assessed by mammosphere assays and flow cytometry.ATMactivity was assessed by pharmacological inhibition(Ku60019)and short hairpinRNA knockdown.c-Myc binding to serine hydroxymethyltransferase 2(SHMT2)and methylenetetrahydrofolate dehydrogenase 2(MTHFD2)promoters was analyzedby dual-luciferase reporter assays and chromatin immunoprecipitation.NADPH/NADP+ratios were quantified,and metabolic reprogramming was profiledby liquid chromatography-tandem mass spectrometry metabolomics.RESULTSHypoxia significantly increased mammosphere formation in both Hs578T and MDA-MB-231 cells,as reflected byhigher numbers of mammospheres(Hs578T:214±18;MDA-MB-231:198±16;both P<0.01)and larger meandiameters(P<0.01).Hypoxia also elevated CD44+/CD24-cell proportions and stemness gene expression(P<0.01).Oxidized ATM was activated under hypoxia withoutγH2AX induction,confirming DNA damage independence.ATM inhibition reduced mammosphere growth and suppressed c-Myc,SHMT2,and MTHFD2.Luciferase and chromatin immunoprecipitation assays confirmed direct c-Myc binding to SHMT2 and MTHFD2promoters,while mutation of the binding sites abolished promoter activity.NADPH/NADP+ratios were significantlyelevated under hypoxia but reduced following ATM inhibition(P<0.05).Metabolomics revealed enrichmentof serine/glycine one-carbon pathways.CONCLUSIONHypoxia-induced oxidized ATM maintains TNBC-CSC stemness by promoting c-Myc-dependent upregulation ofMTHFD2 and SHMT2,linking hypoxia,redox signaling,and one-carbon metabolism.These findings suggest apotential therapeutic axis that could be exploited for TNBC treatment.
基金Supported by the Henan Province Medical Science and Technology Tackling Plan Joint Construction Project,No.LHGJ20220684Zhengzhou University Tianjian Advanced Biomedical Laboratory Funding Project,No.BS20240101.
文摘BACKGROUND Hypoxia-inducible factor 1α(HIF-1α)plays a crucial role in the prognosis of breast cancer,but the current evidence remains inconclusive.AIM To provide comprehensive evidence about the correlation of altered HIF-1αexpression with overall survival(OS)and disease-free survival(DFS)in breast cancer patients.METHODS A systematic search was conducted in PubMed,Embase,and Web of Science databases to collect relevant articles that were published before April 8,2024.A meta-analysis was used to assess the impact of altered HIF-1αexpression on the OS and DFS of breast cancer patients.Subgroup and sensitivity analyses were also performed in this meta-analysis.RESULTS This meta-analysis included 40 studies.The average percentage of breast cancer patients with high HIF-1αexpression was 39.6%.The overall meta-analysis results demonstrated that high HIF-1αexpression is strongly linked to poor outcomes in patients of breast cancer.Compared with low HIF-1αexpression,the overall hazard ratio for OS in patients with high HIF-1αexpression was 1.47[95%confidence interval(CI):1.29-1.69],and the overall hazard ratio for DFS was 1.82(95%CI:1.56-2.12).Furthermore,both OS[1.18(95%CI:1.01-1.38)]and DFS[1.79(95%CI:1.03-3.11)]were markedly shorter in triple-negative breast cancer cases with high HIF-1αexpression.Subgroup analysis revealed that the antibody used to detect HIF-1αexpression affected only the correlation linking HIF-1αexpression to DFS in breast cancer patients(P=0.0004).Furthermore,the sensitivity analysis demonstrates that the overall conclusions of the meta-analysis were unaffected by the removal of individual studies.CONCLUSION Compared to patients with low HIF-1αexpression,those with high expression level had shorter OS and DFS.However,the prognostic significance of high HIF-1αexpression varies across molecularly stratified breast cancer cohorts needs to be further elucidated.
基金This work was financially supported by the National Natural Science Foundation of China(grant number:8217150152)the Clinical Science and Technology Innovation Project of Shanghai Shenkang Hospital Development Center(grant number:SHDC12021102)the Shanghai Three-Year Action Plan to Further Accelerate the Development of Traditional Chinese Medicine Inheritance and Innovation(grant number:ZY(2021-2023)-0209-05).
文摘Background:Adenoid hypertrophy(AH)is a common pediatric disease that signifi-cantly impacts the growth and quality of life of children.However,there is no replica-ble and valid model for AH.Methods:An AH rat model was developed via comprehensive allergic sensitization,chronic inflammation induction,and chronic intermittent hypoxia(CIH).The modeling process involved three steps:female Sprague-Dawley rats(aged 4-5 weeks)were used for modeling.Allergen sensitization was induced via intraperitoneal administra-tion and intranasal provocation using ovalbumin(OVA);chronic nasal inflammation was induced through intranasal lipopolysaccharide(LPS)administration for sustained nasal irritation;CIH akin to obstructive sleep apnea/hypopnea syndrome was induced using an animal hypoxia chamber.Postmodel establishment,behaviors,and histologi-cal changes in nasopharynx-associated lymphoid tissue(NALT)and nasal mucosa were assessed.Arterial blood gas analysis and quantification of serum and tissue levels of(interleukin)IL-4 and IL-13,OVA-specific immunoglobulin E(sIgE),eosinophil cationic protein(ECP),tumor necrosis factor(TNF-α),IL-17,and transforming growth factor(TGF)-βwere conducted for assessment.The treatment group received a combination of mometasone furoate and montelukast sodium for a week and then was evaluated.Results:Rats exhibited notable nasal symptoms and hypoxia after modeling.Histopathological analysis revealed NALT follicle hypertrophy and nasal mucosa in-flammatory cell infiltration.Elevated IL-4,IL-13,IL-17,OVA-sIgE,ECP,and TNF-αlev-els and reduced TGF-βlevels were observed in the serum and tissue of model-group rats.After a week of treatment,the treatment group exhibited symptom and inflam-matory factor improvement.Conclusion:The model effectively simulates AH symptoms and pathological changes.But it should be further validated for genetic,immunological,and hormonal back-grounds in the currently used and other strains and species.
文摘Objective To explore the sequential effects of hypoxic exercising on miR-27/PPARγand lipid metabolism targetgene and protein expression levels in the obesity rats’liver.Methods 13-week-old male diet-induced obesity rats were randomlydivided into three groups(n=10):normal oxygen concentration quiet group(N),hypoxia quiet group(H),hypoxic exercise group(HE).Exercise training on the horizontal animal treadmill for 1 h/d,5 d/week for a total of 4 week,and the intensity of horizontaltreadmill training was 20 m/min(hypoxic concentration was 13.6%).Comparison of the weights of perirenal fat and epididymal fat in rats across different groups and calculation of Lee’s index based on body weight and body length of rats in each group were done.And the serum concentrations of total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C),high-densitylipoprotein cholesterol(HDL-C)levels were detected.RT-PCR and Western Blot were used to detect the levels of miR-27,PPARγ,CYP7A1 and CD36.Results Hypoxic exercise decreased the expression levels of miR-27 in the obese rats’liver,however,theexpression level of PPARγwas gradually increased.The expression levels of miR-27 in HE group were significantly lower than Ngroup(P<0.05).The expression levels of PPARγmRNA in N group were significantly lower than H group(P<0.05),especially lowerthan HE group(P<0.01).The protein expression of PPARγprotein in N group was significantly lower than that other groups(P<0.01).The expression of lipid metabolism-related genes and proteins increased in the obese rats’liver.The expression of CYP7A1mRNA in N group was significantly lower than H group(P<0.05),especially lower than HE group(P<0.01).The expression ofCYP7A1 protein in the obese rats’liver in N group was extremely lower than H group and HE group(P<0.01).The proteinexpression of CD36 in N group was significantly lower than that in HE group(P<0.05).Hypoxia exercise improved the relatedphysiological and biochemical indexes of lipid metabolism disorder.The perirenal fat weight of obese rats in HE group wasextremely lower than N group and H group(P<0.01),and the perirenal fat weight in N group was significantly higher than H group(P<0.05).The epididymal fat weight in N group was significantly higher than H group(P<0.05),and extremely higher than HEgroup(P<0.01).The Lee’s index in HE group was extremely lower than N group and H group(P<0.01).The serum concentration ofTC in obese rats in HE group was extremely lower than N group and H group(P<0.01).The serum concentration of TG in HE groupwas extremely lower than N group and H group(P<0.01).The serum concentration of LDL-C in N group was extremely higher thanHE group(P<0.01).The serum concentration of HDL-C in N group was extremely lower than H group(P<0.01).Conclusion Hypoxiaand hypoxia exercise may negatively regulate the levels of PPARγby inhibiting miR-27 in the obese rats’liver,thereby affecting theexpression of downstream target genes CYP7A1 and CD36,and promoting cholesterol,fatty acid oxidation and HDL-C transport inthe liver,and ultimately the lipid levels in obese rats were improved.The effect of hypoxia exercise on improving blood lipid isbetter than simple hypoxia intervention.
文摘Objective: To investigate the specific mechanism of hypoxia-inducible factor 1 alpha (HIF-1α) in the regulation of human sperm apoptosis, and to provide a new theoretical reference and scientific basis for the diagnosis and treatment of asthenospermia and other related conditions. Methods: Semen samples were categorized into the normal group and asthenospermia group based on sperm motility criteria. HIF-1α interfering agent cobalt chloride (CoCl2) and guanylate cyclase activator (Lificiguat, YC-1) were added respectively, with a control group established accordingly. Sperm motility (using anterior viability rate as an index), apoptosis level, ATP level, mitochondrial membrane potential, and reactive oxygen species (ROS) level were measured. The expression levels of HIF-1α, p-PI3K, and Bcl-2 in the samples were analyzed using Western blotting. Results: Following CoCl2 treatment, there was a significant increase in sperm apoptosis compared to the normal control group (12.51% ± 2.50% VS 11.15% ± 2.42%);additionally, sperm motility (45.34% ± 3.37% VS 51.36% ± 11.68%), ATP production (11.51 ± 2.87 nM/µL VS 14.99 ± 2.83 nM/µL), ROS levels, and mitochondrial membrane potential all decreased significantly (all P α and p-PI3K increased significantly while Bcl-2 expression decreased (all P α in the YC-1 treatment group were decreased, and the expression level of Bcl-2 was increased (all P α can influence human sperm apoptosis and motility through the PI3K signaling pathway.
基金supported by the Specialized Research Fund for the National Natural Science Foundation of China(No.81973511).
文摘Objective Hypoxia plays a critical role in the pathophysiology of cardiomyopathy,myocardial infarction,and heart failure.Promoting ketone metabolism has been shown to be beneficial for myocardial cells under hypoxic conditions.However,the expression and regulatory mechanisms of key enzymes in the ketone pathway under hypoxic conditions are still unclear.This study aimed to investigate the effects of hypoxia on the expression of key enzymes in the ketone metabolic pathway and the underlying regulatory mechanisms involved.Methods H9C2 myocardial cells were cultured for 6 h in an oxygen-glucose-deprived state,and the expression of various genes was detected by quantitative real-time PCR.ELISA and lactate dehydrogenase(LDH)cytotoxicity assay were used to measure CoAs,itaconic acid,and LDH levels,respectively,and the dependence of gene expression on hypoxia-inducible factor-1 alpha(HIF-1α)was evaluated using the inhibitor LW6.Results H9C2 cardiomyocytes exhibited increased ketone body metabolism in response to hypoxia.Hypoxia induced the expression of the ketone body enzymes succinyl-CoA:3-oxoacid CoA transferase(SCOT/OXCT1),3-hydroxybutyrate dehy-drogenase 2(BDH2),and acyl-CoA:cholesterol acyltransferase 1(ACAT1)in cardiomyocytes,with a concomitant increase in the level of acyl-CoA and a decrease in the level of succinyl-CoA.The HIF-1αinhibitor LW6 could partially reverse the expression of BDH2 and ACAT1,as well as the levels of succinyl-CoA.Interestingly,however,hypoxia-induced SCOT/OXCT1 expression was not regulated by the HIF-1αinhibitor.In addition,hypoxia promoted the expression of inflamma-tory factors.Conclusion These data confirm the critical role of ketone metabolism in myocardial hypoxia and help to elucidate the patho-physiology of cardiomyopathy,myocardial infarction and heart failure.
基金supported by the Qin Chuangyuan Traditional Chinese Medicine(TCM)and Innovation Research and Development Project of Shaanxi Provincial Administration of TCM(No.2022-QCYZH-017)Natural Science Foundation of Zhejiang Province(No.LY24E030010)+5 种基金Natural Science Foundation of Shaanxi Province(Nos.2022JM183,2024JC-YBMS-272)the Shaanxi Fundamental Science Research Project for Chemistry&Biology(No.22JHQ072)Shaanxi Provincial Key R&D Program(No.2022SF-342HZ)the Fundamental Research Funds for the Central Universities(Nos.xzy012022037,xzy012023002)the Postdoctoral Science Foundation of Shaanxi Province(No.2023BSHYDZZ05)Foundation by Shaanxi Provincial Administration of TCM(No.2021-ZZ-JC032)。
文摘Innovative anti-cancer therapies that activate the immune system show promise in combating cancers resistant to conventional treatments.Photodynamic therapy(PDT)is one such treatment,which not only directly eliminates tumor cells but also functions as an in situ tumor vaccine by enhancing tumor immunogenicity and triggering anti-tumor immune responses through immunogenic cell death(ICD).However,the effectiveness of PDT in enhancing immune responses is influenced by factors,such as photosensitizers and the tumor microenvironment,particularly hypoxia.Current clinically used PDT heavily relies on oxygen(O_(2))availability and can be limited by tumor hypoxia.Additionally,the tumor immunosuppressive microenvironment induced by hypoxia affects the anti-tumor immunity of tumor-infiltrating effector T cells.Meanwhile,the immunosuppressive myeloid-lineage cells are recruited to the hypoxic tumor tissue and exhibit higher immunosuppressive capabilities under hypoxia conditions.Consequently,numerous strategies have been developed to modulate tumor hypoxia or to create hypoxia-compatible PDT,aiming to reduce the effects of tumor hypoxia on PDT-driven immunotherapy.This review investigates these strategies,including approaches to alleviate,exploit,and disregard tumor hypoxia within the context of PDT/immunotherapy.It also emphasizes the role of advanced nanomedicine and its benefits in these strategies,while outlining current challenges and future prospects in the field.
基金financially supported by the earmarked fund for CARS(CARS-45)National Natural Science Foundation of China(32273144,32072985)National Key R&D Program of China(2019YFD0900200).
文摘Background Ochratoxin A(OTA)is a toxin widely found in aquafeed ingredients,and hypoxia is a common prob-lem in fish farming.In practice,aquatic animals tend to be more sensitive to hypoxia while feeds are contaminated with OTA,but no studies exist in this area.This research investigated the multiple biotoxicities of OTA and hypoxia combined on the liver of grass carp and explored the mitigating effect of curcumin(CUR).Methods A total of 720 healthy juvenile grass carp(11.06±0.05 g)were selected and assigned randomly to 4 experi-mental groups:control group(without OTA and CUR),1.2 mg/kg OTA group,400 mg/kg CUR group,and 1.2 mg/kg OTA+400 mg/kg CUR group with three replicates each for 60 d.Subsequently,32 fish were selected,divided into nor-moxia(18 fish)and hypoxia(18 fish)groups,and subjected to hypoxia stress for 96 h.Results CUR can attenuate histopathological damage caused by coming to OTA and hypoxia by reducing vacu-olation and nuclear excursion.The alleviation of this damage was associated with the attenuation of apoptosis in the mitochondrial pathway by decreasing the expression of the pro-apoptotic proteins Caspase 3,8,9,Bax,and Apaf1 while increasing the expression of the anti-apoptotic protein Bcl-2,and attenuation of endoplasmic reticulum stress(ERS)by reducing Grp78 expression and chop levels.This may be attributed to the fact that the addi-tion of CUR increased the levels of catalase(CAT)and glutathione reductase(GSH),increased antioxidant capacity,and ensured the proper functioning of respiratory chain complexes I and II,which in turn reduced the high produc-tion of reactive oxygen species(ROS),thus alleviating apoptosis and ERS.Conclusions In conclusion,our data demonstrate the effectiveness of CUR in attenuating liver injury caused by the combination of OTA and hypoxia.This study confirms the feasibility and efficacy of adding natural products to mitigate toxic damage to aquatic animals.
基金by Guangdong Basic and Applied Basic Research Foundation,No.2023A1515012394.
文摘BACKGROUND Hypobaric hypoxia exposure(HHE)often causes neuropsychiatric disorders.Due to its complex mechanism,efficient strategies for alleviating HHE-induced anxiety-and depression-like behaviors remain limited.AIM To characterize alterations in the oral and gut microbiota following HHE and to explore a potential microbiota-based intervention to mitigate associated psychiatric symptoms.METHODS C57BL/6J mice were exposed to simulated high-altitude hypoxia(5000 m)for 1,3,5,or 7 days.Behavioral assessments,including the open field test,elevated plus maze,and forced swim test,were conducted to evaluate anxiety-and depressionlike behaviors.Oral and fecal microbiota were analyzed using 16S rRNA sequencing to assess changes in microbial composition and diversity.Immunofluorescence staining was performed to examine c-Fos expression in brain nuclei.A probiotic formulation containing Lactobacillus rhamnosus(L.rhamnosus)DSM17648,Lactobacillus acidophilus DDS-1,and L.rhamnosus UALR-06 was administered to mice subjected to one day of HHE(HH1)to evaluate its therapeutic efficacy.RESULTS Behavioral tests revealed that HHE caused anxiety-and depression-like behaviors,which were most pronounced after 1 day of exposure.The IF data revealed significantly increased expression of c-Fos in various brain nuclei after HHE,including the anterior cingulate cortex,paraventricular thalamic nucleus,lateral habenula nucleus,paraventricular hypothalamic nucleus,lateral hypothalamus,and periaqueductal gray.The 16S rRNA sequencing results demonstrated a sharp decline in the abundance of Lactobacillus in the oral microbiota of mice exposed to HH1 and a marked decrease in the abundance of Lactobacillus and Bifidobacterium in the fecal microbiota of mice exposed to three days of HHE.Finally,oral administration and gavage of Lactobacillus significantly alleviated anxiety-and depression-like behaviors in HH1 mice.CONCLUSION HHE caused significant variations in the oral and fecal microbiota of mice.Lactobacillus supplementation alleviated anxiety-and depression-like behaviors in mice.Improving oral flora may relieve HHE-induced psychiatric disorders.
文摘The published article titled“MicroRNA-33b Inhibits the Proliferation andMigration of Osteosarcoma Cells via TargetingHypoxia-Inducible Factor-1α”has been retracted from Oncology Research,Vol.25,No.3,2017,pp.397–405.
基金The Innovation Group Project of Southern Marine Science and Engineering Guangdong Laboratory(Zhuhai)under contract No.311021004the Biodiversity Assessment of Key Marine Habitat in China under contract Nos PM-zx555-202107-208 and PM-zx555-202106-195.
文摘Macrobenthos can serve as an indicator of hypoxia in the estuarine ecosystem.This comparative study surveyed macrobenthos from hypoxic and non-hypoxic areas of the Zhujiang(Pearl)River Estuary(PRE),and explores the effects of environmental factor on the macrobenthos community structure.In July 2020,49 macrobenthos species were collected from the hypoxic area,contrasting with 91 species found in the non-hypoxic area.July 2021 recorded 51 species in the hypoxic area and 76 in the non-hypoxic area.Analysis of similarities(ANOSIM)and non-metric multidimentional scaling(NMDS)showed no significant difference in the macrobenthos community structure between the two areas.However,Polychaeta displays higher species richness,abundance,and biomass in the hypoxic zone,negatively correlating to dissolved oxygen(DO).Canonical correspondence analysis(CCA)also showed that the abundance of Polychaeta was negatively correlated with that of Crustacea.Interestingly,despite the differences in Polychaeta,macrobenthos community structure remains stable between hypoxic and non-hypoxic samples.This study suggests Polychaeta’s potential adaptation to hypoxic conditions in the PRE’s hypoxic area.Finally,Spearman correlation analysis showed that DO have a significant negative correlation with total phosphorus(TP),total nitrogen(TN)and total organic carbon(TOC)in the PRE,indicating that water eutrophication would exacerbate the occurrence of hypoxia.
基金supported by the National Natural Science Foundation of China (No. 32341060)the National Key Research and Development Program of China (No.2022YFD2400300)+2 种基金the Key Research and Development Program of Shandong Province (No. 2021ZLGX03)the earmarked fund for China Agriculture Research System (CARS-49)support from the High-Performance Biological Supercomputing Center of the Ocean University of China.
文摘The Pacific oyster(Crassostrea gigas)is a primary shellfish species for aquaculture around the world.However,the industry of Pacific oyster has been impaired by the mass summer mortality caused by environmental perturbations,including hypoxia.Selective breeding of oysters with high hypoxia tolerance is a sustainable approach to prevent economic loss caused by hypoxia.In this study,we constructed 36 C.gigas families and executed the hypoxia stress experiment to estimate genetic parameters for hypoxia tolerance.The survival rate among 36 C.gigas families ranged from 0 to 53.33%,suggesting that high levels of phenotypic variation existed in the trait of hypoxia tolerance.Genetic parameters of hypoxia tolerance estimated by six statistical models showed a low to moderate heritability,ranging from 0.167 to 0.291.The Pearson and Spearman correlation coefficients among families estimated breeding values(EBVs)were high and positive,indicating that different models resulted in similar results in the estimation of breeding values.The phenotypic correlation between growth traits and hypoxia tolerance ranged from-0.030 to 0.061,while genetic correlation ranged from 0.110 to 0.285,implying that growth and hypoxia tolerance were independent traits.This work reported the first estimation of genetic parameters for hypoxia tolerance in C.gigas,and provided valuable information for the genetic improvement of hypoxia tolerance.
基金supported by Beijing Natural Science Foundation(No.7232090)the National Natural Science Foundation of China(82101306)the Scientific and Technological Innovation 2030(2021ZD0201100).
文摘Objective High-altitude hypoxia exposure often damages hippocampus-dependent learning and memory.Nogo-A is an important axonal growth inhibitory factor.However,its function in high-altitude hypoxia and its mechanism of action remain unclear.Methods In an in vivo study,a low-pressure oxygen chamber was used to simulate high-altitude hypoxia,and genetic or pharmacological intervention was used to block the Nogo-A/NgR1 signaling pathway.Contextual fear conditioning and Morris water maze behavioral tests were used to assess learning and memory in rats,and synaptic damage in the hippocampus and changes in oxidative stress levels were observed.In vitro,SH-SY5Y cells were used to assess oxidative stress and mitochondrial function with or without Nogo-A knockdown in Oxygen Glucose-Deprivation/Reperfusion(OGD/R)models.Results Exposure to acute high-altitude hypoxia for 3 or 7 days impaired learning and memory in rats,triggered oxidative stress in the hippocampal tissue,and reduced the dendritic spine density of hippocampal neurons.Blocking the Nogo-A/NgR1 pathway ameliorated oxidative stress,synaptic damage,and the learning and memory impairment induced by high-altitude exposure.Conclusion Our results demonstrate the detrimental role of Nogo-A protein in mediating learning and memory impairment under high-altitude hypoxia and suggest the potential of the Nogo-A/NgR1 signaling pathway as a crucial therapeutic target for alleviating learning and memory dysfunction induced by high-altitude exposure.
基金the National Natural Science Foundation of China(82074264)。
文摘Objective:A complex relationship exists between obstructive sleep apnea syndrome and diabetes mellitus(DM).Chronic intermittent hypoxia(CIH),which is a core pathological feature of obstructive sleep apnea syndrome,may play an important role in the onset and development of DM-related atherosclerosis(DM-AS).This study aimed to investigate the mechanism of action of tetramethylpyrazine(TMP)in CIH-associated DM-AS.Methods:In vivo,a DM-AS mouse model was established by intraperitoneal injection of streptozotocin combined with a high-fat diet.They were exposed to CIH or normoxic conditions for 8 weeks and received different doses of TMP,rosuvastatin,toyocamycin,and purified water.Glycolipid metabolism,inflammation levels,degree of aortic AS,and expression levels of endoplasmic reticulum stress(ERS)and autophagy proteins were examined in mice.In vitro,human umbilical vein endothelial cells(HUVECs)were treated with high glucose and fat in combination with insulin to establish an insulin-resistant cell model(HUVEC-IR).After pretreatment with 4μ8C(IRE1 inhibitor)and different doses of TMP,intermittent hypoxic intervention was performed.Changes in cell morphology,proliferative activity,glucose consumption,and ability to migrate were observed,and the expression levels of ERS and autophagy proteins were detected.Results:In vivo experiments showed that CIH significantly increased blood glucose levels and Homeostasis Model Assessment of Insulin Resistance(HOMA-IR)(P<0.001 or P<0.05),low-density lipoprotein cholesterol(LDL-C)content(P<0.001),and the levels of three inflammatory factors[interleukin-1 beta(IL-1β),IL-6,and tumor necrosis factor-alpha(TNF-α)]in the mice(P<0.001)compared with those of the mice with DM alone;moreover,the aortic atherosclerotic(AS)plaque area in CIH mice was significantly enlarged(P<0.001).Western blotting results showed that the expressions of aortic IRE1α,XBP1s,Beclin1,and LC3A proteins were significantly increased in CIH mice compared with DM mice(P<0.05).After treatment with different doses of TMP,rosuvastatin calcium,and toyocamycin,serum inflammation and lipid levels and plaque area were significantly reduced in mice(P<0.001 and P<0.001,respectively).The expression levels of aortic XBP1s,Beclin1,and LC3A were reduced in TMP-and toyocamycin-treated mice(P<0.05).In the in vitro experiments,compared with normoxic cells,the cells treated with intermittent hypoxia(IH)showed a significant decrease in cell migration distance(P<0.05),a significant increase in apoptosis rate(P<0.001),a substantial increase in proliferation inhibition rate(P<0.001),a significant increase in the levels of XBP1s and LC3A proteins(P<0.05),and an increase in the number of autophagic vesicles/lysosomes,as observed under transmission electron microscopy.After treatment with different doses of TMP and 4μ8C,cell morphology was significantly restored,apoptosis rate significantly reduced(P<0.001),and XBP1s,Beclin1,and LC3A expressions significantly inhibited(P<0.05).Conclusion:CIH promoted the onset of DM-AS,whereas TMP attenuated ERS and excessive autophagy by modulating the IRE1α-XBP1 signaling pathway and inhibiting XBP1 splicing,thereby ameliorating DM-AS exacerbated by CIH.
基金supported by the National Key Research and Development Program of China(2021YFA0910000)NSFC Excellent Young Scientist Scheme(22222803)+1 种基金the NSFC Science Center Program(21788102),NSFC(22408105)the China Postdoctoral Science Foundation(2022M72142).
文摘The development of efficient aggregation-induced emission(AIE)active probes is crucial for disease diagnosis,particularly for tumors and cardiovascular diseases.Current AIE-active probes primarily focus on improving their water solubility to resist aggregation,thereby achieving an initial fluorescence-off state.However,the complex biological environment can cause undesirable aggregation,resulting in false signals.To address this issue,we have ingeniously introduced an azo group into the AIE luminogen(AIEgen),developing a reductase-activated AIE probe,Azo-quinoline-malononitrile(QM)-PN,for imaging hypoxic environments.In this probe,the azo group promotes intramolecular motion through rapid E/Z isomerization,causing the excited state energy to dissipate via non-radiative decay,thus turning off the initial fluorescence.In the presence of reductase,Azo-QM-PN is reduced and cleaved to produce the hydrophobic AIEgen NH_(2)-QM-PN,which subsequently aggregates and generates an in situ AIE signal,thereby imaging the hypoxic environment with reductase.Encapsulation of Azo-QM-PN with DSPEPEG2000 results in the formation of the nanoprobe Azo-QM-PN NPs,which can effectively penetrate cell membranes,specifically illuminate tumor cells,monitor fluctuations in azo reductase levels,and deeply penetrate and image multicellular tumor spheroids,demonstrating potential for hypoxic tumor imaging.Additionally,the nanoprobe Azo-QM-PN NPs can selectively image hypoxic atherosclerotic plaque tissues,showing potential for detecting atherosclerosis.Therefore,in this study,we successfully developed an enzyme-activated AIE probe for imaging hypoxic environments,laying the foundation for further clinical applications.
基金Supported by the Major Science and Technology Project of Gansu Province-Social Development Field,No.25ZDFA007Health Industry Research Funding Project of Gansu Province,No.GSWSKY2024-54+3 种基金Youth Science and Technology Fund Program of Gansu Province,No.21JR11RA014National Natural Science Foundation of China,No.81273568Health Industry Research Funding Project of Gansu Province,No.GSWSKY2022-03Logistics Scientific Research Independent Project of the PLA.
文摘BACKGROUND While acute exposure to high-altitude hypoxic environments can lead to increased thrombosis risk,preventive measures are currently limited.Recently,human umbilical cord mesenchymal stem cell(hUC-MSC)transplantation has been found effective in preventing and treating various clinical conditions,including thro-mbotic diseases.Platelets are crucial for thrombus formation,and theirα-granules are key determinants of platelet function.However,little is known about the influence of hUC-MSCs on plateletα-granules.METHODS Rats were assigned to three groups,namely,low-altitude,high-altitude,and hUC-MSC-treated groups.The low-altitude group was pretreated with normal saline and housed at an altitude of 1500 m.Rats in the high-altitude group received similar pretreatment and were housed in a simulated hypobaric hypoxia chamber with an altitude of 6500 m and oxygen partial pressure of 7.7 kPa.hUC-MSC-treated rats were pretreated with hUC-MSCs and exposed to hypoxic conditions.Aortic blood was collected after three days to assess platelet counts and mor-phology andα-granule release.RESULTS Compared to the low-altitude group,the high-altitude group exhibited significantly higher platelet counts,plasma levels of von Willebrand factor,platelet factor 4,beta-thromboglobulin,as well as surface P-selectin(CD62p)and p-protein kinase B,p-mitogen-activated protein kinase,and p-extracellular-signal regulated kinase expression in platelets.Platelet morphology in the high-altitude group was irregular,with extended pseudopodia and increasedα-granule densities.However,these changes were not apparent in the hUC-MSC-treated group.CONCLUSION Acute exposure to high-altitude hypoxia increased platelet counts,altered platelet morphology,and increasedα-granule density and release.These effects were mitigated by hUC-MSC treatment,mediated by the protein kinase B/mitogen-activated protein kinase/extracellular-signal regulated kinase pathway.The results indicate that hUC-MSCs may represent a promising and effective approach for the prevention and treatment of acute high-altitude-associated thrombosis,providing an experimental foundation for the development of clinical applications.
基金supported by the National Natural Science Foundation of China(32102760)“JBGS”Project of Seed Industry Revitalization in Jiangsu Province(JBGS(2021)034)+1 种基金Creation Project of Major New Species of Agriculture in Jiangsu Province(PZCZ201742)Key Laboratory of Healthy Freshwater Aquaculture,Ministry of Agriculture and Rural Affairs,Key Laboratory of Freshwater Aquaculture Genetic and Breeding of Zhejiang Province,Zhejiang Institute of Freshwater Fisheries,Huzhou 313001(ZJK202404)。
文摘Intestinal inflammation is a common challenge in intensive aquaculture,yet its pathogenesis remains unclear.While interleukin 22(IL-22)is recognized as a critical regulator of cellular homeostasis during inflammation in higher vertebrates,its roles in fish are not well understood.This study established hypoxia-induced models in intestinal tissues and primary intestinal epithelial cells of yellow catfish to investigate the involvement of IL-22 in maintaining intestinal homeostasis.Results revealed that Pelteobagrus fulvidraco IL-22(Pf_IL-22)was abundantly expressed in mucosal tissues,with the highest levels in the gill and intestine.Hypoxia induced pronounced intestinal injury,characterized by loosening of the lamina propria and extensive vacuolization,while activating hypoxia-inducible factor(HIF)signaling and markedly up-regulating IL-22 expression.IL-22 levels peaked at 24 h post-hypoxia,suggesting a role in early immune responses.Recombinant Pf_IL-22 also induced transcription of pro-inflammatory mediators,including IL-1βand tumor necrosis factorα(TNF-α),in primary intestinal epithelial cells,indicating a dual regulatory function in balancing protection and inflammation.Mechanistic analyses revealed that HIF-1αdirectly interacted with a hypoxia response element within the IL-22 promoter to drive transcription,as confirmed by dual-luciferase assays,electrophoretic mobility-shift assays,and HIF-1αknockdown.Silencing Pf_IL-22 significantly suppressed Th17 cell differentiation pathways,demonstrating its role in shaping downstream immune responses.These findings establish the HIF-1α/IL-22 axis as a key regulatory pathway modulating immune responses and alleviating intestinal inflammation,providing a basis for developing IL-22-targeted immunotherapies and selective breeding strategies in aquaculture.
基金funded by Guizhou Province Science and Technology Plan Project Qiankehe Foundation-ZK[2023]General 360,362Science and Technology Fund project of Guizhou Provincial Health Commission(gzwkj-2022-09,gzwkj-2023-035)+1 种基金National Natural Science Foundation Cultivation Project of Guizhou Medical University(21NSFCP14,gyfynsfc-2022-25)The PhD Scientific Research Launch Fund Project of the Affiliated Hospital of Guizhou Medical University(gyfybsky-2022-02).
文摘Background:Glioblastoma(GBM)is one of the most malignant types of central nervous system tumors.Oxygen deprivation in the tumor microenvironment is thought to be an important factor in promoting GBM progression.However,the mechanisms of hypoxia-promoted tumor progression remain elusive.Methods:Alternative splicing of diacylglycerol kinase gamma(DGKG)-Δexon13 was amplified and verified by PCR-Sanger sequencing.The functions of DGKG and DGKG-Δexon13 were analyzed by Cell counting kit-8(CCK-8),Transwell,Matrigeltranswell experiments,and in vivo orthotropic GBM animal models.Transcriptome analyses were done to find out the regulated genes.Results:In this study,we found that a new transcript DGKG-Δexon13 was generated in GBM under hypoxia via alternative splicing.Moreover,the results of CCK-8,Transwell,and Matrigel-transwell experiments showed that the proliferation,migration,and invasion abilities of U87-MG and T98G were decreased after DGKG knockdown.Compared to wild-type DGKG,DGKG-Δexon13 overexpression significantly promoted cellular proliferation,migration,and invasion abilities in GBM.Furthermore,in vivo,orthotropic GBM animal models analysis showed that the tumor volumes were much smaller in the DGKG knockdown group.However,the tumor sizes in the DGKG and DGKG-Δexon13 rescue groups were restored,especially in the DGKG-Δexon13 group.Transcriptome analysis revealed that MORC1,KLHDC7B,ATP1A2,INHBE,TMEM119,and FGD3 were altered significantly when DGKG was knocked down.IL-16,CCN2,and EFNB3 were specifically regulated by DGKG-Δexon13.Conclusions:Our study found that hypoxia-induced alternative splicing transcript DGKG-Δexon13 promotes GBM proliferation and infiltration,which might provide a new potential target for the clinical treatment and diagnosis of GBM.
基金supported by the National Natural Science Foundation of China(82325012)the Youth Fund of the National Natural Science Foundation of China(82301043)+1 种基金the Natural Science Basic Research Program of Shaanxi (Program No.2024JC-YBQN-0980)the Shaanxi Key Scientific and Technological Innovation Team(2020TD-033).
文摘Hypoxemia is a common pathological state characterized by low oxygen saturation in the blood.This condition compromises mucosal barrier integrity particularly in the gut and oral cavity.However,the mechanisms underlying this association remain unclear.This study used periodontitis as a model to investigate the role of platelet activation in oral mucosal immunopathology under hypoxic conditions.Hypoxia upregulated methyltransferase-like protein 4(METTL4)expression in platelets,resulting in N6-methyladenine modification of mitochondrial DNA(mtDNA).This modification impaired mitochondrial transcriptional factor A-dependent cytosolic mtDNA degradation,leading to cytosolic mtDNA accumulation.Excess cytosolic mt-DNA aberrantly activated the cGAS-STING pathway in platelets.This resulted in excessive platelet activation and neutrophil extracellular trap formation that ultimately exacerbated periodontitis.Targeting platelet METTL4 and its downstream pathways offers a potential strategy for managing oral mucosa immunopathology.Further research is needed to examine its broader implications for mucosal inflammation under hypoxic conditions.
文摘The cornea is an avascular,transparent tissue that is essential for visual function.Any disturbance to the corneal transparency will result in a severe vision loss.Due to the avascular nature,the cornea acquires most of the oxygen supply directly or indirectly from the atmosphere.Corneal tissue hypoxia has been noticed to influence the structure and function of the cornea for decades.The etiology of hypoxia of the cornea is distinct from the rest of the body,mainly due to the separation of cornea from the atmosphere,such as prolonged contact lens wearing or closed eyes.Corneal hypoxia can also be found in corneal inflammation and injury when a higher oxygen requirement exceeds the oxygen supply.Systemic hypoxic state during lung diseases or high altitude also leads to corneal hypoxia when a second oxygen consumption route from aqueous humor gets blocked.Hypoxia affects the cornea in multiple aspects,including disturbance of the epithelium barrier function,corneal edema due to endothelial dysfunction and metabolism changes in the stroma,and thinning of corneal stroma.Cornea has also evolved mechanisms to adapt to the hypoxic state initiated by the activation of hypoxia inducible factor(HIF).The aim of this review is to introduce the pathology of cornea under hypoxia and the mechanism of hypoxia adaptation,to discuss the current animal models used in this field,and future research directions.
