Hypoxia-induced Injury Research Articles

The Chinese Herbal Medicine Li Qi Huo Xue Di Wan Ameliorates Ischemia or Hypoxia-Induced Cardiac Injury and Remodeling in the Heart Through a Mechanism Involving Reduction of Necroptosis.

Li Qi Huo Xue Di Wan (LQHXDW), a Chinese herbal medicine, is commonly used to treat symptoms such as palpitations, chest tightness, chest pain, and shortness of breath. However, its potential to reduce ischemia or hypoxia-induced cardiac injury and remodeling, along with the precise mechanisms involved, remains unclear. This study aims to investigate the effects of LQHXDW on cardiac injury and remodeling induced by ischemia or hypoxia, both invivo and invitro, and to elucidate the underlying mechanisms. The mouse heart was subjected to ischemia for 14 days, showing evident myocardial injury and notable cardiac remodeling, accompanied by a reduction in cardiac function; these phenomena were reversed in the presence of LQHXDW. In the cultured cardiomyocyte exposed to hypoxia, incubation with LQHXDW increased the cell viability and reduced lactate dehydrogenase release. Mechanistically, LQHXDW exerted inhibitory effect on the phosphorylation levels of RIPK1, RIPK3, and MLKL as well as oxidative stress in the mice hearts suffered ischemia and the cultured cardiomyocytes exposed to hypoxia. Using the methods of ultra-high performance liquid chromatography-quadrupole time-of-flight-mass spectrometry, network pharmacology, and cellular thermal shift assay, phenethyl caffeate and isoliquiritigenin were identified as the potential active compounds in LQHXDW that counteract necroptosis. Based on these observations, we conclude that LQHXDW protects the heart against ischemia or hypoxia-induced cardiac injury and remodeling through suppression of the RIPK1/RIPK3/MLKL pathway-dependent necroptosis and oxidative stress.

Ginsenoside Rg1 Prevents and Treats Acute Pulmonary Injury Induced by High-Altitude Hypoxia

This study aimed to investigate the protective effects of ginsenoside Rg1 on high-altitude hypoxia-induced acute lung injury (ALI) and elucidated its molecular targets and related pathways, specifically its association with the fluid shear stress pathway. Using a combination of bioinformatics analysis and both in vivo and in vitro experiments, we assessed the role of ginsenoside Rg1 in mitigating physiological and biochemical disturbances induced by hypoxia. In the in vivo experiments, we measured arterial blood gas parameters, levels of inflammatory cells and cytokines, erythrocyte and platelet parameters, and conducted histological analysis in rats. The in vitro experiments utilized human pulmonary microvascular endothelial cells (HPMECs) and A549 cells to examine cell viability, intracellular reactive oxygen species (ROS) and Ca2⁺ levels, and mitochondrial function. The results of the in vivo experiments demonstrate that ginsenoside Rg1 significantly increased arterial blood oxygen partial pressure and saturation, elevated arterial blood glucose levels, and stabilized respiratory and metabolic functions in rats. It also reduced inflammatory cells and cytokines, such as tumor necrosis factor-α and interleukin-6, and improved erythrocyte and platelet abnormalities, supporting its protective role through the regulation of the fluid shear stress pathway. Histological and ultrastructural analyses revealed that Rg1 significantly protected lung tissue structure and organelles. In vitro experiments further confirmed that Rg1 improved cell viability in HPMEC and A549 cells under hypoxic conditions, decreased intracellular ROS and Ca2⁺ levels, and enhanced mitochondrial function. These findings collectively demonstrate that ginsenoside Rg1 exerts significant protective effects against high-altitude hypoxia-induced ALI by enhancing oxygen delivery and utilization, reducing inflammatory responses, and maintaining cellular metabolism and vascular function. Notably, the protective effects of Rg1 are closely associated with the regulation of the fluid shear stress pathway, suggesting its potential for treating high-altitude hypoxia-related diseases.

Circ_0068655 silencing ameliorates hypoxia-induced human cardiomyocyte injury by regulating apoptotic and inflammatory responses.

There is growing evidence suggesting that the dysregulation of circular RNAs (circRNAs) plays a significant role in various myocardial disorders, including myocardial ischemia (MI). This study aimed to explore the function of hsa_circ_0068655 (circ_0068655) in hypoxia-induced cardiomyocyte injury. Human AC16 cardiomyocyte cells were cultured under anaerobic condition to induce an in vitro model of MI. Cell apoptosis was assessed by Annexin V-fluorescein isothiocyanate staining and caspase-3 and caspase-9 activity assays. Cell proliferation was analyzed by 5-Ethynyl-2'-deoxyuridine (EdU) incorporation assay. Inflammation was evaluated by enzyme-linked immunosorbent assays. Circ_0068655, miR-370-3p and BCL-2-like 11 (BCL2L11) expression were detected by real-time quantitative polymerase chain reaction or western blotting. The target interactions among circ_0068655, miR-370-3p and BCL2L11 were predicted using bioinformatics tools and validated using dual-luciferase reporter assays and RNA immunoprecipitation assays. Hypoxia treatment led to upregulated expression of circ_0068655 and BCL2L11, and downregulated expression of miR-370-3p in AC16 cells. This treatment also resulted in reduced cell viability, increased apoptosis rate, elevated caspase-9/3 activities and cleavage, and enhanced production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β. Notably, knockdown of circ_0068655 alleviated these detrimental effects. In addition, circ_0068655 silencing-mediated effects were restored by decreasing miR-370-3p expression in hypoxia-treated AC16 cells. Moreover, ectopic BCL2L11 expression remitted the effects of miR-370-3p overexpression on hypoxia-treated AC16 cells. Mechanistically, circ_0068655 was found to act as a sponge for miR-370-3p, thereby regulating BCL2L11 expression. Circ_0068655 silencing ameliorated hypoxia-induced human cardiomyocyte injury through the miR-370-3p/BCL2L11 axis.

Circulating microRNA-409-5p and USP7 are associated with left ventricular remodeling in patients with acute myocardial infarction

BackgroundOur previous study demonstrated that microRNA-409-5p (miR-409-5p) and its target ubiquitin-specific protease 7 (USP7) were involved in hypoxia-induced cardiomyocyte injury and ischemic left ventricular remodeling (LVR) in rats. This study aimed to probe into the relationship between plasma miR-409-5p and USP7 levels and LVR and dysfunction in patients with acute myocardial infarction (AMI).MethodsSixty patients with acute myocardial infarction (AMI) and 60 cases with chronic coronary syndrome (CCS) were enrolled. The clinical characteristics, echocardiographic/serum parameters of LVR, and circulating miR-409-5p and USP7 mRNA levels between the two groups and between admission and 6 weeks after discharge were compared. The correlations between circulating miR-409-5p/USP7 levels and serum/echocardiographic parameters were analyzed.ResultsThe demographic characteristics of the AMI group and CCS group were comparable. Patients with AMI admitted to the study displayed significantly higher levels of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) and growth stimulation expressed gene 2 (ST2), along with a greater left ventricular end-systolic volume (LVESV). Conversely, their left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), and global radial strain (GRS) were significantly lower compared to patients with CCS. These changes were normalized 6 weeks after discharge. Circulating miR-409-5p levels at admission were significantly decreased while circulating USP7 mRNA expression levels were significantly increased in patients with AMI compared with those with CCS (both P < 0.01). However, these changes were restored 6 weeks after discharge (both P < 0.01). Moreover, circulating miR-409-5p and USP7 mRNA levels showed varying correlations with GLS, GRS, LVESV, LVEF, and NT-proBNP in patients with AMI but not in those with CCS. Additionally, circulating miR-409-5p and USP7 levels predicted the incidence of LVR and major adverse cardiovascular events (MACE) after AMI.ConclusionSerum miR-409-5p and USP7 may influence the occurrence and evolution of LVR and left ventricular dysfunction after AMI.

Cerebellar Purkinje cell activity regulates white matter response and locomotor function after neonatal hypoxia.

Neonatal hypoxia (Hx) causes white matter (WM) injury, particularly in the cerebellum. We previously demonstrated Hx-induced reduction of cerebellar Purkinje cell (PC) activity results in locomotor deficits. Yet, the mechanism of Hx-induced cerebellar WM injury and associated locomotor abnormalities remains undetermined. Here, we show that the cerebellar WM injury and linked locomotor deficits are driven by PC activity and are reversed when PC activity is restored. Using optogenetics and multielectrode array recordings, we manipulated PC activity and captured the resulting cellular responses in WM oligodendrocyte precursor cells and GABAergic interneurons. To emulate the effects of Hx, we used light activated Halorhodopsin targeted specifically to the PC layer of normal mice. Suppression of PC firing activity at P13 and P21 phenocopied the locomotor deficits observed in Hx. Moreover, histopathologic analysis of the developing cerebellar WM following PC inhibition (P21) revealed a corresponding reduction in oligodendrocyte maturation and myelination, akin to our findings in Hx mice. Conversely, PC stimulation restored PC activity, promoted oligodendrocyte maturation and enhanced myelination, resulting in reversed Hx-induced locomotor deficits. Our findings highlight the crucial role of PC activity in cerebellar WM development and locomotor performance following neonatal injury.Significance statement Adult survivors of prematurity often experience locomotor incoordination secondary to cerebellar dysfunction. The cerebellum develops in the last trimester of pregnancy, a period that preterm neonates miss. Here, we show how neonatal hypoxia alters the crosstalk between neurons and oligodendrocytes in the developing cerebellum. Through loss-of-function and gain-of-function experiments, we unveiled that neuronal activity drives cerebellum-associated white matter injury and locomotor dysfunction after hypoxia. Importantly, restoring neuronal activity using direct neurophysiological stimulation reversed the hypoxia-induced white matter injury and locomotor deficits. Early cerebellar neuronal stimulation could serve as a potential therapeutic intervention for locomotor dysfunction in neonates.

The role of TRAP1 in regulating mitochondrial dynamics during acute hypoxia-induced brain injury

Brain damage caused by acute hypoxia is associated with the physiological activities of mitochondria. Although mitochondria being dynamically regulated, our comprehensive understanding of the response of specific brain cell types to acute hypoxia remains ambiguous. Tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondrial-based molecular chaperone, plays a role in controlling mitochondrial movements. Herein, we demonstrated that acute hypoxia significantly alters mitochondria morphology and functionality in both in vivo and in vitro brain injury experiments. Summary-data-based Mendelian Randomization (SMR) analyses revealed possible causative links between mitochondria-related genes and hypoxia injury. Advancing the protein-protein interaction network and molecular docking further elucidated the associations between TRAP1 and mitochondrial dynamics. Furthermore, it was shown that TRAP1 knockdown levels variably affected the expression of key mitochondrial dynamics proteins (DRP1, FIS1, and MFN1/2) in primary hippocampal neurons, astrocytes, and BV-2 cell, leading to changes in mitochondrial structure and function. Understanding the function of TRAP1 in altering mitochondrial physiological activity during hypoxia-induced acute brain injury could help serve as a potential therapeutic target to mitigate neurological damage.

Mitochondrial Treatment Mitigates Hypoxia-Induced Renal Cell Injury

Mitochondrial Treatment Mitigates Hypoxia-Induced Renal Cell Injury

The Role of miRNA-29b1 on the Hypoxia-Induced Apoptosis in Mammalian Cardiomyocytes

A hypoxic stress which causes apoptosis of cardiomyocytes is the main problem in the ischemic heart disease. The present research sought to investigate the role of microRNA-29b1 (miR-29b1) in hypoxia-treated cardiomyocytes and its potential mechanism involved. We replicated an in vitro AC16 and H9C2 cardiomyocytes ischemia model by hypoxia (1% O2, 48 h) treatment. Cell apoptosis was evaluated by flow cytometry using Annexin V FITC-PI staining assay. Moreover, we used western blot and immunofluorescence analysis to determine the expression of Bcl-2, Bax caspase-3 and Cx43 proteins. We found that miR-29b1 protected AC16 and H9C2 cells from hypoxia-induced injury as the evidences that miR-29b1 attenuated the effects of hypoxia treatment on AC16 and H9C2 cell apoptosis after hypoxia treatment. In conclusion, these results revealed the potential cardiovascular protective effects of miR-29b1 in the process of ischemia-related myocardial injury.

Noninvasive Monitoring of Changes in Cerebral Hemodynamics During Prolonged Field Care for Hemorrhagic Shock and Hypoxia-Induced Injuries With Portable Diffuse Optical Sensors.

Achieving simultaneous cerebral blood flow (CBF) and oxygenation measures, specifically for point-of-care injury monitoring in prolonged field care, requires the implementation of appropriate methodologies and advanced medical device design, development, and evaluation. The near-infrared spectroscopy (NIRS) method measures the absorbance of light whose attenuation is related to cerebral blood volume and oxygenation. By contrast, diffuse correlation spectroscopy (DCS) allows continuous noninvasive monitoring of microvascular blood flow by directly measuring the degree of light scattering because of red blood cell (RBC) movement in tissue capillaries. Hence, this study utilizes these two optical approaches (DCS-NIRS) to obtain a more complete hemodynamic monitoring by providing cerebral microvascular blood flow, hemoglobin oxygenation and deoxygenation in hemorrhage, and hypoxia-induced injuries. Piglet models of hemorrhage and hypoxia-induced brain injury were used with DCS and NIRS sensors placed over the preorbital to temporal skull regions. To induce hemorrhagic shock, up to 70% of the animal's total blood volume was withdrawn through graded hemorrhage serially via a syringe from a femoral artery cannula in 10 mL/kg aliquots over 1 minute every 10 minutes. A second group of animals was subjected to hypoxia for ∼1 hour through graded hypoxia by serial titration from normoxic fraction inspired oxygen of 21% to hypoxic fraction inspired oxygen of 6%. A subset of animals served as sham-controls undergoing anesthesia, instrumentation, and ventilation as the injury groups, yet experiencing no blood loss or hypoxia. We first investigated the relationship between hemorrhagic shock and no shock by using measured biomarkers, including blood flow index from DCS associated with CBF and oxygenated (HbO) and de-oxygenated hemoglobin from NIRS. The statistical analysis revealed a significant difference between no shock and hemorrhagic shock (P < .01). The HbO decreased with each blood loss as expected, yet the de-oxygenated hemoglobin was slightly changed. During hypoxia-induced global hypoxic-ischemic injury tests, the CBF results from graded hypoxia were consistent with the response previously measured during hemorrhagic shock. Moreover, HbO decreased when the animal was hypoxic, as expected. A statistical analysis was also conducted to compare the results with those of the sham controls. There is a consistency in blood flow measures in both injury mechanisms (hemorrhagic shock and hypoxia), which is significant as the new prototype system provides similar measures and trends for each brain injury type, suggesting that the optical system can be used in response to different injury mechanisms. Notably, the results support the idea that this optical system can probe the hemodynamic status of local cerebral cortical tissue and provide insight into the underlying changes of cerebral tissue perfusion at the microvascular level. These measurement capabilities can improve shock identification and monitoring of medical management of injuries, particularly hemorrhagic shock, in prolonged field care.

Abstract Tu001: MiR-21 mitigated pulmonary hypertension induced right ventricular dysfunction through pulmonary circulating exosomes

Background: Patients with pulmonary arterial hypertension (PAH) often experience adverse outcomes primarily due to right ventricular (RV) dysfunction. However, the intricate relationship between pulmonary circulation and RV remodeling remains largely unexplored. Exosomal microRNAs (miRNAs) function as paracrine signaling mediators in diverse diseases. Aims: To investigate the ability of exosomal miRNAs derived from pulmonary endothelial cells to transmit signals affecting cardiomyocytes. Methods and Results: Utilizing next-generation sequencing, we identified several target miRNAs by analyzing exosome samples obtained through right-heart catheterization. Notably, exosomal miR-21 exhibited the highest expression in the pulmonary circulation (Figure 1) . Under hypoxic conditions, the expression of miR-21 increased in human pulmonary endothelial cells (HPECs) and in exosomes derived from their conditioned medium. Treatment with these exosomes enhanced miR-21 expression and concurrently mitigated apoptosis in hypoxia-exposed cardiomyocytes. Likewise, miR-21 demonstrated a protective role against hypoxia-induced injuries and apoptosis, involving the SPRY-2/p-ERK and PTEN/Akt pathways. In a murine model of sugen/hypoxia-induced PAH, mice lacking miR-21 (miR-21 -/- ) exhibited more severe RV dysfunction, altered hemodynamics, and increased fibrosis compared to wild-type (WT) mice. Employing a parabiosis model, pairs consisting of WT and miR-21 -/- mice were shielded from RV dysfunction, whereas pairs of miR-21 -/- mice displayed exacerbated RV function (Figure 2) . Conclusion: Hypoxia stimulates the production of exosomal miR-21 in both HPECs and their microenvironment, subsequently mitigating apoptosis in cardiomyocytes (Figure 3) . Our findings propose endothelial cell-derived exosomal miR-21 as a promising therapeutic target for PAH.

Network pharmacology and in vivo experimental studies reveal the protective effects of 6-hydroxygenistein against hypobaric hypoxia-induced brain injury

Hypobaric hypoxia-induced brain injury (HHBI) is a progressive neurodegenerative disease that has still not been effectively treated. There are several different mechanisms involved in HHBI. Among them, oxidative stress and inflammation response predominate. 6-hydroxygenistein (4′,5,6,7-tetrahydroxyisoflavone, 6-OHG) is a hydroxylated derivative of genistein with excellent antioxidant activity, however, the protective effects and underlying mechanisms against HHBI have not been clarified. In the present study, we aimed to explore the mechanisms of action of 6-OHG on HHBI using network pharmacology and experimental validation. Network pharmacology analysis revealed 186 candidate targets through the intersection of the targets of 6-OHG and related genes in HHBI, which were mainly enriched in oxidative stress and inflammation response. Moreover, key targets of 6-OHG against HHBI, namely Nrf2 and NF-κB, were screened and found to be closely related to oxidative stress and inflammation response. Subsequent in vivo experiments revealed that 6-OHG treatment attenuated oxidative stress and inflammation response, prevented energy disorder and apoptosis as well as maintained the BBB integrity in HHBI mice. In addition, 6-OHG administration up-regulated the expressions of Nrf2 and HO-1 and down-regulated the expressions of NF-κB and NLRP3, thereby inhibiting oxidative stress and inflammation response. Hence, the present study demonstrates that 6-OHG protects against HHBI by stimulating the Nrf2/HO-1 signaling pathway and suppressing the NF-κB/NLRP3 signaling pathway.

The cytoprotective effect of Gymnema inodorum leaf extract against hypoxia-induced cardiomyocytes injury

Ischemic heart disease stands out as a major global contributor to mortality, with the initiation of hypoxia, marked by reduced oxygen availability, disrupting the balance of reactive oxygen species (ROS), leading to cellular injury. Exploring antioxidants derived from medicinal plants is becoming more interesting as a potential alternative treatment, especially for mitigating myocardial injury. Thus, this study aimed to assess the cytoprotective efficacy of Gymnema inodorum leaf extract (GIE) in a rat cardiac myoblast, H9c2, subjected to an in vitro hypoxia. The cell viability, intracellular ROS production and the expression of inflammatory cytokines were quantified, and hypoxia-induced cell morphology changes were observed using confocal fluorescence microscopy. The results showed that GIE notably enhanced cell viability, preserving membrane integrity, when compared with the hypoxic group. Remarkably, GIE significantly reduced hypoxia-induced intracellular ROS production, attributable to its inherent antioxidant properties. Furthermore, GIE significantly reduced interleukin (IL)-1β, interleukin (IL)-6 mRNA expression level and tended to reduce tumor necrosis factor-α (TNF-α) mRNA expression. In conclusion, these findings underscore the potential of GIE in mitigating hypoxia-induced myocardial injury, highlighting its robust antioxidant and anti-inflammatory attributes.

Novel energy optimizer, meldonium, rapidly restores acute hypobaric hypoxia-induced brain injury by targeting phosphoglycerate kinase 1

BackgroundAcute hypobaric hypoxia-induced brain injury has been a challenge in the health management of mountaineers; therefore, new neuroprotective agents are urgently required. Meldonium, a well-known cardioprotective drug, has been reported to have neuroprotective effects. However, the relevant mechanisms have not been elucidated. We hypothesized that meldonium may play a potentially novel role in hypobaric hypoxia cerebral injury.MethodsWe initially evaluated the neuroprotection efficacy of meldonium against acute hypoxia in mice and primary hippocampal neurons. The potential molecular targets of meldonium were screened using drug-target binding Huprot™ microarray chip and mass spectrometry analyses after which they were validated with surface plasmon resonance (SPR), molecular docking, and pull-down assay. The functional effects of such binding were explored through gene knockdown and overexpression.ResultsThe study clearly shows that pretreatment with meldonium rapidly attenuates neuronal pathological damage, cerebral blood flow changes, and mitochondrial damage and its cascade response to oxidative stress injury, thereby improving survival rates in mice brain and primary hippocampal neurons, revealing the remarkable pharmacological efficacy of meldonium in acute high-altitude brain injury. On the one hand, we confirmed that meldonium directly interacts with phosphoglycerate kinase 1 (PGK1) to promote its activity, which improved glycolysis and pyruvate metabolism to promote ATP production. On the other hand, meldonium also ameliorates mitochondrial damage by PGK1 translocating to mitochondria under acute hypoxia to regulate the activity of TNF receptor-associated protein 1 (TRAP1) molecular chaperones.ConclusionThese results further explain the mechanism of meldonium as an energy optimizer and provide a strategy for preventing acute hypobaric hypoxia brain injury at high altitudes.

Pericytes: Unsung heroes in myelin repair after neonatal brain hypoxia.

Preterm infants can face lasting neurodevelopmental challenges due to hypoxia-induced injury of the cerebral white matter. In this issue of Neuron, Ren etal.1 identify microvascular pericytes as unexpected targets for growth hormone signaling, which enhances angiogenesis and remyelination after hypoxic injury in the developing mouse brain.

The role of miRNA-29b1 on the hypoxia-induced apoptosis in mammalian cardiomyocytes.

Cardiomyocyte apoptosis is a complex biological process involving the interaction of many factors and signaling pathways. In hypoxic environment, cardiomyocytes may trigger apoptosis due to insufficient energy supply, increased production of oxygen free radicals, and disturbance of intracellular calcium ion balance. The present research aimed to investigate the role of microRNA-29b1 (miR-29b1) in hypoxia-treated cardiomyocytes and its potential mechanism involved. We established an in vitro ischemia model using AC16 and H9C2 cardiomyocytes through hypoxia treatment (1% O2, 48 h). Cell apoptosis was evaluated by flow cytometry using Annexin V FITC-PI staining assay. Moreover, we used Western blot and immunofluorescence analysis to determine the expression of Bcl-2, Bax caspase-3 and Cx43 proteins. We found that miR-29b1 protected AC16 and H9C2 cells from hypoxia-induced injury as evidence that miR-29b1 attenuated the effects of hypoxia treatment on AC16 and H9C2 cell apoptosis after hypoxia treatment. In conclusion, our findings suggest that miR-29b1 may have potential cardiovascular protective effects during ischemia-related myocardial injury.

Overexpression of NDNF Improves the Cytoprotective Effects of Aged Human Bone Marrow Mesenchymal Stem Cells by Modulating Oxidative Stress and Apoptosis.

The therapeutic potential of autologous stem cell transplantation for heart repair diminishes in the elderly due to stem cell aging. Rejuvenating aged stem cells to enhance their protective effects on injured cardiomyocytes is crucial for aging patients with heart failure. In this study, we aimed to investigate whether neuron-derived neurotrophic factor (NDNF) over-expression improves the protective effect of aged stem cells for injured cardiomyocytes and explore the underlying mechanism. Human bone marrow was collected from both young and old patients, and bone marrow mesenchymal stem cells (BMSCs) were cultured. Lentivirus expression vectors carrying NDNF genes were used to transfect aged BMSCs. Fatal hypoxia-induced injury in H9C2 cells served as an in vitro ischemia model. The conditioned medium from different BMSC groups was applied to assess the beneficial effects on hypoxia-induced damage in myocardial H9C2 cells. Results revealed that the conditioned medium of NDNF over-expressed old BMSCs increased H9C2 cell viability and reduced oxidative stress and apoptosis levels under fatal hypoxia. NDNF over-expressed old BMSCs exhibited an antiapoptotic role by upregulating the antiapoptotic gene Bcl-2 and downregulating the proapoptotic genes Bax. Additionally, the protective effects were mediated through the elevation of phosphorylated AKT. Our data support the promise of NDNF as a potential target to enhance the protective effects of autologous aged BMSCs on ischemic cardiomyocytes and then improve the curative effects of stem cell for ischemic heart injury in aged patients.

Angiotensin-converting enzyme inhibitors provide a protective effect on hypoxia-induced injury in human coronary artery endothelial cells via Nrf2 signaling and PLVAP.

Angiotensin-converting enzyme inhibitors (ACEIs) were reported to protect from hypoxia-induced oxidative stress in coronary endothelial cells (CECs) after acute myocardial infarction (AMI). Nrf2 shows a protective effect in hypoxia-induced CECs after AMI. Plasmalemma vesicle-associated protein (PLVAP) plays a pivotal role in angiogenesis after AMI. To explore the protective effect of ACEIs and the involved mechanisms under hypoxia challenge. Human coronary endothelial cells (HCAECs) were used to establish hypoxia-induced oxidative stress injury in vitro. Flow cytometry was used to evaluate the protective effect of ACEI on hypoxia conditions.ET-1, NO, ROS, and VEGF were detected by ELISA. HO-1, Nrf2, and Keap-1, the pivotal member in the Nrf2 signaling pathway, eNOS and PLVAP were detected in HEAECs treated with ACEI by immunofluorescence, qPCR, and western blotting. The hypoxia ACEI or Nrf2 agonist groups showed higher cell viability compared with the hypoxia control group at 24 (61.75±1.16 or 61.23±0.59 vs. 44.24±0.58, both P < 0.05) and 48 h (41.85±1.19 or 59.64±1.13 vs. 22.98±0.25, both P < 0.05). ACEI decreased the levels of ET-1 and ROS under hypoxia challenge at 24 and 48 h (all P < 0.05); ACEI increased the VEGF and NO levels (all P < 0.05). ACEI promoted the expression level of eNOS, HO-1, Nrf2 and PLVAP but inhibited Keap-1 expression at the mRNA and protein levels (all P < 0.05). Blockade of the Nrf2 signaling pathway significantly decreased the expression level of PLVAP. ACEI protects hypoxia-treated HEAECs by activating the Nrf2 signaling pathway and upregulating the expression of PLVAP.

An active peptide from yak inhibits hypoxia-induced lung injury via suppressing VEGF/MAPK/inflammatory signaling

Pulmonary vascular remodeling and inflammation play an important role in the hypoxic-induced lung diseases. Our previous investigations showed that peptide from yak milk residues could alleviate inflammation. In this study, our results suggest that peptide (LV) from yak milk residues peptide had protective effect of lung in the animal models of hypoxic-induced lung injury. LV Gavage could improve pulmonary vascular remodeling in the lung tissues of hypoxic mice. A comprehensive analysis of metabolomics and transcriptomics revealed that 5-KETE, 8,9-EET, and 6-keto-prostaglandin F1a might be potential targets to prevent lung injury in the hypoxic mice. These metabolites can be regulated by MAPK/VEGF and inflammatory pathways. Our data indicated that LV treatment could inhibit apoptosis and inflammation via Nrf2/NF-κB/MAPK/PHD-2 pathway and protected hypoxic-induced lung epithelial cells injury. Taken together, our results suggest that LV provides a novel therapeutic clue for the prevention of hypoxia-induced lung injury and inflammation-related lung diseases.

The Role of TPM3 in Protecting Cardiomyocyte from Hypoxia-Induced Injury via Cytoskeleton Stabilization.

Ischemic heart disease (IHD) remains a major global health concern, with ischemia-reperfusion injury exacerbating myocardial damage despite therapeutic interventions. In this study, we investigated the role of tropomyosin 3 (TPM3) in protecting cardiomyocytes against hypoxia-induced injury and oxidative stress. Using the AC16 and H9c2 cell lines, we established a chemical hypoxia model by treating cells with cobalt chloride (CoCl2) to simulate low-oxygen conditions. We found that CoCl2 treatment significantly upregulated the expression of hypoxia-inducible factor 1 alpha (HIF-1α) in cardiomyocytes, indicating the successful induction of hypoxia. Subsequent morphological and biochemical analyses revealed that hypoxia altered cardiomyocyte morphology disrupted the cytoskeleton, and caused cellular damage, accompanied by increased lactate dehydrogenase (LDH) release and malondialdehyde (MDA) levels, and decreased superoxide dismutase (SOD) activity, indicative of oxidative stress. Lentivirus-mediated TPM3 overexpression attenuated hypoxia-induced morphological changes, cellular damage, and oxidative stress imbalance, while TPM3 knockdown exacerbated these effects. Furthermore, treatment with the HDAC1 inhibitor MGCD0103 partially reversed the exacerbation of hypoxia-induced injury caused by TPM3 knockdown. Protein-protein interaction (PPI) network and functional enrichment analysis suggested that TPM3 may modulate cardiac muscle development, contraction, and adrenergic signaling pathways. In conclusion, our findings highlight the therapeutic potential of TPM3 modulation in mitigating hypoxia-associated cardiac injury, suggesting a promising avenue for the treatment of ischemic heart disease and other hypoxia-related cardiac pathologies.

Potential therapeutic effects of traditional Chinese medicine in acute mountain sickness: pathogenesis, mechanisms and future directions.

Acute mountain sickness (AMS) is a pathology with different symptoms in which the organism is not adapted to the environment that occurs under the special environment of high altitude. Its main mechanism is the organism's tissue damage caused by acute hypobaric hypoxia. Traditional Chinese medicine (TCM) theory focuses on the holistic concept. TCM has made remarkable achievements in the treatment of many mountain sicknesses. This review outlines the pathogenesis of AMS in modern and traditional medicine, the progress of animal models of AMS, and summarizes the therapeutic effects of TCM on AMS. Using the keywords "traditional Chinese medicine," "herbal medicine," "acute mountain sickness," "high-altitude pulmonary edema," "high-altitude cerebral edema," "acute hypobaric hypoxia," and "high-altitude," all relevant TCM literature published up to November 2023 were collected from Scopus, Web of Science, PubMed, and China National Knowledge Infrastructure databases, and the key information was analyzed. We systematically summarised the effects of acute hypobaric hypoxia on the tissues of the organism, the study of the methodology for the establishment of an animal model of AMS, and retrieved 18 proprietary Chinese medicines for the clinical treatment of AMS. The therapeutic principle of medicines is mainly invigorating qi, activating blood and removing stasis. The components of botanical drugs mainly include salidroside, ginsenoside Rg1, and tetrahydrocurcumin. The mechanism of action of TCM in the treatment of AMS is mainly through the regulation of HIF-1α/NF-κB signaling pathway, inhibition of inflammatory response and oxidative stress, and enhancement of energy metabolism. The main pathogenesis of AMS is unclear. Still, TCM formulas and components have been used to treat AMS through multifaceted interventions, such as compound danshen drip pills, Huangqi Baihe granules, salidroside, and ginsenoside Rg1. These components generally exert anti-AMS pharmacological effects by inhibiting the expression of VEGF, concentration of MDA and pro-inflammatory factors, down-regulating NF-κB/NLRP3 pathway, and promoting SOD and Na + -K + -ATPase activities, which attenuates acute hypobaric hypoxia-induced tissue injury. This review comprehensively analyses the application of TCM in AMS and makes suggestions for more in-depth studies in the future, aiming to provide some ideas and insights for subsequent studies.