Hypoxia can induce pathological alterations to the kidneys, such as activation of inflammatory signaling pathways. This form of inflammation is pathogen-free and is referred to as aseptic inflammation. Currently, the mechanisms leading to aseptic inflammation under hypoxia are not well understood. Emerging evidence has indicated that Prdx1, a member of the peroxidase family, contributes to the development of various diseases by stimulating aseptic inflammation. This study was conducted to reveal the potential role of Prdx1 in the pathogenesis of hypoxia-induced renal injury. A mouse model of systemic hypoxia was developed, which revealed that Prdx1 levels were elevated in injured kidneys and peripheral circulation. A comparable increase was also observed in hypoxia-treated immortalized bone marrow-derived macrophages (iBMDMs). Knock-down of Prdx1 in mice caused a significant reduction in renal tissue injury and inflammation induced by hypoxic injury. In addition, we demonstrated that Prdx1 modulates inflammatory responses by activating the TLR4/MAPK/NF-κB signaling pathways. Recombinant Prdx1 promoted the activation of these pathways in macrophages, whereas genetic knockout of Prdx1 or pharmacological inhibition suppressed their activity. Altogether, we found a previously unrecognized role for Prdx1 in the regulation of inflammation in hypoxia-induced renal injury. These findings suggest that Prdx1 can be a potential target for treating this severe disease.

N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor.

The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations.

This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.

Pulpitis is characterized by inflammation within dental pulp tissue, primarily triggered by bacterial infection. Hypoxia-inducible factor-1α (HIF-1α), a key transcriptional regulator, is stabilized under the hypoxic conditions associated with pulpitis. This review examines the roles and molecular mechanisms of HIF-1α in the pathogenesis and progression of pulpitis. Hypoxia in pulpitis prevents the degradation of HIF-1α, leading to its elevated expression. Furthermore, lipopolysaccharide from invading bacteria upregulates HIF-1α transcription through nuclear factor kappa B and mitogen-activated protein kinase pathways. HIF-1α regulates immunity and pulp remodeling in a stage-dependent manner by controlling various cytokines. During the inflammation stage, HIF-1α promotes recruitment of neutrophils and enhances their bactericidal effects by facilitating neutrophil extracellular trap release and M1 macrophage polarization. Concurrently, HIF-1α contributes to programmed cell death by increasing mitophagy. In the proliferation stage, HIF-1α stimulates immune responses involving T cells and dendritic cells. In the remodeling stage, HIF-1α supports angiogenesis and pulp-dentin regeneration. However, excessive pulpitis-induced hypoxia may disrupt vascular dynamics within the pulp chamber. This disruption highlights a critical threshold for HIF-1α, beyond which its effects might accelerate pulp necrosis. Overall, HIF-1α plays a central role in regulating immunity and tissue remodeling during pulpitis. A comprehensive understanding of the physiological and pathological roles of HIF-1α is essential for the advancement of effective strategies to manage irreversible pulpitis.

Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD) which is the most common chronic liver disease worldwide. Hypoxia-inducible factor-1α (HIF1α) inhibitor is emerging as a promising therapeutic strategy for diseases. However, the role of HIF1α inhibitor in NASH is still unclear. A choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) -induced NASH mouse model was established to identify the impacts of HIF1α inhibitor KC7F2 on the development of NASH. We found that KC7F2 treatment substantially aggravated lipid accumulation, inflammation, and fibrosis in the liver of NASH mice presumably via increasing Tsukushi (TSKU) expression in the liver. Mechanistically, KC7F2 up-regulated expression of TSKU in hepatocyte in vitro, which led to increased hepatocellular lipid accumulation and was reversed when TSKU was knockdown in hepatocyte. Our findings indicated that HIF1α inhibitor promotes the development of NASH presumably via increasing TSKU expression in the liver, suggesting that HIF1α attenuates NASH, and that we should assess the potential liver toxicity when use HIF1α inhibitor or medicines that can decrease the expression of HIF1α to therapy other diseases.

Abdominal aortic aneurysm (AAA) is a deadly condition of the aorta, carrying a significant risk of death upon rupture. Currently, there is a dearth of efficacious pharmaceutical interventions to impede the advancement of AAA and avert it from rupturing. Here, we investigated dihydromyricetin (DHM), one of the predominant bioactive flavonoids in Ampelopsis grossedentata (A. grossedentata), as a potential agent for inhibiting AAA. DHM effectively blocked the formation of AAA in angiotensin II-infused apolipoprotein E-deficient (ApoE-/-) mice. A combination of network pharmacology and whole transcriptome sequencing analysis revealed that DHM's anti-AAA action is linked to heme oxygenase (HO)-1 (Hmox-1 for the rodent gene) and hypoxia-inducible factor (HIF)-1α in vascular smooth muscle cells (VSMCs). Remarkably, DHM caused a robust rise (∼10-fold) of HO-1 protein expression in VSMCs, thereby suppressing VSMC inflammation and oxidative stress and preserving the VSMC contractile phenotype. Intriguingly, the therapeutic effect of DHM on AAA was largely abrogated by VSMC-specific Hmox1 knockdown in mice. Mechanistically, on one hand, DHM increased the transcription of Hmox-1 by triggering the nuclear translocation and activation of HIF-1α, but not nuclear factor erythroid 2-related factor 2 (NRF2). On the other hand, molecular docking, combined with cellular thermal shift assay (CETSA), isothermal titration calorimetry (ITC), drug affinity responsive target stability (DARTS), co-immunoprecipitation (Co-IP), and site mutant experiments revealed that DHM bonded to HO-1 at Lys243 and prevented its degradation, thereby resulting in considerable HO-1 buildup. In summary, our findings suggest that naturally derived DHM has the capacity to markedly enhance HO-1 expression in VSMCs, which may hold promise as a therapeutic strategy for AAA.

Hypoxia is a part of many pathological and some physiological processes. It also occurs as a result of surgical techniques associated with limiting the blood supply to the operated organs and tissues. Hypoxia leads to a significant decrease in the ability of cells to implement energy-dependent processes due to a reduced contribution of mitochondria to the synthesis of adenosine triphosphate (ATP). In order to protect cells and increase the time of surgery, infusion of a solution of sodium fumarate for several days before the surgical procedure is suggested. However, the mechanism of the observed protective effect is still a subject of discussion. The aim of the research was to study the mechanism of the sodium fumarate cytoprotective effect on renal epithelial cells in acute hypoxia modeling in vitro by reducing oxygen in the medium using sodium dithionite.

The study was conducted using the MDCK renal epithelial cell line with sodium dithionite at a concentration of 5 mM to create hypoxic conditions. The parameters of cellular metabolism (including the value of mitochondrial membrane potential, the state of mitochondrial NADH and FAD, the content of Ca2+ and Mg2+ and the pH level in the cytosol, the rate of glucose absorption by cells, and cell death) were assessed by means of confocal and wide-field fluorescence microscopy. The concentration of dissolved oxygen was established using the polarographic method with a Clark electrode.

It was demonstrated that the use of sodium dithionite allows modeling acute hypoxia in vitro with a rapid decrease in the oxygen concentration in the cell incubation medium, which resulted in a change in mitochondrial function and the apoptosis progression. At that, sodium fumarate reduces the level of cell death, which is associated not with the restoration of the ATP-producing ability of mitochondria, but rather with an increase in the contribution of alternative sources of high-energy compounds.

At the cellular level, using an optimized hypoxia model, the study revealed the mechanism of the protective role of sodium fumarate, which explained the antihypoxant effectiveness in assisted ischemia of organs and tissues.

Ischemic stroke is a leading cause of mortality and disability, with cerebellar strokes posing severe complications such as herniation and brainstem compression. Edaravone, a radical scavenger known for reducing oxidative stress, has shown neuroprotective effects in cerebral strokes, but its impact on cerebellar strokes remains unclear. This study investigates Edaravone's protective properties in organotypic slice cultures of rat cerebellum and hippocampus, employing an oxygen-glucose deprivation (OGD) model to simulate ischemic stroke. The hippocampus served as comparative structure due to its high hypoxia sensitivity. Our results confirmed effective hypoxic induction with increases in HIF-1α and HIF-2α expression. Edaravone significantly reduced lactate dehydrogenase (LDH) levels, indicating diminished cellular damage, with cerebellar tissues showing greater vulnerability. Additionally, Edaravone reduced reactive oxygen species (ROS) in both tissues, though its efficacy may be limited by higher oxidative stress in cerebellar cultures. Seahorse XF analysis revealed that Edaravone preserved mitochondrial respiration and tissue integrity in cerebellar and hippocampal slice cultures. However, Edaravone was more effective in preserving mitochondrial respiration in hippocampal slices, suggesting that OGD-induced damage is more severe in cerebellar tissue. In conclusion, Edaravone demonstrates significant cell protective effects in both cerebellar and hippocampal tissues under OGD conditions, preserving tissue integrity and enhancing mitochondrial function in a tissue-dependent manner. These findings suggest Edaravone as a promising therapeutic candidate for cerebellar stroke. Further in vivo studies are required to assess its full clinical potential.

Aging is marked by a progressive decrease in physiological function and reserve capacity, which results in increased susceptibility to diseases. Understanding the mechanisms of driving aging is crucial for extending health span and promoting human longevity. Hypoxia, marked by reduced oxygen availability, has emerged as a promising area of study within aging research. This review explores recent findings on the potential of oxygen restriction to promote healthy aging and extend lifespan. While the role of hypoxia-inducible factor 1 (HIF-1) in cellular responses to hypoxia is well-established, its impact on lifespan remains complex and context-dependent. Investigations in invertebrate models suggest a role for HIF-1 in longevity, while evidence in mammalian models is limited. Hypoxia extends the lifespan independent of dietary restriction (DR), a known intervention underlying longevity. However, both hypoxia and DR converge on common downstream effectors, such as forkhead box O (FOXO) and flavin-containing monooxygenase (FMOs) to modulate the lifespan. Further work is required to elucidate the molecular mechanisms underlying hypoxia-induced longevity and optimize clinical applications. Understanding the crosstalk between HIF-1 and other longevity-associated pathways is crucial for developing interventions to enhance lifespan and healthspan. Future studies may uncover novel therapeutic strategies to promote healthy aging and longevity in human populations.

Tumors grow by receiving oxygen and nutrients from the surrounding blood vessels, leading to rapid angiogenesis. This results in functionally and structurally abnormal vasculature characterized by high permeability and irregular blood flow, causing hypoxia within the tumor microenvironment (TME). Hypoxia exacerbates the secretion of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), further perpetuating abnormal vessel formation. This environment compromises the efficacy of radiotherapy, immunotherapy, and chemotherapy. In this study, we developed a pH-sensitive liposome (PSL) system, termed OD_PSL@AKB, to co-deliver oxygen (OD) and razuprotafib (AKB-9778) to tumors. This system rapidly responds to the acidic TME to alleviate hypoxia and inhibit VEGF secretion, restoring VE-cadherin expression in hypoxic endothelial cell/cancer cell cocultures. Our findings highlight the potential of OD_PSL@AKB in normalizing tumor vasculature and improving therapeutic efficacy.

A fundamental dichotomy in lymphocytes separates adaptive T and B lymphocytes, with clonally expressed antigen receptors, from innate lymphocytes, which carry out more rapid responses. Some T cell populations, however, are intermediates between these 2 poles, with the capacity to respond rapidly through T cell receptor activation or by cytokine stimulation. Here, using publicly available datasets, we constructed linear mixed models that not only define a gradient of innate gene expression in common for mouse innate-like T cells, but also are applicable to other mouse T lymphoid populations. A similar gradient could be identified for chromatin landscape based on ATAC-seq (assay for transposase-accessible chromatin using sequencing) data. The gradient included increased transcripts related to many traits of innate immune responses, with increased scores related to evidence for antigen experience. While including genes typical for T helper 1 (Th1) responses, the innateness gene program could be separated from Th1, Th2, and Th17 responses. Lymphocyte populations with higher innateness scores correlated with lower calcium-dependent T cell receptor-mediated cell activation, with some downstream signaling proteins dependent on calcium or affecting metabolism prephosphorylation. Therefore, as a group, different mouse innate-like T cell populations had related gene expression programs and activation pathways that are different from naive CD4 and CD8 T cells.

Atrial natriuretic peptide (ANP) and Zn2⁺ have been shown to confer cardioprotection against ischemia/reperfusion (I/R) injury. Zn2⁺ alleviates myocardial hypertrophy and pulmonary hypertension by regulating ANP expression, but its precise role in ANP-mediated cardioprotection remains unclear. This study aimed to investigate whether ANP protects the heart during reperfusion by modulating Zn2⁺ levels and to explore the underlying mechanisms involved.

In this study, we utilized an isolated reperfused heart model in rats, as well as wild-type (WT) and ANP knockout (ANP-/-) mouse models, for in vivo I/R experiments. For clinical investigations, plasma samples were collected from 216 patients with ischemia-related diseases. Evans blue and TTC staining, radioimmunoassay, ICP‒OES, echocardiography, Hydro-Cy3-mediated ROS detection, and Western blotting were employed to evaluate the effect of ANP on Zn2⁺ homeostasis.

Plasma ANP levels were significantly elevated in patients with ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and heart failure (HF). ANP secretion increased during reperfusion, rather than infarction, both ex vivo and in vivo, promoting Zn2⁺ accumulation in reperfused tissue. ANP and Zn2⁺ protected mitochondria and reduced infarct size; these effects were reversed by the Zn2⁺ chelator TPEN. In WT and ANP-/- mice, EF% and FS% decreased after reperfusion, with ANP-/- mice exhibiting significantly worse cardiac function. ANP pretreatment alone improved cardiac function, but combined pretreatment with ANP and TPEN decreased EF% and FS% while increasing LVID. Reperfusion increased ROS levels in both WT and ANP-/- hearts, which were reduced by ANP pretreatment. I/R injury elevated Zn2⁺ transporter 8 (ZnT8) expression, an effect that was counteracted by ANP, although this effect was reversed by TPEN. Hypoxia-inducible factor 1-alpha (HIF-1α) expression was elevated in I/R rats and ANP-/- mice, and it was inhibited by both Zn2⁺ and ANP pretreatment. However, the HIF-1α inhibitor 2-Me did not reverse the effect of ANP on ZnT8 expression. Additionally, ANP increased PI3K expression in both WT and ANP-/- I/R mice, but this effect was blocked by the PI3K inhibitor LY294002.

ANP modulates Zn2⁺ homeostasis during reperfusion injury by downregulating ZnT8 through the PI3K signalling pathway, thereby reducing myocardial I/R injury.

Obesity per se is rapidly emerging all over the planet and further accounts for many other life-threatening conditions, such as diabetes, cardiovascular diseases, and cancers. Decreased oxygen supply or increased relative oxygen consumption in the adipose tissue results in adipose tissue hypoxia, which is a hallmark of obesity. This review aims to provide an up-to-date overview of the hypoxia signaling in the adipose tissue. First, we summarize literature evidence to demonstrate that hypoxia is regularly observed during adipose tissue remodeling in humans and rodent models with obesity. Next, we discuss how hypoxia-inducible factors (HIFs) are regulated and how adipose tissues behave in response to hypoxia. Then, the differential roles of adipose HIF-1α and HIF-2α in adipose tissue biology and obesity pathology are highlighted. Finally, the review emphasizes the importance of modulating adipose hypoxia as a therapeutic avenue to assist adipose tissues in functionally adapting to hypoxic conditions, ultimately promoting adipose health and improving outcomes due to obesity.

Despite the progress made in the development of targeted therapies, breast cancer (BC) continues to pose a significant threat to the health of women. Transcriptomics has emerged due to the advancements in high-throughput sequencing technology. This provides crucial information about the role of non-coding RNAs (ncRNAs) in human cells, particularly long ncRNAs (lncRNAs), in disease development and function. When the control of these ncRNAs is disrupted, various illnesses emerge, including cancer. Numerous studies have produced empirical data on the function of lncRNAs in tumorigenesis and disease development. However, the roles and mechanisms of numerous lncRNAs remain unidentified at the molecular level because their regulatory role and the functional implications of abnormalities in cancer biology have yet to be thoroughly defined. The review gives an itemized summary of the most current developments in the role of lncRNA in BC, focusing on three main pathways, PI3K, MAPK, NF-kB, and hypoxia, and their resistance mechanisms.

A significant number of deaths and disabilities worldwide are brought on by inflammatory lung diseases. Many inflammatory lung disorders, including chronic respiratory emphysema, resistant asthma, resistance to steroids, and coronavirus-infected lung infections, have severe variants for which there are no viable treatments; as a result, new treatment alternatives are needed. Here, we emphasize how oxidative imbalance contributes to the emergence of provocative lung problems that are challenging to treat. Endogenic antioxidant systems are not enough to avert free radical-mediated damage due to the induced overproduction of ROS. Pro-inflammatory mediators are then produced due to intracellular signaling events, which can harm the tissue and worsen the inflammatory response. Overproduction of ROS causes oxidative stress, which causes lung damage and various disease conditions. Invasive microorganisms or hazardous substances that are inhaled repeatedly can cause an excessive amount of ROS to be produced. By starting signal transduction pathways, increased ROS generation during inflammation may cause recurrent DNA damage and apoptosis and activate proto-oncogenes. This review provides information about new targets for conducting research in related domains or target factors to prevent, control, or treat such inflammatory oxidative stress-induced inflammatory lung disorders.

HIF-1α plays a crucial regulatory role in vascular calcification (VC), primarily influencing the osteogenic differentiation of VSMCs through oxygen-sensing mechanisms. Under hypoxic conditions, the stability of HIF-1α increases, avoiding PHD and VHL protein-mediated degradation, which promotes its accumulation in cells and then activates gene expressions related to calcification. Additionally, HIF-1α modulates the metabolic state of VSMCs by regulating the pathways that govern the switch between glycolysis and oxidative phosphorylation, thereby further advancing the calcification process. The interaction between HIF-1α and other signaling pathways, such as nuclear factor-κB, Notch, and Wnt/β-catenin, creates a complex regulatory network that serves as a critical driving force in VC. Therefore, a deeper understanding of the role and regulatory mechanism of the HIF-1α signaling during the development and progression of VC is of great significance, as it is not only a key molecular marker for understanding the pathological mechanisms of VC but also represents a promising target for future anti-calcification therapies.

Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterized by persistent inflammation and oxidative stress, which ultimately leads to progressive restriction of airflow. Extensive research findings have cogently suggested that the dysregulation of essential transition metal ions, notably iron, copper, and zinc, stands as a critical nexus in the perpetuation of inflammatory processes and oxidative damage within the lungs of COPD patients. Unraveling the intricate interplay between metal homeostasis, oxidative stress, and inflammatory signaling is of paramount importance in unraveling the intricacies of COPD pathogenesis. This comprehensive review aims to examine the current literature on the sources, regulation, and mechanisms by which metal dyshomeostasis contributes to COPD progression. We specifically focus on iron, copper, and zinc, given their well-characterized roles in orchestrating cytokine production, immune cell function, antioxidant depletion, and matrix remodeling. Despite the limited number of clinical trials investigating metal modulation in COPD, the advent of emerging methodologies tailored to monitor metal fluxes and gauge responses to chelation and supplementation hold great promise in unlocking the potential of metal-based interventions. We conclude that targeted restoration of metal homeostasis represents a promising frontier for ameliorating pathological processes driving COPD progression.

The clinical and pathological features of asthma and chronic obstructive pulmonary disease (COPD) can converge in smokers and elderly individuals as asthma-COPD overlap (ACO). This overlap challenges the diagnosis and treatment of the distinct aetiologies underlying these conditions.

We analysed 2453 smokers (≥10 pack-years), aged 45-80 years, from the Genetic Epidemiology of COPD (COPDGene) Study, stratified as Control, Asthma, COPD, and ACO based on Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. A comprehensive assessment was performed, encompassing symptomatology, pulmonary function tests (PFTs), complete blood counts (CBCs), bulk RNA sequencing (RNA-seq), and high-resolution quantitative computed tomography (QCT) imaging to evaluate clinical impact, lung function, systemic inflammation, and structural alterations contributing to disease progression across respiratory phenotypes. Differential expression (DE) analysis was performed using whole blood RNA-seq (BH-corrected FDR < 0.01), followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Group differences were assessed using the Mann-Whitney U-test (MWU) or Chi-squared test (χ2), with Bonferroni correction applied for multiple comparisons. Multivariate linear regression models were used to adjust the associations between disease status and specific clinical outcomes for confounders, with one-way ANOVA and Tukey's Honest Significant Difference (HSD) post-hoc test applied for pairwise comparisons. Our analysis aimed to delineate the extent and variability of clinical features among disease phenotypes to guide targeted therapeutic strategies.

Our study highlights distinct yet overlapping profiles across ACO, asthma, and COPD. We effectively isolated disease-specific mechanisms by comparing each phenotype to smoking controls (GOLD 0) while accounting for baseline smoking-related inflammation. ACO exhibited the most severe symptom burden, with significantly higher COPD Assessment Test (CAT) score (18.32, 95% CI: [17.02, 19.63], P < 0.0001) and Modified Medical Research Council (mMRC) Dyspnea score (2.14, 95% CI: [1.92, 2.35], P < 0.0001) compared to COPD and asthma. ACO also displayed reduced lung capacity (forced expiratory volume in 1 s [FEV1]: 52.5%, 95% CI: [50.08, 54.93], P < 0.0001) and airflow limitation (FEV1/forced vital capacity [FVC]: 0.55, 95% CI: [0.5471, 0.5546], P < 0.0001), closely resembling COPD but significantly worse than asthma. The inflammatory profile of ACO exhibited a mixed response, featuring elevated neutrophil counts (4.57 K/μL, 95% CI: [4.28, 4.86], P < 0.0001) and eosinophil levels (0.22 K/μL, 95% CI: [0.20, 0.25], P < 0.01), contrasting with the predominantly neutrophilic inflammation in COPD and the absence of systemic inflammation in asthma. Structurally, ACO demonstrated significant airway remodelling (Pi10: 2.87, 95% CI: [2.83, 2.91], P < 0.0001), intermediate emphysema (5.66%, 95% CI: [4.72, 6.60], P < 0.0001), and moderate small airway disease (parametric response mapping for functional small airway disease [PRMfSAD]: 22.94%, 95% CI: [21.53, 24.34], P < 0.0001), reflecting features of both asthma and COPD. COPD was characterised by more extensive emphysema (8.9%, 95% CI: [8.34, 9.45], P < 0.0001), small airway disease (PRMfSAD: 27.09%, 95% CI: [26.51, 27.66], P < 0.0001), and gas trapping (37.34%, 95% CI: [36.33, 38.35], P < 0.0001), alongside moderate airway remodelling. At a molecular level, DE analysis revealed enrichment of the Hypoxia-Inducible Factor 1 (HIF-1) pathway in ACO, highlighting unique hypoxia-driven metabolic adaptations, while COPD was associated with neutrophil extracellular trap (NET) formation and necroptosis. In contrast, asthma exhibited significant airway remodelling (Pi10: 2.09, 95% CI: [2.05, 2.13], P < 0.0001), minimal parenchymal damage, and no systemic gene expression changes.

Collectively, our findings underscore the lung function impairments, systemic inflammation, molecular mechanisms, and structural correlates distinguishing ACO from COPD and asthma, emphasising the need for precise clinical management and the potential for novel therapeutic interventions.

This work was supported by National Heart, Lung, and Blood Institute (NHLBI) grants U01 HL089897 and U01 HL089856, as well as by National Institutes of Health (NIH) contract 75N92023D00011. Additional support was provided by grants R01 HL166231 (C.P.H.) and K01 HL157613 (A.S.).

Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard of care involves maximal surgery followed by radiotherapy and concomitant chemotherapy with temozolomide (TMZ), in addition to adjuvant TMZ. However, the recurrence rate of GBM within 1-2 years post-diagnosis is still elevated and has been attributed to the accumulation of multiple factors including the heterogeneity of GBM, genomic instability, angiogenesis, and chronic tumor hypoxia. Tumor hypoxia activates downstream signaling pathways involved in the adaptation of GBM to the newly oxygen-deprived environment, thereby contributing to the resistance and recurrence phenomena, despite the multimodal therapeutic approach used to eradicate the tumor. Therefore, in this review, we will focus on the development and implication of chronic or limited-diffusion hypoxia in tumor persistence through genetic and epigenetic modifications. Then, we will detail the hypoxia-induced activation of vital biological pathways and mechanisms that contribute to GBM resistance. Finally, we will discuss a proteomics-based approach to encourage the implication of personalized GBM treatments based on a hypoxia signature.

The development of tumors and their metastasis relies heavily on the process of angiogenesis. When the volume of a tumor expands, the resulting internal hypoxic conditions trigger the body to enhance the production of various angiogenic factors. These include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor-α (TGF-α), all of which work together to stimulate the activation of endothelial cells and catalyze angiogenesis. Antiangiogenic therapy (AAT) aims to normalize tumor blood vessels by inhibiting these angiogenic signals. In this review, we will explore the molecular mechanisms of angiogenesis within the tumor microenvironment, discuss traditional antiangiogenic drugs along with their limitations, examine new antiangiogenic drugs and the advantages of combination therapy, and consider future research directions in the field of antiangiogenic drugs. This comprehensive overview aims to provide insights that may aid in the development of more effective anti-tumor treatments.

The postmortem diagnosis of acute myocardial ischemia (AMI) represents a challenging issue in forensic practice. Immunohistochemical studies and gene expression studies are becoming a promising field of research in forensic pathology. The present study aims to evaluate HIF-1α expression through immunohistochemistry (IHC), and mRNA-210 level using real-time polymerase chain reaction (RT-PCR), in order to define if HIF-1α and mRNA-210 in post-mortem myocardium could be adopted in the diagnosis of AMI.

Thirty-five deceased individuals, who underwent forensic autopsy at the Legal Medicine Service of the University of Parma, between 2010 and 2018, were investigated. The cohort was divided into two groups according to the cause of death (sudden deaths caused by AMI vs control cases). Cardiac specimens were collected during autopsy, then samples were processed for morphological evaluation using haematoxylin-eosin staining, for IHC, and for RT-PCR. HIF-1α expression and mRNA-210 levels were investigated.

Statistical evaluation demonstrated statistically significant differences in terms of number of IHC positive vessels, leukocytes, and cardiomyocytes between the two groups. Moreover, in the majority of cases, immunostaining positivity was observed only in myocardial and subendocardial samples. With reference to mRNA-210, the difference between the two groups proved to be statistically significant.

The present study indicates that HIF-1α and mRNA-210 in post-mortem cardiac specimens could represent appropriate biomarkers in the diagnosis of AMI. The current study was primarily limited by the scarcity of the cohort, so further research is required to confirm these preliminary observations.

Allergic contact dermatitis (ACD), a prevalent skin disorder affecting up to 20% of the population, triggers significant discomfort and health implications. Our research investigates the pivotal role of Vascular Endothelial Growth Factor A (VEGFA) in chronic itching associated with ACD.

Bioinformatics methods were utilized to identify differentially expressed genes (DEGs) between ACD models and patients. In vivo models of chronic pruritus in mice induced by 2,4-dinitrofluorobenzene (DNFB) were employed. Mice were administered subcutaneously with a VEGFA inhibitor, sFlt1, and compared to a control group. Real-time RT-PCR, Western blot, and immunohistochemical staining were performed to evaluate VEGFA expression and the impact of sFlt1 on itching behavior.

The analysis revealed that VEGFA is significantly upregulated in ACD skin, primarily expressed by keratinocytes. Administration of the VEGFA inhibitor sFlt1 in the ACD mouse model led to a substantial reduction in scratching behavior, indicating that VEGFA may mediate pruritus through the VEGFA-VEGFR2-PI3K-TRPV1 signaling pathway.

These findings suggest that VEGFA plays a crucial role in ACD-associated pruritus and may serve as a potential therapeutic target. However, further research is required to validate these findings and to explore additional molecular pathways involved in the pruritic response in ACD.

Female infants with congenital heart disease (CHD) face significantly higher postoperative mortality rates after adjusting for cardiac complexity. Sex differences in metabolic adaptation to cardiac stressors may be an early contributor to cardiac dysfunction. In adult diseases, hypoxic/ischemic cardiomyocytes undergo a cardioprotective metabolic shift from oxidative phosphorylation to glycolysis which appears to be regulated in a sexually dimorphic manner. We hypothesize sex differences in cardiac metabolism are present in cyanotic CHD and detectable as early as the infant period.

RNA sequencing was performed on blood samples (cyanotic CHD cases, n = 11; controls, n = 11) and analyzed using gene set enrichment analysis (GSEA). Global plasma metabolite profiling (UPLC-MS/MS) was performed using a larger representative cohort (cyanotic CHD, n = 27; non-cyanotic CHD, n = 11; unaffected controls, n = 12).

Hallmark gene sets in glycolysis, fatty acid metabolism, and oxidative phosphorylation were significantly enriched in cyanotic CHD females compared to male counterparts, which was consistent with metabolomic differences between sexes. Minimal sex differences in metabolic pathways were observed in normoxic patients (both controls and non-cyanotic CHD cases).

These observations suggest underlying differences in metabolic adaptation to chronic hypoxia between males and females with cyanotic CHD.

Children with cyanotic CHD exhibit sex differences in utilization of glycolysis vs. fatty acid oxidation pathways to meet the high-energy demands of the heart in the neonatal period. Transcriptomic and metabolomic results suggest that under hypoxic conditions, males and females undergo metabolic shifts that are sexually dimorphic. These sex differences were not observed in neonates in normoxic conditions (i.e., non-cyanotic CHD and unaffected controls). The involved metabolic pathways are similar to those observed in advanced heart failure, suggesting metabolic adaptations beginning in the neonatal period may contribute to sex differences in infant survival.

Organoids, three-dimensional in vitro organ-like tissue cultures derived from stem cells, show promising potential for developmental biology, drug discovery, and regenerative medicine. However, the function and phenotype of current organoids, especially neural organoids, are still limited by insufficient diffusion of oxygen, nutrients, metabolites, signaling molecules, and drugs. Herein, we present Vascular network-Inspired Diffusible (VID) scaffolds to fully recapture the benefits of physiological diffusion physics for generating functional organoids and phenotyping their drug response. In a proof-of-concept application, the VID scaffolds, 3D-printed meshed tubular channel networks, support the successful generation of engineered human midbrain organoids almost without necrosis and hypoxia in commonly used well-plates. Compared to conventional organoids, these engineered organoids develop with more physiologically relevant features and functions including midbrain-specific identity, oxygen metabolism, neuronal maturation, and network activity. Moreover, these engineered organoids also better recapitulate pharmacological responses, such as neural activity changes to fentanyl exposure, compared to conventional organoids with significant diffusion limits. Combining these unique scaffolds and engineered organoids may provide insights for organoid development and therapeutic innovation.

Ischemia-reperfusion injury (IRI) profoundly impacts organ transplantation, especially in orthotopic liver transplantation (OLT). Disruption of the mitochondrial respiratory chain during ischemia leads to ATP loss and ROS production. Reperfusion exacerbates mitochondrial damage, triggering the release of damage-associated molecular patterns (DAMPs) and inflammatory responses. Mitochondrial dysfunction, a pivotal aspect of IRI, is explored in the context of the regulatory role of ectonucleotidases in purinergic signaling and immune responses. CD39, by hydrolyzing ATP and ADP; and CD73, by converting AMP to adenosine, emerge as key players in mitigating liver IRI, particularly through ischemic preconditioning and adenosine receptor signaling. Despite established roles in vascular health and immunity, the impact of ectonucleotidases on mitochondrial function during hepatic IRI is unclear. This review aims to elucidate the interplay between CD39/73 and mitochondria, emphasizing their potential as therapeutic targets for liver transplantation. This article explores the role of CD39/73 in tissue hypoxia, emphasizing adenosine production during inflammation. CD39 and CD73 upregulation under hypoxic conditions regulate immune responses, demonstrating protective effects in various organ-specific ischemic models. However, prolonged adenosine activation may have dual effects, beneficial in acute settings but detrimental in chronic hypoxia. Herein, we raise questions about ectonucleotidases influencing mitochondrial function during hepatic IRI, drawing parallels with cancer cell responses to chemotherapy. The review underscores the need for comprehensive research into the intricate interplay between ectonucleotidases, mitochondrial dynamics, and their therapeutic implications in hepatic IRI, providing valuable insights for advancing transplantation outcomes.

Cardiogenic shock (CS) remains a high-mortality condition despite technological and therapeutic advances. One key to potentially improving CS prognosis is understanding patient heterogeneity and which patients may benefit most from different treatment options, a key element of which is sex differences. While cardiovascular diseases (CVDs) have historically been considered a male-dominant condition, the field is increasingly aware that females are also a substantial portion of the patient population. While estrogen has been implicated in protective roles against CVD and tissue hypoxia, its role in CS remains unclear. Clinically, female CS patients tend to be older, have more severe comorbidities and are more likely to have non-acute myocardial infarction etiologies with preserved ejection fractions. Female CS patients are more likely to receive pharmacotherapy while less likely to receive mechanical circulatory support. There is increased short-term mortality in females, although long-term mortality is similar between the sexes. More sex-specific and age-stratified research needs to be done to fully understand the relevant pathophysiological differences in CS, to better recognize and manage CS patients and reduce its mortality.

The transcriptional factor HIF-1α is recognized for its contribution to cardioprotection against acute ischemia/reperfusion injury. Adaptation to chronic hypoxia (CH) is known to stabilize HIF-1α and increase myocardial ischemic tolerance. However, the precise role of HIF-1α in mediating the protective effect remains incompletely understood.

Male wild-type (WT) mice and mice with partial Hif1a deficiency (hif1a +/-) were exposed to CH for 4 weeks, while their respective controls were kept under normoxic conditions. Subsequently, their isolated perfused hearts were subjected to ischemia/reperfusion to determine infarct size, while RNA-sequencing of isolated cardiomyocytes was performed. Mitochondrial respiration was measured to evaluate mitochondrial function, and western blots were performed to assess mitophagy.

We demonstrated enhanced ischemic tolerance in WT mice induced by adaptation to CH compared with their normoxic controls and chronically hypoxic hif1a +/- mice. Through cardiomyocyte bulk mRNA sequencing analysis, we unveiled significant reprogramming of cardiomyocytes induced by CH emphasizing mitochondrial processes. CH reduced mitochondrial content and respiration and altered mitochondrial ultrastructure. Notably, the reduced mitochondrial content correlated with enhanced autophagosome formation exclusively in chronically hypoxic WT mice, supported by an increase in the LC3-II/LC3-I ratio, expression of PINK1, and degradation of SQSTM1/p62. Furthermore, pretreatment with the mitochondrial division inhibitor (mdivi-1) abolished the infarct size-limiting effect of CH in WT mice, highlighting the key role of mitophagy in CH-induced cardioprotection.

These findings provide new insights into the contribution of HIF-1α to cardiomyocyte survival during acute ischemia/reperfusion injury by activating the selective autophagy pathway.

Microphysiological systems (MPS) offer simulation of (patho)physiological parameters. Investigation includes items which lead to fibrosis and calcification in development and progress of calcific aortic valve disease, based e.g. on culturing of isolated valvular interstitial cells (VICs). Hypoxia regulated by hypoxia inducible factors impacts pathological differentiation in aortic valve (AV) disease. This is mimicked via an MPS implemented oxygenator in combination with calcification inducing medium supplementation.

Human valvular interstitial cells were isolated and dynamically cultured in MPS at hypoxic, normoxic, arterial blood oxygen concentration and cell incubator condition. Expression profile of fibrosis and calcification markers was monitored and calcification was quantified in induction and control media with and without hypoxia and in comparison to statically cultured counterparts.

Hypoxic 24-hour culture of human VICs leads to HIF1α nuclear localization and induction of EGLN1, EGLN3 and LDHA mRNA expression but does not directly impact expression of fibrosis and calcification markers. Dependent on medium formulation, induction medium induces monolayer calcification and elevates RUNX2, ACTA2 and FN1 but reduces SOX9 mRNA expression in dynamic and static MPS culture. But combining hypoxic oxygen concentration leads to higher calcification potential of human VICs in calcification and standard medium formulation dynamically cultured for 96 h.

In hypoxic oxygen concentration an increased human VIC calcification in 2D VIC culture in an oxygenator assisted MPS was detected. Oxygen regulation therefore can be combined with calcification induction media to monitor additional effects of pathological marker expression. Validation of oxygenator dependent VIC behavior envisions future advancement and transfer to long term aortic valve tissue culture MPS.

Stem cell-derived exosomes exert comparable therapeutic effects to those of their parental stem cells without causing immunogenic, tumorigenic, and ethical disadvantages. Their therapeutic advantages are manifested in the management of a broad spectrum of diseases, and their dosing versatility are exemplified by systemic administration and local delivery. Furthermore, the activation and regulation of various signaling cascades have provided foundation for the claimed curative effects of exosomal therapy. Unlike other relevant reviews focusing on the upstream aspects (e.g., yield, isolation, modification), and downstream aspects (e.g. phenotypic changes, tissue response, cellular behavior) of stem cell-derived exosome therapy, this unique review endeavors to focus on various affected signaling pathways. After meticulous dissection of relevant literature from the past five years, we present this comprehensive, up-to-date, disease-specific, and pathway-oriented review. Exosomes sourced from various types of stem cells can regulate major signaling pathways (e.g., the PTEN/PI3K/Akt/mTOR, NF-κB, TGF-β, HIF-1α, Wnt, MAPK, JAK-STAT, Hippo, and Notch signaling cascades) and minor pathways during the treatment of numerous diseases encountered in orthopedic surgery, neurosurgery, cardiothoracic surgery, plastic surgery, general surgery, and other specialties. We provide a novel perspective in future exosome research through bridging the gap between signaling pathways and surgical indications when designing further preclinical studies and clinical trials.

Hypoxia is an essential gastrointestinal (GI) tract phenomenon that influences both physiologic and pathologic states. Hypoxia-inducible factors (HIFs), the primary drivers of cell adaptation to low-oxygen environments, have been identified as critical regulators of gut homeostasis: directly, through the induction of different proteins linked to intestinal barrier stabilization (ie, adherent proteins, tight junctions, mucins, integrins, intestinal trefoil factor, and adenosine); and indirectly, through the regulation of several immune cell types and the modulation of autophagy and inflammatory processes. Furthermore, hypoxia and HIF-related sensing pathways influence the delicate relationship existing between bacteria and mammalian host cells. In turn, gut commensals establish and maintain the physiologic hypoxia of the GI tract and HIF-α expression. Based on this premise, the goals of this review are to (1) highlight hypoxic molecular pathways in the GI tract, both in physiologic and pathophysiologic settings, such as inflammatory bowel disease; and (2) discuss a potential strategy for ameliorating gut-related disorders, by targeting HIF signaling, which can alleviate inflammatory processes, restore autophagy correct mechanisms, and benefit the host-microbiota equilibrium.

Hypoxia, a critical feature during cancer development, leads to the stabilization and activation of the hypoxia-inducible factor 1-alpha (HIF-1α) to drive the expression of many target genes which in turn can promote many aspects of breast cancer biology, mainly metastasis and resistance to therapy. MicroRNAs are known to modulate the expression of many genes involved in breast cancer tumorigenesis. In this study, we examined the regulatory effect of miRNAs on HIF1α expression.

MCF-7 and MDA-MB-231 were cultivated under normoxia or hypoxia conditions. TaqMan-Low Density Array (TLDA) was used to characterize the miRNA signatures. Wild-Type (WT) or mutated fragments of HIF-1α 3'UTR containing the miR-138 potential target site were cloned downstream of the Renilla luciferase gene in the psiCHECK-1 plasmid. Luciferase assays were then carried out. A lentiviral vector containing copGFP as a reporter gene was prepared and transduced into MCF-7 and MDA-MB-231 cells to assess the effect of identified deregulated miRNAs on HIF-1α expression.

Under hypoxic conditions, MCF-7 cells showed deregulated expression for 12 miRNAs. In the case of MDA-MB-231 cells, 16 miRNAs were deregulated in response to hypoxia. Interestingly, miR-138 that was downregulated in both MCF-7 and MDA-MB-231 cells cultivated under hypoxic conditions appeared to have a binding site in 3'UTR of HIF-1α. Moreover, our results indicated that miR-138 could down regulate HIF-1α expression, upon binding directly to its 3'UTR.

Interestingly, our data highlights miR-138 as a potential therapeutic target to reduce HIF-1α expression and subsequently restrain breast cancer invasion and metastasis.

The complex and dynamic interaction between cellular energy control and gene expression modulation is shown by the intersection between mitochondrial metabolism and epigenetics in hypoxic environments. Poor oxygen delivery to tissues, or hypoxia, is a basic physiological stressor that sets off a series of reactions in cells to adapt and endure oxygen-starved environments. Often called the "powerhouse of the cell," mitochondria are essential to cellular metabolism, especially regarding producing energy through oxidative phosphorylation. The cellular response to hypoxia entails a change in mitochondrial metabolism to improve survival, including epigenetic modifications that control gene expression without altering the underlying genome. By altering the expression of genes involved in angiogenesis, cell survival, and metabolism, these epigenetic modifications help cells adapt to hypoxia. The sophisticated interplay between mitochondrial metabolism and epigenetics in hypoxia is highlighted by several important points, which have been summarized in the current article. Deciphering the relationship between mitochondrial metabolism and epigenetics during hypoxia is essential to understanding the molecular processes that regulate cellular adaptation to reduced oxygen concentrations.

Hypoxia-induced apoptosis and oxidative stress in spermatogenic cells are considered to be important factors leading to male infertility. It was reported that CDX2 expression was downregulated in hypoxia-stimulated spermatogenic cells. However, the effects of CDX2 on hypoxia-induced apoptosis and oxidative stress in spermatogenic cells are still unknown. This study aimed to explore the roles of CDX2 in hypoxia-induced injury of spermatogenic cells, as well as its mechanism of action. Spermatogenic cells were cultured under 1% oxygen for 48 h to established hypoxia damage model. Reactive oxygen species (ROS) generation was determined using 2',7'-dichlorofluorescein diacetate assay. Apoptosis was assessed using flow cytometry. Enzyme-linked immunosorbent assay was used to evaluate oxidative stress markers, including malondialdehyde (MDA) content and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidases (GSH-Px). Protein levels were detected using western blotting. Hypoxia exposure induced increase in ROS generation, apoptosis rate, and oxidative stress in spermatogenic cells. ROS scavenger inhibited hypoxia-induced apoptosis, oxidative stress, and Wnt/β-catenin pathway activation. Hypoxia exposure induced CDX2 downregulation. CDX2 overexpression suppressed hypoxia-induced ROS generation, apoptosis rate, oxidative stress, and Wnt/β-catenin pathway activation. Moreover, CDX2 knockdown restores the inhibitory effects of si-β-catenin or NAC on hypoxia-induced activation of the Wnt/β-catenin pathway, apoptosis, and oxidative stress. In conclusion, our study suggests that CDX2 overexpression alleviates hypoxia-induced apoptosis and oxidative stress by suppression of ROS-mediated Wnt/β-catenin pathway in spermatogenic cells.

Brain metastasis is the most devasting form of lung cancer. Recent studies highlight significant differences in the tumor microenvironment (TME) between lung cancer brain metastasis (LCBM) and primary lung cancer, which contribute significantly to tumor progression and drug resistance. Cancer-associated fibroblasts (CAFs) are the major component of pro-tumor TME with high plasticity. However, the lineage composition and function of CAFs in LCBM remain elusive. By reanalyzing single-cell RNA sequencing (scRNA-seq) data (GSE131907) from lung cancer patients with different stages of metastasis comprising primary lesions and brain metastasis, we found that CAFs undergo distinctive lineage transition during LCBM under a hypoxic situation, which is directly driven by hypoxia-induced HIF-2α activation. Transited CAFs enhance angiogenesis through VEGF pathways, trigger metabolic reprogramming, and promote the growth of tumor cells. Bulk RNA sequencing data was utilized as validation cohorts. Multiplex immunohistochemistry (mIHC) assay was performed on four paired samples of brain metastasis and their primary lung cancer counterparts to validate the findings. Our study revealed a novel mechanism of lung cancer brain metastasis featuring HIF-2α-induced lineage transition and functional alteration of CAFs, which offers potential therapeutic targets.

The progression of heart failure (HF) is complex and involves multiple regulatory pathways. Iron ions play a crucial supportive role as a cofactor for important proteins such as hemoglobin, myoglobin, oxidative respiratory chain, and DNA synthetase, in the myocardial energy metabolism process. In recent years, numerous studies have shown that HF is associated with iron dysmetabolism, and deficiencies in iron and overload of iron can both lead to the development of various myocarditis diseases, which ultimately progress to HF. Iron toxicity and iron metabolism may be key targets for the diagnosis, treatment, and prevention of HF. Some iron chelators (such as desferrioxamine), antioxidants (such as ascorbate), Fer-1, and molecules that regulate iron levels (such as lactoferrin) have been shown to be effective in treating HF and protecting the myocardium in multiple studies. Additionally, certain natural compounds can play a significant role by mediating the imbalance of iron-related signaling pathways and expression levels. Therefore, this review not only summarizes the basic processes of iron metabolism in the body and the mechanisms by which they play a role in HF, with the aim of providing new clues and considerations for the treatment of HF, but also summarizes recent studies on natural chemical components that involve ferroptosis and its role in HF pathology, as well as the mechanisms by which naturally occurring products regulate ferroptosis in HF, with the aim of providing reference information for the development of new ferroptosis inhibitors and lead compounds for the treatment of HF in the future.

Asthma is widely recognized as an inflammatory disorder. In the context of this inflammatory microenvironment, the involvement of hypoxia and its impact on related pathways have drawn considerable attention. However, the exact role of hypoxia, a prevalent environmental factor, in the development and progression of asthma remains poorly understood.

Mice were treated with house dust mite (HDM) extracts for 23 days to induce asthma. Mice were divided into room air (RA) group and intermittent hypoxic (IH) group by exposing to different conditions and IH preconditioning (IHP) were underwent to the above groups before the hypoxic regimen. Airway inflammation in mice was evaluated by airway hyperresponsiveness, excessive mucus secretion, and recruitment of inflammatory cells. Immunohistochemistry was employed to quantify the expression levels of NF-κB. Subsequently, the dose of allergen was modified to investigate whether the impact of hypoxia on asthma is affected by different doses of allergens.

Compared to the RA and IH groups, HDM-treated mice in the IHP group exhibited aggravated inflammatory cell infiltration and airway hyperresponsiveness (p＜.05). Moreover, there was an increased release of inflammatory mediators and higher expression levels of NF-κB (p＜.05). Importantly, the impact ia on asthma was found to be influenced by high dose of allergen (p＜.05).

IHP treatment potentially exacerbates HDM-induced airway inflammation in asthma, with the involvement of NF-κB, particularly under high-dose allergen stimulation.

Alteration of HIF-1α expression levels under hypoxic conditions affects the sequence of its downstream target genes thereby producing different effects. In order to investigate whether the effect of hypoxic compound exercise (HE) on HIF-1α expression alters cardiac pumping function, myocardial structure, and exercise capacity, we developed a suitable model of hypoxic exercise using Drosophila, a model organism, and additionally investigated the effect of hypoxic compound exercise on nocturnal sleep and activity behavior. The results showed that hypoxic compound exercise at 6% oxygen concentration for five consecutive days, lasting 1 h per day, significantly improved the cardiac stress resistance of Drosophila. The hypoxic complex exercise promoted the whole-body HIF-1α expression in Drosophila, and improved the jumping ability, climbing ability, moving speed, and moving distance. The expression of HIF-1α in the heart was increased after hypoxic exercise, which made a closer arrangement of myofilaments, an increase in the diameter of cardiac tubules, and an increase in the pumping function of the heart. The hypoxic compound exercise improved the sleep quality of Drosophila by increasing its nocturnal sleep time, the number of deep sleeps, and decreasing its nocturnal awakenings and activities. Therefore, we conclude that hypoxic compound exercise promoted the expression of HIF-1α to enhance the exercise capacity and heart pumping function of Drosophila, and improved the quality of sleep.

Electronic cigarettes (e-cigarettes) have rapidly gained popularity as alternatives to traditional combustible cigarettes. However, their long-term health impact remains uncertain. This study aimed to investigate the effects of chronic exposure to e-cigarette aerosol (ECA) in mice compared to conventional cigarette smoke (CS) exposure. The mice were exposed to air (control), low, medium, or high doses of ECA, or a reference CS dose orally and nasally for eight months. Various cardiovascular and pulmonary assessments have been conducted to determine the biological and prosthetic effects. Histopathological analysis was used to determine structural changes in the heart and lungs. Biological markers associated with fibrosis, inflammation, and oxidative stress were investigated. Cardiac proteomic analysis was applied to reveal the shared and unique protein expression changes in ECA and CS groups, which related to processes such as immune activation, lipid metabolism, and intracellular transport. Overall, chronic exposure to ECA led to adverse cardiovascular and pulmonary effects in mice, although they were less pronounced than those of CS exposure. This study provides evidence that e-cigarettes may be less harmful than combustible cigarettes for the long-term health of the cardiovascular and respiratory systems in mice. However, further human studies are needed to clarify the long-term health risks associated with e-cigarette use.