Hypoxic Stress Research Articles

Hydrogen sulfide upregulates hypoxia inducible factors and erythropoietin production in chronic kidney disease induced by 5/6 nephrectomized rats.

In end stage renal disease )ESRD(, reduced EPO production resulted in decreased oxygen diffusion that cause Hypoxia-inducible factors (HIFs) stabilization. The mechanism of beneficial effects of H2S in chronic kidney disease (CKD) is the aim of the present study to examine the effects of the H2S donor sodium hydrosulfide (NaHS) on renal function parameters, oxidative stress indices and expression levels of HIF-2α gene and erythropoietin protein in 5/6 nephrectomy-induced chronic renal failure in rats. Male rats were assigned into 3 groups (n = 8): Sham, CKD and NaHS groups. In the CKD group, 5/6 nephrectomy was performed. In the sham group, rats were anesthetized but 5/6 nephrectomy was not induced. In the NaHS group, 30 µmol/L of NaHS in drinking water for 8 weeks was adminstrated 4 weeks after 5/6 nephrectomy induction. At the end of the 12 week, blood and renal tissues were taken to evaluate renal function parameters, oxidative stress indices and expression levels of HIF-2α gene and erythropoietin protein. The induction of 5/6 nephrectomy significantly caused renal dysfunction, oxidative stress, increased HIF-2α gene expression and decreased erythropoietin levels in renal tissue samples. NaHS administration resulted in a marked improvement in renal function and oxidative stress indicators, a marked reduction in HIF-2α gene expression as well as an increase in erythropoietin protein levels in comparison with the CKD group. In this study, regional hypoxia and oxidative stress in CKD, may cause the stabilization of the HIFs complexes, although erythropoietin synthesis was not increased due to destructive effects of CKD on the kidney tissues. Administration of NaHS caused up-regulating HIF-erythropoietin signaling pathway.

Transcriptomic changes reveal hypoxic stress response in submerged seeds of maize (Zea mays L.)

Maize is highly sensitive to waterlogging stress, and seeds fail to germinate under hypoxic conditions induced by submergence, leading to severe yield losses. We conducted a comparative transcriptome analysis during the initial stages of seed germination, exploring aerobic and hypoxic conditions in two inbred lines, B73 and Okcheon Chal-1. Notably, significant differences emerged between aerobic and hypoxic conditions on the first day of germination, particularly in genes associated with fermentation and phytohormone regulation. However, consistent transcriptomic changes were observed in primary metabolic pathways such as glycolysis, the TCA cycle, and the pentose phosphate pathway. These differences strongly correlate with each other, illustrating the efficacy of the hypoxic response for survival in water. Furthermore, this suggests that germinating seeds serve as a promising model for studying plant hypoxia responses with controlled environmental conditions. Insights from this study contribute to understanding the fundamental mechanisms of hypoxia response and hold promise for developing strategies to cultivate waterlogging-tolerant maize cultivars.

A Nitroreductase-Activatable Metabolic Reporter for Covalent Labeling of Pathological Hypoxic Cells in Tumorigenesis.

Aberrant hypoxic stress will initiate a cascade of pathological consequence observed prominently in tumorigenesis. Understanding of hypoxia's role in tumorigenesis is highly essential for developing effective therapeutics, which necessitates reliable tools to specifically distinguish hypoxic tumor cells (or tissues) and correlate their dynamics with the status of disease in complex living settings for precise theranostics. So far, disparate hypoxia-responsive probe molecules and prodrugs were designed via chemical or enzymatic reactions, yet their capability in real-time reporting pathogenesis development is often compromised due to unrestricted diffusion and less selectivity towards the environmental responsiveness. Herein we present an oxygen-insensitive nitroreductase (NTR)-activatable glycan metabolic reporter (pNB-ManNAz) capable of covalently labeling hypoxic tumor cells and tissues. Under pathophysiological hypoxic environments, the caged non-metabolizable precursor pNB-ManNAz exhibited unique responsiveness to cellular NTR, culminating in structural self-immolation and the resultant ManNAz could incorporate onto cell surface glycoproteins, thereby facilitating fluorescence labeling via bioorthogonal chemistry. This NTR-responsive metabolic reporter demonstrated broad applicability for multicellular hypoxia labeling, particularly in the dynamic monitoring of orthotopic tumorigenesis and targeted tumor phototherapy in vivo. We anticipate that this approach holds promise for investigating hypoxia-related pathological progression, offering valuable insights for accurate diagnosis and treatment.

PM2.5 potentiates oxygen glucose deprivation-induced neurovascular unit damage via inhibition of the Akt/β-catenin pathway and autophagy dysregulation

Air pollution has recently emerged as a significant risk factor for ischemic stroke. Although there is a robust association between higher concentrations of ambient particulate matter (PM2.5) and increased incidence and mortality rates of ischemic stroke, the precise mechanisms underlying PM2.5-induced ischemic stroke remain to be fully elucidated. The purpose of this study was to examine the synergistic effect of PM2.5 and hypoxic stress using in vivo and in vitro ischemic stroke models. Intravenously administered PM2.5 exacerbated the ischemic brain damage induced by middle cerebral artery occlusion (MCAo) in Sprague Dawley rats. Alterations in autophagy flux and decreased levels of tight junction proteins were observed in the brain of PM2.5-administered rats after MCAo. The underlying mechanism of PM2.5-induced potentiation of ischemic brain damage was investigated in neurons, perivascular macrophages, and brain endothelial cells, which are the major components of the integrated neurovascular unit. Co-treatment with PM2.5 and oxygen-glucose deprivation (OGD) amplified the effects of OGD on the reduction of viability in primary neurons, immortalized murine hippocampal neuron (HT-22), and brain endothelial cells (bEND.3). After co-treatment with PM2.5 and OGD, the Akt/β-catenin and autophagy flux were significantly inhibited in HT-22 cells. Notably, the protein levels of metalloproteinase-9 and cystatin C were elevated in the conditioned media of murine macrophages (RAW264.7) exposed to PM2.5, and tight junction protein expression was significantly decreased after OGD exposure in bEND.3 cells pretreated with the conditioned media. Our findings suggest that perivascular macrophages may mediate PM2.5-induced brain endothelial dysfunction following ischemia and that PM2.5 can exacerbate ischemia-induced neurovascular damage.

Mechanisms of mitochondrial resilience in teleostean radial glia under hypoxic stress

Radial glial cells (RGCs) are remarkable cells, essential for normal development of the vertebrate central nervous system. In teleost fishes, RGCs play a pivotal role in neurogenesis and regeneration of injured neurons and glia. RGCs also exhibit resilience to environmental stressors like hypoxia via metabolic adaptations. In this study, we assessed the physiology of RGCs following varying degrees of hypoxia, with an emphasis on reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP), mitophagy, and energy metabolism. Our findings demonstrated that hypoxia significantly elevated ROS production and induced MMP depolarization in RGCs. The mitochondrial disturbances were closely associated with increased mitophagy, based on the co-localization of mitochondria and lysosomes. Key mitophagy-related genes were also up-regulated, including those of the BNIP3/NIX mediated pathway as well as the FUNDC1 mediated pathway. Such responses suggest robust cellular mechanisms are initiated to counteract mitochondrial damage due to increasing hypoxia. A significant metabolic shift from oxidative phosphorylation to glycolysis was also observed in RGCs, which may underlie an adaptive response to sustain cellular function and viability following a reduction in oxygen availability. Furthermore, hypoxia inhibited the synthesis of mitochondrial complexes subunits in RGCs, potentially related to elevated HIF-2α expression with 3 % O2. Taken together, RGCs appear to exhibit complex adaptive responses to hypoxic stress, characterized by metabolic reprogramming and the activation of mitophagy pathways to mitigate mitochondrial dysfunction.

EIF4E-independent translation is largely eIF3d-dependent

Translation initiation is a highly regulated step needed for protein synthesis. Most cell-based mechanistic work on translation initiation has been done using non-stressed cells growing in medium with sufficient nutrients and oxygen. This has yielded our current understanding of ‘canonical’ translation initiation, involving recognition of the mRNA cap by eIF4E1 followed by successive recruitment of initiation factors and the ribosome. Many cells, however, such as tumor cells, are exposed to stresses such as hypoxia, low nutrients or proteotoxic stress. This leads to inactivation of mTORC1 and thereby inactivation of eIF4E1. Hence the question arises how cells translate mRNAs under such stress conditions. We study here how mRNAs are translated in an eIF4E1-independent manner by blocking eIF4E1 using a constitutively active version of eIF4E-binding protein (4E-BP). Via ribosome profiling we identify a subset of mRNAs that are still efficiently translated when eIF4E1 is inactive. We find that these mRNAs preferentially release eIF4E1 when eIF4E1 is inactive and bind instead to eIF3d via its cap-binding pocket. eIF3d then enables these mRNAs to be efficiently translated due to its cap-binding activity. In sum, our work identifies eIF3d-dependent translation as a major mechanism enabling mRNA translation in an eIF4E-independent manner.

New Insights into the Connections between Flooding/Hypoxia Response and Plant Defenses against Pathogens.

The impact of global climate change has highlighted the need for a better understanding of how plants respond to multiple simultaneous or sequential stresses, not only to gain fundamental knowledge of how plants integrate signals and mount a coordinated response to stresses but also for applications to improve crop resilience to environmental stresses. In recent years, there has been a stronger emphasis on understanding how plants integrate stresses and the molecular mechanisms underlying the crosstalk between the signaling pathways and transcriptional programs that underpin plant responses to multiple stresses. The combination of flooding (or resulting hypoxic stress) with pathogen infection is particularly relevant due to the frequent co-occurrence of both stresses in nature. This review focuses on (i) experimental approaches and challenges associated with the study of combined and sequential flooding/hypoxia and pathogen infection, (ii) how flooding (or resulting hypoxic stress) influences plant immunity and defense responses to pathogens, and (iii) how flooding contributes to shaping the soil microbiome and is linked to plants' ability to fight pathogen infection.

Abstract We038: Metal-organic frameworks as next-generation cardiac therapeutics

Background: Zinc (Zn) is an essential trace element for the normal functioning of the heart. Long-term dietary supplementation of Zn has been shown to improve cardiac function and prevent myocardial damage caused by ischemia-reperfusion injury. However, the major limitation in delivering Zn to the cardiac tissue is the off-targeted absorption and the duration of treatment to achieve a therapeutic effect. Hypothesis: Cardiac-targeted delivery of trace elements like Zn may attenuate myocardial damage caused by ischemia-reperfusion injury, improve cardiac function, and exert a cardioprotective effect. Methods: Zn-based metal-organic frameworks (ZIF-NPs) were fabricated and tested on Microvascular Endothelial Cells (MVECs), and human-induced pluripotent derived cardiomyocytes (hiCMs) for cytoprotective effect against hypoxic stress using Live/dead assay and multi-electrode array (MEA) analysis respectively. The in vivo efficacy of ZIF-NPs was tested in the rodent myocardial infarction (MI) model and cardiac function was assessed via M-mode echocardiography. Results: The fabricated ZIF-NPs were biocompatible and showed significant intracellular uptake causing the induction of cytoprotective metallothioneins. ZIF-NP treatment showed enhanced cell survival in serum-starved MVECs and exhibited pro-angiogenic effects in vitro. Similarly, hiCMs treated with ZIF-NPs displayed enhanced endurance and electrophysiological function, when subjected to hypoxic stress and protected the cells against ROS-induced DNA damage. Intramyocardial delivery of ZIF-NPs in the cardiac tissue improved cardiac function and attenuated fibrosis post-MI. Conclusions: ZIF-NPs exerted a pro-survival, cytoprotective response in both in vitro and in vivo conditions. Our study highlights the significance of cardiac targeted Zn delivery by ZIF-NPs for cardioprotection as next-generation cardiac therapeutics.

Exosomal Preconditioning of Human iPSC-Derived Cardiomyocytes Beneficially Alters Cardiac Electrophysiology and Micro RNA Expression.

Experimental evidence, both in vitro and in vivo, has indicated cardioprotective effects of extracellular vesicles (EVs) derived from various cell types, including induced pluripotent stem cell-derived cardiomyocytes. The biological effects of EV secretion, particularly in the context of ischemia and cardiac electrophysiology, remain to be fully explored. Therefore, the goal of this study was to unveil the effects of exosome (EXO)-mediated cell-cell signaling during hypoxia by employing a simulated preconditioning approach on human-induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CMs). Electrophysiological activity of hIPSC-CMs was measured using a multielectrode array (MEA) system. A total of 16 h of hypoxic stress drastically increased the beat period. Moreover, hIPSC-CMs preconditioned with EXOs displayed significantly longer beat periods compared with non-treated cells after 16 h of hypoxia (+15.7%, p < 0.05). Furthermore, preconditioning with hypoxic EXOs resulted in faster excitation-contraction (EC) coupling compared with non-treated hIPSC-CMs after 16 h of hypoxia (-25.3%, p < 0.05). Additionally, microRNA (miR) sequencing and gene target prediction analysis of the non-treated and pre-conditioned hIPSC-CMs identified 10 differentially regulated miRs and 44 gene targets. These results shed light on the intricate involvement of miRs, emphasizing gene targets associated with cell survival, contraction, apoptosis, reactive oxygen species (ROS) regulation, and ion channel modulation. Overall, this study demonstrates that EXOs secreted by hIPSC-CM during hypoxia beneficially alter electrophysiological properties in recipient cells exposed to hypoxic stress, which could play a crucial role in the development of targeted interventions to improve outcomes in ischemic heart conditions.

Abstract Tu044: Cardiac Mitochondrial Dysfunction Induces Region-Specific Mitochondrial Stress Response In The Brain To Adapt Neuronal Changes

Background: The hippocampus and cortex are susceptible to changes in blood supply, metabolites, and oxygenation. However, how disrupted cardiac function affects these critical areas of the brain, leading to the cognitive and neurological consequences of heart failure, remains unclear. Hypothesis: We hypothesize that disrupted cardiac function cross-talks with the brain by inducing region-specific mitochondrial stress responses, leading to adaptive changes. Methods: We utilized cardiac-specific LonP1 knockout (LonP1cKO) mice to induce heart failure within 21 days of birth. Alongside cre- control mice, we assessed cerebral blood flow using Laser speckle contrast imaging, locomotor activity through a comprehensive laboratory animal monitoring system (CLAMS), and gene expression profiles in the hippocampus and cortex by RT-PCR. Student’s ‘t’ test determined statistical significance with a p-value&lt;0.05. Results: At 21 days, LonP1cKO mice demonstrated a significant (p&lt;0.0001) reduction in cerebral blood flow (587.1±33.68, n=7) compared to the control (1034±31.26, n=5). Additionally, there were notable decreases in both X and Y-axis ambulatory and total locomotor activities in LonP1cKO mice [XAMB (100.3±6.6 vs 224±13.6 n=16), YAMB) (67.9±4.7 vs 150±8.5 n=16), XTOT (351.8±18.1 vs 534.4±26.3 n=16) and YTOT (190.7±9.6 vs 354.9±17.07 n=16). RT-PCR analysis revealed significant upregulation of genes related to hypoxia and cellular stress (Hif1a, FGf2, Atf6), mitochondrial biogenesis (mtDNA, Tfam, mt-COI, mt-COII), mitochondrial stress response proteases (LonP1, Afg3l2, Spg7, Yme1l1), and downregulation in neurotrophic factors (Bdnf, Ngf, Gfap) in the hippocampus and cortex. Conclusion: The study highlights that cardiac dysfunction in LonP1cKO mice leads to mitochondrial and cellular stress response in the brain to adapt neuronal changes, suggesting a critical link between cardiac health and brain function regulated through mitochondrial stress response pathways.

Dynamic landscape of a competing endogenous RNA (ceRNA) network in Early-Onset Preeclampsia under hypoxia conditions

Objective: Early-onset preeclampsia (EOPE) manifests as elevated blood pressure and indications of organ damage, predominantly in the kidneys, in women before 34 weeks of gestation. A growing body of evidence suggests that hypoxia triggers a series of maladaptive responses culminating in the progression of EOPE. However, the precise mechanisms underlying these processes remain largely undefined. This study aimed to map the dynamic interplay within the competing endogenous RNA (ceRNA) network in EOPE under hypoxic conditions to provide insights into its molecular etiology. Methods: To investigate the oxidative stress response in EOPE, RNA sequencing data (ID: GSE119265) were retrieved from the Gene Expression Omnibus (GEO) database for exhaustive analysis. Oxygen-sensitive differential expressed genes (DEGs) were identified by comparing EOPE samples to controls at 5% and 20% O2 concentrations, respectively. Furthermore, the STRING database facilitated the construction of a protein-protein interaction network, highlighting critical hub genes among the identified DEGs. Results: An intricate ceRNA network encompassing four representative DEGs (AOC1, DCN, TGFB1, and SYNE3) and seven differentially expressed long non-coding RNAs (HCG27, MEG3, XIST, LINC01119, LINC00964, LINC01118, and LINC01588) was established. Conclusions: Our analysis revealed a set of long non-coding RNA that respond to hypoxic stress, shedding light on their possible roles in the oxygen-dependent pathophysiology of EOPE. These insights offer new avenues for targeted EOPE diagnosis and treatment. Further studies are required to elucidate their precise functions.

Hypoxia related genes modulate in similar fashion in skin fibroblast cells of yak (Bos grunniens) adapted to high altitude and native cows (Bos indicus) adapted to tropical climate during hypoxia stress.

The present study was conducted to understand transcriptional response of skin fibroblast of yak (Bos grunniens) and cows of Bos indicus origin to hypoxia stress. Six primary fibroblast cell lines derived from three individuals each of Ladakhi yak (Bos grunniens) and Sahiwal cows (Bos indicus) were exposed to low oxygen concentration for a period of 24h, 48h and 72h. The expression of 10 important genes known to regulate hypoxia response such as HIF1A, VEGFA, EPAS1, ATP1A1, GLUT1, HMOX1, ECE1, TNF-A, GPx and SOD were evaluated in fibroblast cells of Ladakhi yak (LAY-Fb) and Sahiwal cows (SAC-Fb) during pre- and post-hypoxia stress. A panel of 10 reference genes (GAPDH, RPL4, EEF1A1, RPS9, HPRT1, UXT, RPS23, B2M, RPS15, ACTB) were also evaluated for their expression stability to perform accurate normalization. The expression of HIF1A was significantly (p < 0.05) induced in both LAY-Fb (2.29-fold) and SAC-Fb (2.07-fold) after 24h of hypoxia stress. The angiogenic (VEGFA), metabolic (GLUT1) and antioxidant genes (SOD and GPx) were also induced after 24h of hypoxia stress. However, EPAS1 and ATP1A1 induced significantly (p < 0.05) after 48h whereas, ECE1 expression induced significantly (p < 0.05) at 72h after exposure to hypoxia. The TNF-alpha which is a pro-inflammatory gene induced significantly (p < 0.05) at 24h in SAC-Fb and at 72h in LAY-Fb. The induction of hypoxia associated genes indicated the utility of skin derived fibroblast as cellular model to evaluate transcriptome signatures post hypoxia stress in populations adapted to diverse altitudes.

Metabolic Reprogramming in Gliocyte Post-cerebral Ischemia/ Reperfusion: From Pathophysiology to Therapeutic Potential.

Ischemic stroke is a leading cause of disability and death worldwide. However, the clinical efficacy of recanalization therapy as a preferred option is significantly hindered by reperfusion injury. The transformation between different phenotypes of gliocytes is closely associated with cerebral ischemia/ reperfusion injury (CI/RI). Moreover, gliocyte polarization induces metabolic reprogramming, which refers to the shift in gliocyte phenotype and the overall transformation of the metabolic network to compensate for energy demand and building block requirements during CI/RI caused by hypoxia, energy deficiency, and oxidative stress. Within microglia, the pro-inflammatory phenotype exhibits upregulated glycolysis, pentose phosphate pathway, fatty acid synthesis, and glutamine synthesis, whereas the anti-inflammatory phenotype demonstrates enhanced mitochondrial oxidative phosphorylation and fatty acid oxidation. Reactive astrocytes display increased glycolysis but impaired glycogenolysis and reduced glutamate uptake after CI/RI. There is mounting evidence suggesting that manipulation of energy metabolism homeostasis can induce microglial cells and astrocytes to switch from neurotoxic to neuroprotective phenotypes. A comprehensive understanding of underlying mechanisms and manipulation strategies targeting metabolic pathways could potentially enable gliocytes to be reprogrammed toward beneficial functions while opening new therapeutic avenues for CI/RI treatment. This review provides an overview of current insights into metabolic reprogramming mechanisms in microglia and astrocytes within the pathophysiological context of CI/RI, along with potential pharmacological targets. Herein, we emphasize the potential of metabolic reprogramming of gliocytes as a therapeutic target for CI/RI and aim to offer a novel perspective in the treatment of CI/RI.

Autophagy in drusen biogenesis secondary to age-related macular degeneration.

Age-related macular degeneration (AMD) is an emerging cause of blindness in aged people worldwide. One of the key signs of AMD is the degeneration of the retinal pigment epithelium (RPE), which is indispensable for the maintenance of the adjacent photoreceptors. Because of impaired energy metabolism resulting from constant light exposure, hypoxia, and oxidative stress, accumulation of drusen in AMD-affected eyes is observed. Drusen contain damaged cellular proteins, lipoprotein particles, lipids and carbohydrates and they are related to impaired protein clearance, inflammation, and extracellular matrix modification. When autophagy, a major cellular proteostasis pathway, is impaired, the accumulations of intracellular lipofuscin and extracellular drusen are detected. As these aggregates grow over time, they finally cause the disorganisation and destruction of the RPE and photoreceptors leading to visual loss. In this review, the role of autophagy in drusen biogenesis is discussed since impairment in removing cellular waste in RPE cells plays a key role in AMD progression. In the future, means which improve intracellular clearance might be of use in AMD therapy to slow the progression of drusen formation.

Sexually Dimorphic Response to Hepatic Injury in Newborn Suffering from Intrauterine Growth Restriction.

Intrauterine growth restriction (IUGR), when a fetus does not grow as expected, is associated with a reduction in hepatic functionality and a higher risk for chronic liver disease in adulthood. Utilizing early developmental plasticity to reverse the outcome of poor fetal programming remains an unexplored area. Focusing on the biochemical profiles of neonates and previous transcriptome findings, piglets from the same fetus are selected as models for studying IUGR. The cellular landscape of the liver is created by scRNA-seq to reveal sex-dependent patterns in IUGR-induced hepatic injury. One week after birth, IUGR piglets experience hypoxic stress. IUGR females exhibit fibroblast-driven T cell conversion into an immune-adapted phenotype, which effectively alleviates inflammation and fosters hepatic regeneration. In contrast, males experience even more severe hepatic injury. Prolonged inflammation due to disrupted lipid metabolism hinders intercellular communication among non-immune cells, which ultimately impairs liver regeneration even into adulthood. Additionally, Apolipoprotein A4 (APOA4) is explored as a novel biomarker by reducing hepatic triglyceride deposition as a protective response against hypoxia in IUGR males. PPARα activation can mitigate hepatic damage and meanwhile restore over-expressed APOA4 to normal in IUGR males. The pioneering study offers valuable insights into the sexually dimorphic responses to hepatic injury during IUGR.

Environmental genome-wide association studies across precipitation regimes reveal that the E3 ubiquitin ligase MBR1 regulates plant adaptation to rainy environments

In an era characterized by rapidly changing and less-predictable weather conditions fueled by the climate crisis, understanding the mechanisms underlying local adaptation in plants is of paramount importance for the conservation of species. As the frequency and intensity of extreme precipitation events increase, so are the flooding events resulting from soil water saturation. The subsequent onset of hypoxic stress is one of the leading causes of crop damage and yield loss. By combining genomics and remote sensing data, it is now possible to probe natural plant populations that have evolved in different rainfall regimes and look for molecular adaptation to hypoxia. Here, using an environmental genome-wide association study (eGWAS) of 934 non-redundant georeferenced Arabidopsis ecotypes, we have identified functional variants of the gene MED25 BINDING RING-H2 PROTEIN 1 (MBR1). This gene encodes a ubiquitin-protein ligase that regulates MEDIATOR25 (MED25), part of a multiprotein complex that interacts with transcription factors that act as key drivers of the hypoxic response in Arabidopsis, namely the RELATED TO AP2 proteins RAP2.2 and RAP2.12. Through experimental validation, we show that natural variants of MBR1 have different effects on the stability of MED25 and, in turn, on hypoxia tolerance. This study also highlights the pivotal role of the MBR1/MED25 module in establishing a comprehensive hypoxic response. Our findings show that molecular candidates for plant environmental adaptation can be effectively mined from large datasets. This thus supports the need for integration of forward and reverse genetics with robust molecular physiology validation of outcomes.

Genome assembly of redclaw crayfish (Cherax quadricarinatus) provides insights into its immune adaptation and hypoxia tolerance

BackgroundThe introduction of non-native species is a primary driver of biodiversity loss in freshwater ecosystems. The redclaw crayfish (Cherax quadricarinatus) is a freshwater species that exhibits tolerance to hypoxic stresses, fluctuating temperatures, high ammonia concentration. These hardy physiological characteristics make C. quadricarinatus a popular aquaculture species and a potential invasive species that can negatively impact tropical and subtropical ecosystems. Investigating the genomic basis of environmental tolerances and immune adaptation in C. quadricarinatus will facilitate the development of management strategies of this potential invasive species.ResultsWe constructed a chromosome-level genome of C. quadricarinatus by integrating Nanopore and PacBio techniques. Comparative genomic analysis suggested that transposable elements and tandem repeats drove genome size evolution in decapod crustaceans. The expansion of nine immune-related gene families contributed to the disease resistance of C. quadricarinatus. Three hypoxia-related genes (KDM3A, KDM5A, HMOX2) were identified as being subjected to positive selection in C. quadricarinatus. Additionally, in vivo analysis revealed that upregulating KDM5A was crucial for hypoxic response in C. quadricarinatus. Knockdown of KDM5A impaired hypoxia tolerance in this species.ConclusionsOur results provide the genomic basis for hypoxic tolerance and immune adaptation in C. quadricarinatus, facilitating the management of this potential invasive species. Additionally, in vivo analysis in C. quadricarinatus suggests that the role of KDM5A in the hypoxic response of animals is complex.

Evaluation of diagnostic potential of maternal serum ischemia modified albumin in cases of pre-eclampsia.

The underlying causes and mechanisms of pre-eclampsia (PE), its exact etiology remains unclear and poorly understood. Hypoxia, ischemia, and oxidative stress induced by free radicals have been associated with development of PE. Ischemia-modified albumin (IMA) is a chemically modified albumin due to oxidative stress. IMA, a serum biomarker of hypoxia, ischemia, and oxidative free radicals is a potential biomarker for PE. The aim of the current proposal was to study serum IMA as a diagnostic biomarker of pre-eclampsia (PE) in pregnant females and to evaluate the correlation between serum IMA and different markers of pre-eclampsia (BP, urinary protein, LFT, KFT, serum total protein & uric acid). A total of 60 pregnant women aged between 21 and 35 years were recruited (30 PE cases and 30 normal pregnancy). Serum IMA was measured by spectrophotometric method developed by Bar-Or D. BP and biochemical parameters (urinary protein, LFT, KFT, serum total protein & uric acid) were also assayed and compared between two groups. Correlation analysis was done for analyzing the relationship between serum IMA and biochemical parameters. The mean serum IMA was significantly higher in normotensive pregnant females (0.93 ABSU) than PE cases (0.71 ABSU). Kidney function and liver function parameters were more deranged in PE cases than in controls. Serum IMA was positively correlated with serum creatinine (r=0.322), serum uric acid (r=0.54) and urinary protein (0.376) whereas negatively correlated with total serum bilirubin (r=-0.515) and serum albumin (r=-0.380). Elevated serum IMA concentrations in normotensive pregnant controls as compared to PE cases suggest that apart from ongoing ischemia and oxidative stress in placenta IMA values are influenced by many other mechanisms in pregnancy.

RNA-Seq and metabolomic analysis reveal dynamic response mechanism to hypoxia in the pearl oyster Pinctada fucata martensii

Hypoxia is becoming a stressor in aquatic environments due to human activities and climate change. To reveal the dynamic response mechanisms of pearl oyster, this study investigated transcriptomic and metabolomic changes in pearl oyster (Pinctada fucata martensii) exposed to hypoxia for 2 and 25 days. In total, 488 differentially expressed genes (DEGs) were detected between 2 and 25 days of hypoxia stress. The identified DEGs were primarily associated with Gene Ontology (GO) terms such as "histone H4 acetylation", "DNA methylation", "histone (H3-K9/H4-K20/H3-K27/H3-K4) trimethylation", "positive regulation of ATPase activity", "myosin complex", “microtubule-based processes", "actin cytoskeleton", and "glutathione peroxidase activity", as well as KEGG pathways such as "neuroactive ligand-receptor interactions", "ECM-receptor interactions", and "apoptosis". We also identified 77 significantly differential metabolites (SDMs), which were associated with 32 metabolic pathways, including arginine and proline metabolism, glycerophospholipid metabolism, aminoacyl-tRNA biosynthesis, and sphingolipid metabolism. Integrated DEGs and SDMs analyses showed that pearl oysters were found to suffer from reduced biomineralization, hindered cytoskeletal reorganization, decreased neuronal excitability, apoptosis, immune inhibition, and oxidative stress after 25 days of hypoxic stress. Overall, these results help to elucidate the complex responses of pearl oysters to hypoxic conditions.

Arachidonic acid metabolism regulates the development of retinopathy of prematurity among preterm infants.

Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP), characterized by neovascularization and neuroinflammation leading to blindness. Polyunsaturated fatty acid (PUFA) supplementation is recommended in preterm infants to lower the risk of ROP, however, with no significant improvement in visual acuity. Reasonably, this could be as a result of the non-consideration of PUFA metabolizing enzymes. We hypothesize that abnormal metabolism of the arachidonic acid (AA) pathway may contribute to severe stages of ROP. The present study investigated the AA-metabolizing enzymes in ROP pathogenesis by a targeted gene expression analysis of blood (severe ROP = 70, No/Mild = 56), placenta (preterm placenta = 6, full term placenta = 3), and human primary retinal cell cultures and further confirmed at the protein level by performing IHC in sections of ROP retina. The lipid metabolites were identified by LC-MS in the vitreous humor (VH; severe ROP = 15, control = 15). Prostaglandins D2 (p = 0.02), leukotrienes B5 (p = 0.0001), 11,12-epoxyeicosatrienoic acid (p = 0.01), and lipid-metabolizing enzymes of the AA pathway such as CYP1B1, CYP2C8, COX2, and ALOX15 were significantly upregulated while EPHX2 was significantly (0.04) downregulated in ROP cases. Genes involved in hypoxic stress, angiogenesis, and apoptosis showed increased expression in ROP. An increase in the metabolic intermediates generated from the AA metabolism pathway further confirmed the role of these enzymes in ROP, while metabolites for EPHX2 activity were low in abundance. Inflammatory lipid intermediates were higher compared to anti-inflammatory lipids in VH and showed an association with enzyme activity. Both the placenta of preterm infants who developed ROP and hypoxic retinal cultures showed a reduced expression of EPHX2. These findings suggested a strong involvement of EPHX2 in regulating retinal neovascularization and inflammation. The study results underscore the role of arachidonic acid metabolism in the development of ROP and as a potential target for preventing vision loss among preterm-born infants.