Nogo-A Protein Mediates Oxidative Stress and Synaptic Damage Induced by High-Altitude Hypoxia in the Rat Hippocampus

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.

Effects of high glucose and severe hypoxia on the biological behavior of mesenchymal stem cells at various passages

BACKGROUND Mesenchymal stem cells(MSCs)have been extensively studied for therapeutic potential,due to their regenerative and immunomodulatory properties.Serial passage and stress factors may affect the biological characteristics of MSCs,but the details of these effects have not been recognized yet.AIM To investigate the effects of stress factors(high glucose and severe hypoxia)on the biological characteristics of MSCs at different passages,in order to optimize the therapeutic applications of MSCs.METHODS In this study,we investigated the impact of two stress conditions;severe hypoxia and high glucose on human adipose-tissue derived MSCs(hAD-MSCs)at passages 6(P6),P8,and P10.Proliferation,senescence and apoptosis were evaluated measuring WST-1,senescence-associated beta-galactosidase,and annexin V,respectively.RESULTS Cells at P6 showed decreased proliferation and increased apoptosis under conditions of high glucose and hypoxia compared to control,while the extent of senescence did not change significantly under stress conditions.At P8 hAD-MSCs cultured in stress conditions had a significant decrease in proliferation and apoptosis and a significant increase in senescence compared to counterpart cells at P6.Cells cultured in high glucose at P10 had lower proliferation and higher senescence than their counterparts in the previous passage,while no change in apoptosis was observed.On the other hand,MSCs cultured under hypoxia showed decreased senescence,increased apoptosis and no significant change in proliferation when compared to the same conditions at P8.CONCLUSION These results indicate that stress factors had distinct effects on the biological processes of MSCs at different passages,and suggest that senescence may be a protective mechanism for MSCs to survive under stress conditions at higher passage numbers.

Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization

Spinal cord injury is a disabling condition with limited treatment options.Multiple studies have provided evidence suggesting that small extracellular vesicles(SEVs)secreted by bone marrow mesenchymal stem cells(MSCs)help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury.Strikingly,hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs(HSEVs)exhibit increased therapeutic potency.We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair.SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation.HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation.HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro.Micro RNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that mi R-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1.Reducing mi R-146a-5p expression in HSEVs partially attenuated macrophage polarization.Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting mi R-146a-5p,which alters macrophage polarization.This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.

Hypoxia-mediated programmed cell death is involved in the formation of wooden breast in broilers

Background Wooden breast(WB)myopathy is a common myopathy found in commercial broiler chickens worldwide.Histological examination has revealed that WB myopathy is accompanied by damage to the pectoralis major(PM)muscle.However,the underlying mechanisms responsible for the formation of WB in broilers have not been fully elucidated.This study aimed to investigate the potential role of hypoxia-mediated programmed cell death(PCD)in the formation of WB myopathy.Results Histological examination and biochemical analysis were performed on the PM muscle of the control(CON)and WB groups.A significantly increased thickness of the breast muscle in the top,middle,and bottom portions(P<0.01)was found along with pathological structure damage of myofibers in the WB group.The number of capillaries per fiber in PM muscle,and the levels of p O_(2) and s O_(2) in the blood,were significantly decreased(P<0.01),while the levels of p CO_(2) and TCO_(2) in the blood were significantly increased(P<0.05),suggesting hypoxic conditions in the PM muscle of the WB group.We further evaluated the PCD-related pathways including autophagy,apoptosis,and necroptosis to understand the consequence response to enhanced hypoxic conditions in the PM muscle of birds with WB.The ratio of LC3 II to LC3 I,and the autophagy-related factors HIF-1α,BNIP3,Beclin1,AMPKα,and ULK1 at the m RNA and protein levels,were all significantly upregulated(P<0.05),showing that autophagy occurred in the PM muscle of the WB group.The apoptotic index,as well as the expressions of Bax,Cytc,caspase 9,and caspase 3,were significantly increased(P<0.05),whereas Bcl-2 was significantly decreased(P<0.05)in the WB-affected PM muscle,indicating the occurrence of apoptosis mediated by the mitochondrial pathway.Additionally,the expressions of necroptosis-related factors RIP1,RIP3,and MLKL,as well as NF-κB and the pro-inflammatory cytokines TNF-α,IL-1β,and IL-6,were all significantly enhanced(P<0.05)in the WB-affected PM muscle.Conclusions The WB myopathy reduces blood supply and induces hypoxia in the PM muscle,which is closely related to the occurrence of PCD including apoptosis,autophagy,and necroptosis within myofibers,and finally leads to abnormal muscle damage and the development of WB in broilers.

Immune consequences of exercise in hypoxia:A narrative review

Immune outcomes are key mediators of many health benefits of exercise and are determined by exercise type,dose(frequency/duration,intensity),and individual characteristics.Similarly,reduced availability of ambient oxygen(hypoxia)modulates immune functions depending on the hypoxic dose and the individual capacity to respond to hypoxia.How combined exercise and hypoxia(e.g.,high-altitude training)sculpts immune responses is not well understood,although such combinations are becoming increasingly popular.Therefore,in this paper,we summarize the impact on immune responses of exercise and of hypoxia,both independently and together,with a focus on specialized cells in the innate and adaptive immune system.We review the regulation of the immune system by tissue oxygen levels and the overlapping and distinct immune responses related to exercise and hypoxia,then we discuss how they may be modulated by nutritional strategies.Mitochondrial,antioxidant,and anti-inflammatory mechanisms underlie many of the adaptations that can lead to improved cellular metabolism,resilience,and overall immune functions by regulating the survival,differentiation,activation,and migration of immune cells.This review shows that exercise and hypoxia can impair or complement/synergize with each other while regulating immune system functions.Appropriate acclimatization,training,and nutritional strategies can be used to avoid risks and tap into the synergistic potentials of the poorly studied immune consequences of exercising in a hypoxic state.

Vital contribution of brassinosteroids to hypoxia-stimulated coleoptile elongation in submerged rice

The rapid elongation of rice(Oryza sativa)coleoptile is pivotal for the plant plumule to evade hypoxia stress induced by submergence,a condition often arising from overirrigation,ponding,rainstorms,or flooding.While brassinosteroids(BRs)are recognized for their diverse roles in plant growth and development,their influence on coleoptile elongation under hypoxic conditions remains largely unexplored.In this study,we demonstrate the significant requirement of BRs for coleoptile elongation in deep water.During coleoptile development,Glycogen Synthase Kinase3-Like Kinase2(GSK2),the central inhibitor of BR signaling in rice,undergoes substantial suppression in deep water but induction in air.In contrast,the dephosphorylated form of BRASSINAZOLE RESISTANT1(OsBZR1),representing the active form of the key BR signaling transcription factor,is induced in water but suppressed in air.Remarkably,the knockout of GSK3-like kinase genes significantly enhances coleoptile elongation in deep water,strongly indicating a vital contribution of BR response to hypoxia-stimulated coleoptile elongation.Transcriptome analysis uncovers both BR-associated and BR-independent hypoxia responses,implicating substance metabolism,redox reactions,abiotic stress responses,and crosstalk with other hormones in the regulation of BR-induced hypoxia responses.In summary,our findings suggest that rice plumules rapidly elongate coleoptiles through the activation of BR response in deep water,enabling them to escape from submergence-induced hypoxia stress.

Effect of tubastatin A on NLRP3 inflammasome activation in macrophages under hypoxia/ reoxygenation conditions

BACKGROUND:There are currently no effective drugs to mitigate the ischemia/reperfusion injury caused by fluid resuscitation after hemorrhagic shock(HS).The aim of this study was to explore the potential of the histone deacetylase 6(HDAC6)-specific inhibitor tubastatin A(TubA)to suppress nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)inflammasome activation in macrophages under hypoxia/reoxygenation(H/R)conditions.METHODS:The viability of RAW264.7 cells subjected to H/R after treatment with different concentrations of TubA was assessed using a cell-counting kit-8(CCK8)assay.Briefly,2.5μmol/L TubA was used with RAW264.7 cells under H/R condition.RAW264.7 cells were divided into three groups,namely the control,H/R,and TubA groups.The levels of reactive oxygen species(ROS)in the cells were detected using fluorescence microscopy.The protein expression of HDAC6,heat shock protein 90(Hsp90),inducible nitric oxide synthase(iNOS),NLRP3,gasdermin-D(GSDMD),Caspase-1,GSDMD-N,and Caspase-1 p20 was detected by western blotting.The levels of interleukin-1β(IL-1β)and IL-18 in the supernatants were detected using enzyme-linked immunosorbent assay(ELISA).RESULTS:HDAC6,Hsp90,and iNOS expression levels were significantly higher(P<0.01)in the H/R group than in the control group,but lower in the TubA group than in the H/R group(P<0.05).When comparing the H/R group to the control group,ROS levels were significantly higher(P<0.01),but significantly reduced in the TubA group(P<0.05).The H/R group had higher NLRP3,GSDMD,Caspase-1,GSDMD-N,and Caspase-1 p20 expression levels than the control group(P<0.05),however,the TubA group had significantly lower expression levels than the H/R group(P<0.05).IL-1βand IL-18 levels in the supernatants were significantly higher in the H/R group compared to the control group(P<0.01),but significantly lower in the TubA group compared to the H/R group(P<0.01).CONCLUSION:TubA inhibited the expression of HDAC6,Hsp90,and iNOS in macrophages subjected to H/R.This inhibition led to a decrease in the content of ROS in cells,which subsequently inhibited the activation of the NLRP3 inflammasome and the secretion of IL-1βand IL-18.

Melatonin enhances the efficacy of anti-PD-L1 by improving hypoxia in residual tumors after insufficient radiofrequency ablation

The hypoxic microenvironment and inflammatory state of residual tumors caused by insufficient radiofrequency ablation(iRFA)are major reasons for rapid tumor progression and pose challenges for immunotherapy.We retrospectively analyzed the clinical data of patients with hepatocellular carcinoma(HCC)treated with RFA and observed that iRFAwas associated with poor survival outcomes and progression-free survival.Using an orthotopic HCC mouse model and a colorectal liver metastasis model,we observed that treatment with melatonin after iRFA reduced tumor growth and metastasis and achieved the best outcomes when combined with anti-programmed death-ligand 1(anti-PD-L1)therapy.In mechanism,melatonin inhibited the expression of epithelial-mesenchymal transitions,hypoxia-inducible factor(HIF)-1a,and PD-L1 in tumor cells after iRFA.Flow cytometry revealed that melatonin reduced the proportion of myeloid-derived suppressor cells and increased the proportion of CD8t T cells.Transcriptomic analysis revealed an upregulation of immune-activated function-related genes in residual tumors.These findings demonstrated that melatonin can reverse hypoxia and iRFA-induced inflammation,thereby overcoming the immunosuppressive tumor microenvironment(TME)and enhancing the efficacy of immunotherapy.

Zooplankton community variations in response to summer hypoxia in Sishili Bay,North Yellow Sea,China

Hypoxia may cause severe disturbances to coastal ecosystems.The potential effects of summer hypoxia on zooplankton communities in Sishili Bay,China,was investigated in three cruises conducted during the summer from 2015 to 2017.Comparative analysis was performed on zooplankton communities at hypoxic and normoxic sites.Results show that the number and abundance of zooplankton species at hypoxic sites were lower than those at normoxic sites.Copepods exhibited greater dominance at the hypoxic sites compared to the normoxic sites,suggesting a higher tolerance to low oxygen concentrations than other taxonomic groups.Specifically,Oithona spp.was particularly prevalent at hypoxic sites and displayed a negative correlation with dissolved oxygen concentration at sea bottom.Additionally,the zooplankton community at hypoxic sites also exhibited lower Shannon-Wiener diversity and Margalef richness indices.The normalized biovolume size spectrum of the hypoxic sites showed steep slopes,suggesting a shift towards smaller species and lower transfer efficiency in pelagic food webs for the zooplankton community.

Convergent evolution in high-altitude and marine mammals:Molecular adaptations to pulmonary fibrosis and hypoxia

High-altitude and marine mammals inhabit distinct ecosystems but share a common challenge:hypoxia.To survive in low-oxygen environments,these species have evolved similar phenotypic pulmonary adaptations,characterized by a high density of elastic fibers.In this study,we explored the molecular mechanisms underlying these adaptations,focusing on pulmonary fibrosis and hypoxia tolerance through comparative genomics and convergent evolution analyses.We observed significant expansions and contractions in certain gene families across both high-altitude and marine mammals,closely associated with processes involved in pulmonary fibrosis.Notably,members of the keratin gene family,such as KRT17 and KRT14,appear to be associated with the development of the dense elastic fiber phenotype observed in the lungs of hypoxia-tolerant mammals.Through selection pressure and amino acid substitution analyses,we identified multiple genes exhibiting convergent accelerated evolution,positive selection,and amino acid substitution in these species,associated with adaptation to hypoxic environments.Specifically,the convergent evolution of ZFP36L1,FN1,and NEDD9 was found to contribute to the high density of elastic fibers in the lungs of both high-altitude and marine mammals,facilitating their hypoxia tolerance.Additionally,we identified convergent amino acid substitutions and gene loss events associated with sperm development,differentiation,and spermatogenesis,such as amino acid substitutions in SLC26A3 and pseudogenization of CFAP47,as confirmed by PCR.These genetic alterations may be linked to changes in the reproductive capabilities of these animals.Overall,this study offers novel perspectives on the genetic and molecular adaptations of high-altitude and marine mammals to hypoxic environments,with a particular emphasis on pulmonary fibrosis.

Hypoxia-related bioinformatic signatures associated with prognosis and tumor microenvironment of pancreatic cancer:Current status,concerns,and future perspectives

Pancreatic cancer(PC),a highly lethal tumor with nearly identical incidence and mortality rates,has become the sixth leading cause of cancer-related deaths.Hypoxia is an important malignant factor in PC,as it regulates angiogenesis,metabolic reprogramming,tumor progression,and metastasis.Disrupting the hypoxic microenvironment can enhance the efficacy of antitumor therapy and improve the prognosis of patients with PC.With the advent of bioinformatics,hypoxia-related PC models have emerged in recent years.They provide a reference for estimating the prognosis and immune microenvironment of patients with PC and identify potential biomarkers for targeting hypoxic microenvironment.However,these findings based on bioinformatic analysis may not be completely reliable without further experimental evidence and clinical cohort validation.The application of these models and biomarkers in clinical practice to predict survival time and develop anti hypoxic therapeutic strategies for patients with PC remains in its infancy.In this editorial,we review the current status of hypoxia-related prognostic models in PC,analyze their similarities and differences,discuss several existing challenges,and provide potential solutions and directions for further studies.This editorial will facilitate the optimization,validation,and determination of the molecular mechanisms of related models.

Molecular mechanism of hypoxia and alpha-ketoglutaric acid on collagen expression in scleral fibroblasts

AIM:To investigate the molecular mechanisms underlying the influence of hypoxia and alpha-ketoglutaric acid(α-KG)on scleral collagen expression.METHODS:Meta-analysis and clinical statistics were used to prove the changes in choroidal thickness(ChT)during myopia.The establishment of a hypoxic myopia model(HYP)for rabbit scleral fibroblasts through hypoxic culture and the effects of hypoxia andα-KG on collagen expression were demonstrated by Sirius red staining.Transcriptome analysis was used to verify the genes and pathways that hypoxia andα-KG affect collagen expression.Finally,real-time quantitative reverse transcription polymerase chain reaction(RT-qPCR)was used for reverse verification.RESULTS:Meta-analysis results aligned with clinical statistics,revealing a thinning of ChT,leading to scleral hypoxia.Sirius red staining indicated lower collagen expression in the HYP group and higher collagen expression in the HYP+α-KG group,showed that hypoxia reduced collagen expression in scleral fibroblasts,whileα-KG can elevated collagen expression under HYP conditions.Transcriptome analysis unveiled the related genes and signaling pathways of hypoxia andα-KG affect scleral collagen expression and the results were verified by RT-qPCR.CONCLUSION:The potential molecular mechanisms through which hypoxia andα-KG influencing myopia is unraveled and three novel genes TLCD4,TBC1D4,and EPHX3 are identified.These findings provide a new perspective on the prevention and treatment of myopia via regulating collagen expression.

CA IX-targeted Ag_(2)S quantum dots bioprobe for NIR-II imaging-guided hypoxia tumor chemo-photothermal therapy

Hypoxia is the common characteristic of almost all solid tumors,which prevents therapeutic drugs from reaching the tumors.Therefore,the development of new targeted agents for the accurate diagnosis of hypoxia tumors is widely concerned.As carbonic anhydrase IX(CA IX)is abundantly distributed on the hypoxia tumor cells,it is considered as a potential tumor biomarker.4-(2-Aminoethyl)benzenesulfonamide(ABS)as a CA IX inhibitor has inherent inhibitory activity and good targeting effect.In this study,Ag_(2)S quantum dots(QDs)were used as the carrier to prepare a novel diagnostic and therapeutic bioprobe(Ag_(2)S@polyethylene glycol(PEG)-ABS)through ligand exchange and amide condensation reaction.Ag_(2)S@PEG-ABS can selectively target tumors by surface-modified ABS and achieve accurate tumor imaging by the near infrared-II(NIR-II)fluorescence characteristics of Ag_(2)S QDs.PEG modification of Ag_(2)S QDs greatly improves its water solubility and stability,and therefore achieves high photothermal stability and high photothermal conversion efficiency(PCE)of 45.17%.Under laser irradiation,Ag_(2)S@PEG-ABS has powerful photothermal and inherent antitumor combinations on colon cancer cells(CT-26)in vitro.It also has been proved that Ag_(2)S@PEG-ABS can realize the effective treatment of hypoxia tumors in vivo and show good biocompatibility.Therefore,it is a new efficient integrated platform for the diagnosis and treatment of hypoxia tumors.

CircPMS1 promotes proliferation of pulmonary artery smooth muscle cells,pulmonary microvascular endothelial cells,and pericytes under hypoxia

Background:Circular RNAs(circRNAs)have been recognized as significant regulators of pulmonary hypertension(PH);however,the differential expression and function of circRNAs in different vascular cells under hypoxia remain unknown.Here,we identified co-differentially expressed circRNAs and determined their putative roles in the proliferation of pulmonary artery smooth muscle cells(PASMCs),pulmonary microvascular endothelial cells(PMECs),and pericytes(PCs)under hypoxia.Methods:Whole transcriptome sequencing was performed to analyze the differential expression of circRNAs in three different vascular cell types.Bioinformatic analysis was used to predict their putative biological function.Quantitative real-time polymerase chain reaction,Cell Counting Kit-8,and EdU Cell Proliferation assays were carried out to determine the role of circular postmeiotic segregation 1(circPMS1)as well as its potential sponge mechanism in PASMCs,PMECs,and PCs.Results:PASMCs,PMECs,and PCs exhibited 16,99,and 31 differentially expressed circRNAs under hypoxia,respectively.CircPMS1 was upregulated in PASMCs,PMECs,and PCs under hypoxia and enhanced the proliferation of vascular cells.CircPMS1may upregulate DEP domain containing 1(DEPDC1)and RNA polymerase II subunit D expression by targeting microRNA-432-5p(miR-432-5p)in PASMCs,upregulate MAX interactor 1(MXI1)expression by targeting miR-433-3p in PMECs,and upregulate zinc finger AN1-type containing 5(ZFAND5)expression by targeting miR-3613-5p in PCs.Conclusions:Our results suggest that circPMS1 promotes cell proliferation through the miR-432-5p/DEPDC1 or miR-432-5p/POL2D axis in PASMCs,through the miR-433-3p/MXI1 axis in PMECs,and through the miR-3613-5p/ZFAND5 axis in PCs,which provides putative targets for the early diagnosis and treatment of PH.

Nicotinamide adenine dinucleotide treatment confers resistance to neonatal ischemia and hypoxia:effects on neurobehavioral phenotypes

Neonatal hypoxic-ischemic brain injury is the main cause of hypoxic-ischemic encephalopathy and cerebral palsy.Currently,there are few effective clinical treatments for neonatal hypoxic-ischemic brain injury.Here,we investigated the neuroprotective and molecular mechanisms of exogenous nicotinamide adenine dinucleotide,which can protect against hypoxic injury in adulthood,in a mouse model of neonatal hypoxic-ischemic brain injury.In this study,nicotinamide adenine dinucleotide(5 mg/kg)was intraperitoneally administered 30 minutes befo re surgery and every 24 hours thereafter.The results showed that nicotinamide adenine dinucleotide treatment improved body weight,brain structure,adenosine triphosphate levels,oxidative damage,neurobehavioral test outcomes,and seizure threshold in experimental mice.Tandem mass tag proteomics revealed that numerous proteins were altered after nicotinamide adenine dinucleotide treatment in hypoxic-ischemic brain injury mice.Parallel reaction monitoring and western blotting confirmed changes in the expression levels of proteins including serine(or cysteine)peptidase inhibitor,clade A,member 3N,fibronectin 1,5'-nucleotidase,cytosolic IA,microtubule associated protein 2,and complexin 2.Proteomics analyses showed that nicotinamide adenine dinucleotide ameliorated hypoxic-ischemic injury through inflammation-related signaling pathways(e.g.,nuclear factor-kappa B,mitogen-activated protein kinase,and phosphatidylinositol 3 kinase/protein kinase B).These findings suggest that nicotinamide adenine dinucleotide treatment can improve neurobehavioral phenotypes in hypoxic-ischemic brain injury mice through inflammation-related pathways.

Coastal hypoxia response to the coupling of catastrophic flood,extreme marine heatwave and typhoon:a case study off the Changjiang River Estuary in summer 2020

Massive bodies of low-oxygen bottom waters are found in coastal areas worldwide,which are detrimental to coastal ecosystems.In summer 2020,the response of coastal hypoxia to extreme weather events,including a catastrophic flooding,an extreme marine heatwave,and Typhoon Bavi,is investigated based on multiple satellite,four cruises,and mooring observations.The extensive fan-shaped hypoxia zone presents significant northward extension during July-September 2020,and is estimated as large as 13 000 km^(2) with rather low oxygen minimum(0.42 mg/L) during its peak in 28-30 August.This severe hypoxia is attributed to the persistent strong stratification,which is indicated by flood-induced larger amount of riverine freshwater input and subsequent marine heatwave off the Changjiang River Estuary.Moreover,the Typhoon Bavi has limited effect on the marine heatwave and coastal hypoxia in summer 2020.

Acidic/hypoxia dual-alleviated nanoregulators for enhanced treatment of tumor chemo-immunotherapy

Chemotherapy plays a crucial role in triple-negative breast cancer (TNBC) treatment as it not only directly kills cancer cells but also induces immunogenic cell death. However, the chemotherapeutic efficacy was strongly restricted by the acidic and hypoxic tumor environment. Herein, we have successfully formulated PLGA-based nanoparticles concurrently loaded with doxorubicin (DOX), hemoglobin (Hb) and CaCO3 by a CaCO3-assisted emulsion method, aiming at the effective treatment of TNBC. We found that the obtained nanomedicine (DHCaNPs) exhibited effective drug encapsulation and pH-responsive drug release behavior. Moreover, DHCaNPs demonstrated robust capabilities in neutralizing protons and oxygen transport. Consequently, DHCaNPs could not only serve as oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment (TME) by depleting lactic acid, thereby effectively overcoming the resistance to chemotherapy. Furthermore, DHCaNPs demonstrated a notable ability to enhance antitumor immune responses by increasing the frequency of tumor-infiltrating effector lymphocytes and reducing the frequency of various immune-suppressive cells, therefore exhibiting a superior efficacy in suppressing tumor growth and metastasis when combined with anti-PD-L1 (αPD-L1) immunotherapy. In summary, this study highlights that DHCaNPs could effectively attenuate the acidic and hypoxic TME, offering a promising strategy to figure out an enhanced chemo-immunotherapy to benefit TNBC patients.

Effect of exercise during pregnancy on offspring development through ameliorating high glucose and hypoxia in gestational diabetes mellitus

BACKGROUND Gestational diabetes mellitus(GDM)women require prenatal care to minimize short-and long-term complications.The mechanism by which exercise during pregnancy affects organ development and whether glucose transporter(GLUT)1 plays a role in GDM offspring organ development remains unknown.AIM To determine the effect of exercise during pregnancy on the cardiac,hepatic and renal development of GDM mother’s offspring.METHODS Placenta samples were collected from humans and mice.GDM mouse models were created using streptozotocin along with a GDM with exercise group.The hearts,livers and kidneys of 3-and 8-week-old offspring were collected for body composition analysis and staining.The effects of high glucose levels and hypoxia were investigated using HTR8/SVneo.Transwell and wound-healing assays were performed to assess cell migration.Immunofluorescence accompanied with TUNEL and Ki67 staining was used to explore apoptosis and proliferation.RESULTS Exercise during pregnancy downregulated the GLUT1 and hypoxia inducible factor-1αexpression in placenta from individuals with GDM.Cobalt chloride induced hypoxia and high glucose levels also significantly decreased migration and apoptosis of HTR8/SVneo cells.In addition,exercise reduced inflammatory cell infiltration in the liver and decreased the tubular vacuolar area in the kidneys of offspring.CONCLUSION GDM affects the growth and development of organs in offspring.Exercise during pregnancy can reverse adverse effects of GDM on the development of the heart,liver,and kidney in offspring.

Hypoxia-inducible factor-1αin myocardial infarction

Hypoxia-inducible factor 1(HIF1)has a crucial function in the regulation of oxygen levels in mammalian cells,especially under hypoxic conditions.Its importance in cardiovascular diseases,particularly in cardiac ischemia,is because of its ability to alleviate cardiac dysfunction.The oxygen-responsive subunit,HIF1α,plays a crucial role in this process,as it has been shown to have cardioprotective effects in myocardial infarction through regulating the expression of genes affecting cellular survival,angiogenesis,and metabolism.Furthermore,HIF1αexpression induced reperfusion in the ischemic skeletal muscle,and hypoxic skin wounds in diabetic animal models showed reduced HIF1αexpression.Increased expression of HIF1αhas been shown to reduce apoptosis and oxidative stress in cardiomyocytes during acute myocardial infarction.Genetic variations in HIF1αhave also been found to correlate with altered responses to ischemic cardiovascular disease.In addition,a link has been established between the circadian rhythm and hypoxic molecular signaling pathways,with HIF1αfunctioning as an oxygen sensor and circadian genes such as period circadian regulator 2 responding to changes in light.This editorial analyzes the relationship between HIF1αand the circadian rhythm and highlights its significance in myocardial adaptation to hypoxia.Understanding the changes in molecular signaling pathways associated with diseases,specifically cardiovascular diseases,provides the opportunity for innovative therapeutic interventions,especially in low-oxygen environments such as myocardial infarction.

Effects of Intermittent Hypoxia Exposure on Symptoms of Chronic Fatigue Syndrome in Repeated Restraint Stress and Forced Swimming Induced-Mouse Model

Background: Chronic fatigue syndrome (CFS) shows as its main symptoms debilitating fatigue that is not relieved by physiological rest, depression, inflammation, learning disability and memory impairment. But, intermittent hypoxia, consisting of alternating exposure to hypoxia and normoxia, plays a very important role in improving CFS. However, the essential components for improving learning and memory in CFS patients as well as their mechanism are largely unknown. Objectives: This study aims to analyze the effects of 12% and 15% hypoxia on the expression of alpha tumor necrosis factor (TNF-α) and nuclear factor kappa B (NF-κB) in CFS induced-mouse model for clarifying the effects on the learning and memory function. Methods: A total of 48 type IC mice were used. The CFS mouse model was established using restrained stress and repeated forced swimming. Treatment of CFS was done by exposing CFS mice to intermittent hypoxia at 12% and 15%. The effects of intermittent hypoxia on learning and memory as well as its mechanism of action on inflammation were tested respectively with the Morris test, the SDS page, the immunohistochemistry technique and the Nissl staining. Results: We found that 12% and 15% intermittent hypoxia exposure improved learning capacity and memory of CFS induced-mice. SDS page showed that CFS caused higher TNF-α expression. By exposing CFS mice to 12% and 15% intermittent hypoxia, TNF-α expression decreased significantly, with a much better effect at 15%. Both TNF-α and NF-κB increased in CFS state and decreased after treatment with intermittent hypoxia. Conclusion: Intermittent hypoxia improves learning capacity and memory. It acted by decreasing NF-κB come to down-regulating TNF-α and ameliorates learning capacity and memory impairment in CFS mice.