Hypoxia Tolerance Research Articles

Absence of heterosis for hypoxia tolerance in F1 hybrids of Tigriopus californicus.

Hybridization produces a range of outcomes from advantageous to disadvantageous, and a goal of genetic research is to understand the gene interactions that generate these outcomes. Interactions between cytoplasmic elements, such as mitochondria, and the nucleus may be particularly vulnerable to accruing disadvantageous combinations as a result of their different rates of evolution. However, mitonuclear incompatibilities often do not have an observable effect until the F2 and later generations. We used Tigriopus californicus, a model system for mitonuclear incompatibilities that is also known for exhibiting heterosis in the F1 generation, to test whether hypoxia was more stressful for mitonuclear interactions than other environmental stressors. We generated 284 parental and 436 F1 hybrids from four population crosses (720 total) and compared parental and F1 populations for hypoxia tolerance. We observed that, on average, F1 hybrids were less likely to survive a hypoxia stress test than parental populations (Parental:F1 coefficients ranged from -0.04 to 0.14 with none significantly different from 0). This suggests that hypoxia may be a particularly intense stressor for mitonuclear coordination, and that hybridization outcomes vary by trait.

Effects of acute hypoxia and reoxygenation on the coelomic fluid of Phascolosoma esculenta: Oxidative stress and transcriptome analysis

Phascolosoma esculenta is an economically species inhabiting a soft substrate of mud in the intertidal zone, which is bad breathability, especially during the prolonged heavy rainstorms, that will bring hypoxia environment to P. esculenta. In this study, the negative impact of hypoxia on P. esculenta was firstly studied. The results showed that there were no P. esculenta died post 7 days hypoxia. However, P. esculenta surface became black after hypoxia stress and changed to brown after reoxygenation. The body cavity fluid’s total antioxidant capacity (T-AOC) showed notable increases at 48 h, 120 h, and 168 h post hypoxia stress and returned to the control level after reoxygenation. The contents of malondialdehyde (MDA) increased significantly at 24 h, 48 h, and 96 h but decreased substantially after reoxygenation. The activity of lactate dehydrogenase (LDH) increased during the hypoxia but decreased significantly after reoxygenation. Transcriptomic analysis was performed and a total of 55.26 GB of clean data were collected, 362 DEGs were obtained based on FPKM values, including 77 DEGs between control and hypoxia groups, 48 DEGs between control and reoxygenation groups, and 237 DEGs between hypoxia and reoxygenation groups. DEGs are enriched in pathways associated with immune system, carbon metabolism, apoptosis, ribosome and ion transport. These data enriched the molecular mechanism of invertebrate hypoxia tolerance and provided genetic material reference for future breeding of hypoxia-tolerant P. esculenta and other aquatic species.

The Structure Analysis and mRNA Expression of CaV2 Gene Responding to Hypoxia Stress in Anadara granosa

The blood clam (Anadara granosa) is an economic bivalve that is relatively tolerant to hypoxia, but its molecular mechanism of hypoxia tolerance is unclear. We found that a significant decrease in extracellular Ca2+ concentration and a marked increase in intracellular Ca2+ concentration was observed in the blood clam through the fluorescence probe method, under hypoxic conditions at 0.5 mg/L. Concomitantly, there was a downward trend in the expression level of CaV2 mRNA, whereas NFAT (nuclear factor of activated T cells) expression increased by qRT-PCR. These findings suggest that the elevated intracellular Ca2+ concentration may activate negative transcription factors of NFAT, which subsequently suppresses the transcription of CaV2, leading to its decreased expression. Then, the NFAT RNA interference experiments supported this hypothesis. Sequence analysis and 3D structure prediction revealed conserved and mutated residue sites in blood clam compared to other bivalves. Hypoxia-induced changes in intracellular and extracellular Ca2+ concentrations, activating transcription factor NFAT and suppressing CaV2 expression. This study highlights the key roles of CaV2 and NFAT in hypoxia adaptation, paving the way for further exploration of hypoxia tolerance mechanisms in mollusca.

Identification of the effects of hypoxia on the liver tissues of Nile tilapia Oreochromis Niloticus

BackgroundHypoxia stress resulted in mortality during the fish aquaculture program, affecting the sustainable development of the aquaculture industry. The Egyptian strain of O. niloticus showed a strong ability to hypoxia. In this study, a Nile tilapia strain that was kept and selected for 45 years by the author’s team was used to elucidate the mechanism of the hypoxia response in the liver, including the identification of metabolic pathways and genes, involved in the hypoxia response of this strain.ResultsThe effects of hypoxia stress were detected at 0-hour, 6-hour, and 72-hour time points (0 h, 6 h, 72 h) on tilapia liver at 1 mg/L dissolved oxygen conditions. The blood triglyceride, blood glucose and cholesterol values exhibited significantly different change trends, but the hemoglobin content showed no significant differences between 0 h, 6 h and 72 h (P > 0.05). The activities of catalase (CAT), glutathione peroxidase (GSH-PX), total antioxidant capacity (T-AOC), lactate dehydrogenase (LDH), and acid phosphatase (ACP) in the liver tissue gradually increased at 0 h, 6 h and 72 h (P < 0.05). Histological analyses revealed structural changes in intracellular lipid droplets, nuclear migration and dissolution, and cell vacuolization in liver tissues. Six pathways were identified as the main enriched metabolic pathways according to the transcriptome profiling analysis, which were protein processing in endoplasmic reticulum, steroid biosynthesis, peroxisome, PPAR signaling pathway, glycolysis/gluconeogenesis and Insulin signaling pathway. The expressions of the important differentially expressed genes were verified by qPCR analysis, including erola, LOC100692144, sqle, cratb, pipox, cpt1a2b, hik and acss2l, ehhadh, prkcz, fasn and plaa, which showed the same expressions trends as those of RNA-Seq.ConclusionsThe Nile tilapia strain improves the abilities of hypoxia response through energy metabolism. Antioxidant enzyme measurements in the liver indicate that these five antioxidant enzymes play important roles in protecting the body from hypoxic damage. The histological changes in liver cells indicate that the damage caused by hypoxia stress. The immune-related metabolic pathways and energy metabolism-related pathways were obtained by transcriptome profiling, and these metabolic pathways and the differentially expressed genes selected from these metabolic pathways may be involved in the mechanism of hypoxia tolerance in this strain. These findings provide a better understanding of the hypoxia response mechanism of fish, and represent a useful resource for the genetic breeding of O. niloticus.

Common tenrecs (Tenrec ecaudatus) reduce oxygen consumption in hypoxia and in hypercapnia without concordant changes to body temperature or heart rate.

Common tenrecs (Tenrec ecaudatus) are fossorial mammals that use burrows during both active and hibernating seasons in Madagascar and its neighboring islands. Prevailing thought was that tenrecs hibernate for 8-9months individually, but 13 tenrecs were removed from the same sealed burrow 1m deep from the surface. Such group hibernation in sealed burrows presumably creates a hypoxic and/or hypercapnic environment and suggests that this placental mammal may have an increased tolerance to hypoxia and hypercapnia. Higher tolerances to hypoxia and hypercapnia have been documented for other mammals capable of hibernation and to determine if this is the case for tenrecs, we exposed them to acute hypoxia (4h of 16 or 7% O2), progressive hypoxia (2h of 16, 10 and 4% O2), or progressive hypercapnia (2h of 2, 5 and 10% CO2) at cold (16°C) or warm (28°C) ambient temperatures (Ta). Oxygen equilibrium curves were also constructed on the whole blood of tenrecs at 10, 25, and 37°C to determine if hemoglobin (Hb)-O2 affinity contributes to hypoxia tolerance. In animals held at 16°C, normoxic and normocapnic levels of oxygen consumption rate ( ), body temperature (Tb), and heart rate (HR) were highly variable between individuals. This inter-individual variation was greatly reduced in animals held at 28°C for oxygen consumption rate and body temperature. Both hypoxia (acute and progressive) and progressive hypercapnia led to decreases in as well as the variation in between animals held at 16°C. The fall in oxygen consumption rate in 7% O2 independent of changes in body temperature in tenrecs held at 16°C is unique and not consistent with the typical hypoxic metabolic response seen in other hibernating species that depends on concomitant falls in Tb. In animals held at 28°C, exposure to O2 levels as low as 4% and CO2 levels as high as 10% had no significant effect on , HR, or Tb, indicative of high tolerance to both hypoxia and hypercapnia. High variation in heart rate remained between individuals in all gas compositions and at all temperatures. Tenrec Hb-O2 affinity was similar to other homeothermic placental mammals and likely does not contribute to the increased hypoxia tolerance. Ultimately, our results suggest changes in Ta dictate physiological responses to hypoxia or hypercapnia in tenrecs, responses more characteristic of reptiles than of most placental mammals. Given that numerous anatomical and physiological characteristics of tenrecs suggest that they may be representative of an ancestral placental mammal, our findings suggest the typical hypoxic metabolic response evolved later in mammalian evolution.

Sodium Hydrosulfide Protects Rats from Hypobaric-Hypoxia-Induced Acute Lung Injury

Hydrogen sulfide (H2S), as a key gas signaling molecule, plays an important role in regulating various diseases, with appropriate concentrations providing antioxidative, anti-inflammatory, and anti-apoptotic effects. The specific role of H2S in acute hypoxic injury remains to be clarified. This study focuses on the H2S donor sodium hydrosulfide (NaHS) and explores its protective effects and mechanisms against acute hypoxic lung injury. First, various mouse hypoxia models were established to evaluate H2S’s protection in hypoxia tolerance. Next, a rat model of acute lung injury (ALI) induced by hypoxia at 6500 m above sea level for 72 h was created to assess H2S’s protective effects and mechanisms. Evaluation metrics included blood gas analysis, blood routine indicators, lung water content, and lung tissue pathology. Additionally, LC-MS/MS and bioinformatic analyses were combined in performing quantitative proteomics on lung tissues from the normoxic control group, the hypoxia model group, and the hypoxia model group with NaHS treatment to preliminarily explore the protective mechanisms of H2S. Further, enzyme-linked immunosorbent assays (ELISA) were used to measure oxidative stress markers and inflammatory factors in rat lung tissues. Lastly, Western blot analysis was performed to detect Nrf2, HO-1, P-NF-κB, NF-κB, HIF-1α, Bcl-2, and Bax proteins in lung tissues. Results showed that H2S exhibited significant anti-hypoxic effects in various hypoxia models, effectively modulating blood gas and blood routine indicators in ALI rats, reducing pulmonary edema, improving lung tissue pathology, and alleviating oxidative stress, inflammatory responses, and apoptosis levels.

Geography, altitude, agriculture and hypoxia.

Reduced oxygen availability (hypoxia) represents a key plant abiotic stress in natural and agricultural systems, but conversely it is also an important component of normal growth and development. We review recent advances that demonstrate how genetic adaptations associated with hypoxia impact the known plant oxygen sensing mechanism through the PLANT CYSTEINE OXIDASE (PCO) N-degron pathway. Only three protein substrates of this pathway have been identified, and all adaptations identified to date are associated with the most important of these, the group VII ETHYLENE RESPONSE FACTOR transcription factors (ERFVIIs). We discuss how geography, altitude, and agriculture have all shaped molecular responses to hypoxia, and how these responses have emerged at different taxonomic levels through the evolution of land plants. Understanding how ecological and agricultural genetic variation acts positively to enhance hypoxia tolerance will provide novel tools and concepts to improve the performance of crops in the face of increasing extreme flooding events.

Mechanisms of hypoxia (in)tolerance in prematurely born adults: PhD thesis (PhD Academy Award)

Mechanisms of hypoxia (in)tolerance in prematurely born adults: PhD thesis (PhD Academy Award)

Chromosome-Level Genome Assembly for the Chinese Serow (Capricornis milneedwardsii) Provides Insights Into Its Taxonomic Status and Evolution.

Chinese serow (Capricornis milneedwardsii) is mainly distributed in the south of Yellow River in China, which has been listed as vulnerable by the International Union for Conservation of Nature (IUCN). However, the reference genome of serow has not been reported and its taxonomic status is still unclear. Here, we first constructed a high-quality chromosome-level reference genome of C. milneedwardsii using PacBio long HiFi reads combined with Hi-C technology. The assembled genome was ~2.83 Gb in size, with a contig N50 of 100.96 Mb and scaffold N50 of 112.75 Mb, which were anchored onto 24 chromosomes. Furthermore, we found that the Chinese serow was more closely related to muskox, which diverged from ~4.85 million years ago (Mya). Compared to the karyotype of goat (2n = 60), we found the Chinese serow (2n = 48) experienced six chromosome fusions, which resulted in the formation of six central centromere chromosomes. We also identified two positively selected genes (MYH6 and DCSTAMP) specific to Chinese serow, which were involved in 'viral myocarditis' and 'Cardiac muscle contraction'. Interestingly, compared to other Caprinae animals, the MYH6 protein of Chinese serow occurred two mutations (E1520S and G1521S), which might be related to hypoxia tolerance. The high-quality reference genome of C. milneedwardsii provides a valuable information for protection of serows and insights into its evolution.

Whether hypoxia tolerance improved after short-term fasting is closely related to phylogeny but not to foraging mode in freshwater fish species.

The combined stresses of fasting and hypoxia are common events during the life history of freshwater fish species. Hypoxia tolerance is vital for survival in aquatic environments, which requires organisms to down-regulate their maintenance energetic expenditure while simultaneously preserving physiological features such as oxygen supply capacity under conditions of food deprivation. Generally, infrequent-feeding species who commonly experience food shortages might evolve more adaptive strategies to cope with food deprivation than frequent-feeding species. Thus, the present study aimed to test whether the response of hypoxia tolerance in fish to short-term fasting (2 weeks) varied with different foraging modes. Fasting resulted in similar decreases in maintenance energetic expenditure and similar decreases in Pcrit and Ploe between fishes with different foraging modes, whereas it resulted in decreased oxygen supply capacity only in frequent-feeding fishes. Furthermore, independent of foraging mode, fasting decreased Pcrit and Ploe in all Cypriniformes and Siluriformes species but not in Perciformes species. The mechanism for decreased Pcrit and Ploe in Cypriniformes and Siluriformes species is at least partially due to the downregulated metabolic demand and/or the maintenance of a high oxygen supply capacity while fasting. The present study found that the effect of fasting on hypoxia tolerance depends upon phylogeny in freshwater fish species. The information acquired in the present study is highly valuable in aquaculture industries and can be used for species conservation in the field.

Genomic analysis of hypoxia-tolerant population of the Chinese mitten crab (Eriocheir sinensis)

Hypoxic stress, triggered by a multitude of factors, has inflicted significant economic repercussions on the aquaculture of Eriocheir sinensis. In this research, we sequenced a collective of 60 samples from both hypoxia-sensitive and hypoxia-resistant groups utilizing streamlined genome sequencing techniques. Subsequently, we delved into population evolution, scrutinized the selective sweep within these populations, and performed a genome-wide association study (GWAS) focused on the hypoxia tolerance traits within the population, all through the lens of SNPs molecular markers. This comprehensive analysis aimed to uncover the SNPs and pinpoint the pertinent candidate genes that influence the hypoxia tolerance capabilities of E. sinensis. The selective sweep analysis revealed that genes harboring potential genetic variations within the two populations were predominantly enriched in areas such as signaling molecules and interactions, energy metabolism, glycolipid metabolism, and immune response. In the genome-wide association study focusing on hypoxia tolerance traits, we identified four SNPs significantly associated with hypoxia resistance. Furthermore, one potential candidate gene, Dscam2, which is believed to influence hypoxia tolerance, was discovered within a 50 kb vicinity of these SNPs. These identified SNPs can serve as molecular markers for screening hypoxia tolerance, offering valuable insights for the genetic improvement of E. sinensis.

Effects of Taurine and Vitamin C on the Improvement of Antioxidant Capacity, Immunity and Hypoxia Tolerance in Gibel Carp (Carrassius auratus gibeilo).

To investigate the effects of taurine and vitamin C on gibel carp (Carrassius auratus gibeilo), fish (41.85 ± 0.03 g) were fed three diets with 0% taurine + 0% vitamin C (D0), 0.1% taurine + 0% vitamin C (D1), and 0.1% taurine + 0.1% vitamin C (D2) for 8 weeks. Then 12-hour hypoxic stress test was conducted. The results showed that weight gain rate (WGR), specific growth rate (SGR), and sustained swimming time (SST) were significantly increased in the D2. CAT, SOD, T-AOC, and GSH were increased. GSH-Px and il-6 were decreased in D1 and D2. In hypoxia, CAT and T-AOC were decreased, while GSH, sod, and nrf2 were the highest in D1. Compared to normoxia, GSH-Px was increased, while SOD and MDA were decreased. Il-10 and nf-κb were increased. Vegf, epo, and ho-1 were increased and they all were higher than that in normoxia. The number of gill cell mitochondria and survival rate (SR) of gibel carp had an increasing trend but no significant difference among groups. In conclusion, taurine with vitamin C improved the growth and SST of gibel carp, and taurine and taurine with vitamin C improved antioxidant capacity, immunity, and hypoxia tolerance.

Thymus morphological characteristics in acute and chronic colitis in animals with different hypoxia tolerance

Hypoxia is connected with inflammation, and the severity of inflammatory diseases predominantly depends on individual tolerance to oxygen deficiency. Hypoxia-inducible factor, HIF-1, regulates the thymus functional state, and its activity varies in organisms with different hypoxia tolerance. It is likely that differences in individual hypoxia tolerance and the associated HIF-1 functional activity may influence the inflammatory diseases severity, such as acute and chronic ulcerative colitis. The study aim is to characterize the thymus morphological changes during acute and chronic colitis in animals with different hypoxia tolerance. The hypoxia tolerance of male C57Bl/6 mice was determined by “gasping time” at an “altitude” of 10,000 m in a decompression chamber. A month after determining hypoxia tolerance, the animals were modeled as acute colitis by replacing drinking water with a 1.5% dextran sulfate sodium for 5 days; the animals were removed from the experiment on the 7th day. Chronic colitis was modeled by animals consuming a 1% dextran sulfate sodium on days 1-4, 12-14 and 22-26; animals were removed from the experiment on the 60th day. The volume fraction of thymus structural and functional zones was assessed using the point counting method. The relative number of different thymic bodies types was assessed: consisting of 3-5 cells, 5 or more epithelial cells, with keratohyalin deposits and thymic bodies in the form of cyst-like cavities. During acute colitis, in the thymus only in susceptible mice, there was a significant cortex narrowing and an increase in the number of thymic bodies consisting of 5 or more cells. In chronic colitis, only in susceptible animals in comparison with the control group, the cortex volume fraction and the cortex to the medulla ratio increased significantly. In susceptible mice, the number of bodies with keratohyalin increased. In tolerant animals, the indicators did not change. Thus, differences in the thymus response to acute and chronic ulcerative colitis were identified between tolerant and susceptible to hypoxia animals. Only in susceptible mice, in acute colitis, was observed cortex narrowing, but in chronic colitis, cortex hyperplasia. The data obtained must be taken into account when conducting experimental studies of the thymus.

Evaluating the hypoxic tolerance of two maturity stages of Antarctic krill (Euphausia superba) at its range edge

AbstractThe South Georgia region of the Southern Ocean represents the northernmost range edge for Antarctic krill. Of concern is the extent to which rapid warming of surface water temperatures and reduced oxygen contents around this region might challenge the physiological tolerance of krill, particularly the later maturity stages. Hypoxia is generally considered to be less than 30 to 20% of air saturation, hereafter as threshold hypoxia, while less than 10% of air saturation would qualify as severe hypoxia. These levels are unlikely to occur in the Southern Ocean but might happen in the middle of dense krill swarms. We investigated gene expression and biochemical markers related to aerobic metabolism, antioxidant defence, and heat-shock response under 6-h threshold (4 kPa; TH) and 1-h severe (0.6 kPa; SH) hypoxia exposure, to understand how hypoxia might alter respiratory and biochemical pathways in adult and subadult krill. After 6-h TH, subadults induced expression of citrate synthase (CS), and mitochondrial superoxide dismutase (also after 1-h SH) over normoxic expression levels. The maturity stages responded differently in glutathione peroxidase (1-h SH; lower in subadults and higher in adults), and CS (6-h TH; higher in subadults and lower in adults) activities as for the oxidative damage marker to lipids (6-h TH; lower in subadults and higher in adults). Subadults had a greater capacity than adults to deal with hypoxic conditions. This may be a strategy allowing them to exist in larger swarms to reduce predation pressure before reaching reproductive condition.

Transcriptomic responses to hypoxia in two populations of eastern oyster with differing tolerance

The eastern oyster, Crassostrea virginica, is a keystone species native to the Gulf of Mexico and Atlantic coasts of the United States and Canada. It provides habitat for other marine organisms and makes up the majority of oyster production in the United States. Despite its tolerance to hypoxic conditions, C. virginica is threatened by anthropogenic climate change, which is increasing both average temperature and the frequency and severity of hypoxic events. In this study, we explore the differences in hypoxia-transcriptional response between two populations of eastern oysters with known differences in hypoxia tolerance at three time points over the course of a 5-day hypoxia treatment. We identified sets of genes involved in the hypoxia response and found differences in both the timing and baseline expression of hypoxia-responsive genes between tolerant and sensitive populations, consistent with a scenario of local adaptation. Analysis of differential gene expression between the two populations and conditions revealed two gene modules with higher baseline expression of hypoxia-sensitive genes in the more hypoxia tolerant population. Key GO terms for genes corresponding to differences between populations include DNA repair, ribosome biogenesis, and ribonucleotide binding. Our results imply that differences in hypoxia tolerance between populations could be due to genetic frontloading of hypoxia response pathways in the more tolerant population.

Development of a Cabbage Protoplast System for Studying Hypoxia Tolerance in Brassica.

As climate change brings more heavy rainfall, cabbage, a key Brassicaceae vegetable, faces significant yield losses due to flooding-induced hypoxia stress. To identify mechanisms of flooding tolerance in cabbages, a versatile platform for genetic functional studies is needed to overcome the transformation-recalcitrant nature of cabbages. In this study, a cabbage protoplast transient expression system and a corresponding protoplast hypoxia induction protocol were developed. This protocol achieved a high yield and integrity of protoplast isolation from cabbage leaves, with a transfection efficiency exceeding 40% using optimized enzymatic conditions. To alleviate potential hypoxic influence before treatments, the W5 solution was bubbled with oxygen gas to increase dissolved oxygen levels. Several chemicals for adjusting oxygen levels and physiological oxygen-scavenging treatments were tested, including EC-Oxyrase, OxyFluor, sodium sulfite, and an oxygen absorber pack. Dual-luciferase assays showed that promoters of anaerobic respiration response genes BoADH1 and BoSUS1L were activated in cabbage protoplasts after hypoxia treatments, with the highest induction level observed after treatment with the oxygen absorber pack. In summary, the cabbage protoplast transient expression system combined with hypoxia treatment demonstrates an efficient and convenient platform. This platform can facilitate studies of gene function and molecular mechanisms associated with hypoxia responses in cabbages.

FTO-mediated DSP m6A demethylation promotes an aggressive subtype of growth hormone-secreting pituitary neuroendocrine tumors

BackgroundGrowth hormone-secreting pituitary neuroendocrine tumors can be pathologically classified into densely granulated (DGGH) and sparsely granulated types (SGGH). SGGH is more aggressive and associated with a poorer prognosis. While epigenetic regulation is vital in tumorigenesis and progression, the role of N6-methyladenosine (m6A) in aggressive behavior has yet to be elucidated.MethodsWe performed m6A-sequencing on tumor samples from 8 DGGH and 8 SGGH patients, complemented by a suite of assays including ELISA, immuno-histochemistry, -blotting and -fluorescence, qPCR, MeRIP, RIP, and RNA stability experiments, aiming to delineate the influence of m6A on tumor behavior. We further assessed the therapeutic potential of targeted drugs using cell cultures, organoid models, and animal studies.ResultsWe discovered a significant reduction of m6A levels in SGGH compared to DGGH, with an elevated expression of fat mass and obesity-associated protein (FTO), an m6A demethylase, in SGGH subtype. Series of in vivo and in vitro experiments demonstrated that FTO inhibition in tumor cells robustly diminishes hypoxia resistance, attenuates growth hormone secretion, and augments responsiveness to octreotide. Mechanically, FTO-mediated m6A demethylation destabilizes desmoplakin (DSP) mRNA, mediated by the m6A reader FMR1, leading to prohibited desmosome integrity and enhanced tumor hypoxia tolerance. Targeting the FTO-DSP-SSTR2 axis curtailed growth hormone secretion, therefor sensitizing tumors to octreotide therapy.ConclusionOur study reveals the critical role of FTO in the aggressive growth hormone-secreting pituitary neuroendocrine tumors subtype and suggests FTO may represent a new therapeutic target for refractory/persistent SGGH.

Development of a sequential release nanomaterial for co-delivery of hypoxia-induced tirapazamine and HIF-1α siRNA in cancer therapy

Unlike traditional drug carriers, sequential drug delivery systems can release different drugs in order, with the first released drug providing a prerequisite for the later released drug to maximize its function, thereby achieving stronger anti-tumor effects. Herein we constructed a temporal sequential system designated TPZ@MSN/HIF-1α siRNA@PDA@GOx (MTRPG) in which mesoporous silica nanoparticles were used as cores to load hypoxia induced chemotherapy drug tirapazamine (TPZ) and gene targeted nucleic acid drug HIF-1α siRNA, polydopamine (PDA) as acid –responsive coating as well as to realize photothermal therapy, and glucose oxidase (GOx) as the outermost layer to achieve starvation therapy and construct a deepened hypoxia to activate TPZ. Through in vitro and in vivo experiments, we demonstrated that the first released glucose oxidase catalyzed the oxidation of glucose, achieving starvation treatment while reducing the acidic environment and further exacerbating hypoxia in tumor cells. The reduced acidic conditions enabled the degradation of PDA, resulting in the release of loaded HIF-1α siRNA and TPZ. At the same time, PDA could also exert photothermal therapy under 808 nm near-infrared (808 nm NIR) laser irradiation. The later released hypoxia induced chemotherapy drug TPZ amplifies its anti-tumor activity under intensified hypoxia conditions. Meanwhile, the released HIF-1α siRNA interfered with the up-regulated HIF-1α induced by the deepened hypoxia condition, which caused hypoxia tolerance in tumors, reduced its expression activity, and achieved synergistic killing of tumor cells with chemotherapy. This work provides an effective multimodal synergistic therapy strategy to promote tumor therapeutic index, which may possess a promising future in clinical application.

Sexual dimorphism in physiological responses of turbot (Scophthalmus maximus L) under acute hypoxia and reoxygenation

Dissolved oxygen (DO) is a crucial factor throughout fish life cycle. In this study, the hematology, hepatic antioxidant levels, histomorphology of the liver and gill were determined in both female and male turbot under acute hypoxia to evaluated the underlying mechanisms and potential sexual dimorphism difference. Results showed that acute hypoxia stress treatment for 3 h significantly increased plasma cortisol, glucose, hemoglobin (HGB), cholesterol (CHO), triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and hepatic malondialdehyde (MDA) contents, red blood cell count (RBC) number, hepatic superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), alanine-aminotransferase (ALT) and aspartate-aminotransferase (AST) activity in both male and female turbot. Male obtained higher plasma CHO, TG and LDL contents, GSH-Px and SOD activity than female under hypoxia. Meanwhile, hypoxia increased gill respiratory frequency, secondary lamellar length, secondary lamellar width, perimeter, lamellar surface area and gill surface area and decreased interlamellar distance. Acute hypoxia induced clubbing, hyperplasia, hypertrophy of gill filaments and hepatic vacuolization in both male and female turbot. The aforementioned parameters were recovered to normal levels after reoxygenation for 12 h. In conclusion, sex dimorphism difference of turbot hematological (RBC, HGB) and biochemical (glucose, CAT, GSH-Px, MDA) parameters were observed under hypoxia stress, while male demonstrated more hypoxia tolerance than female. These results help understand turbot hypoxia tolerance mechanisms and provide more data for management in captivity.

ERFVII-controlled hypoxia responses are in part facilitated by MEDIATOR SUBUNIT 25 in Arabidopsis thaliana.

Flooding impairs plant growth through oxygen deprivation, which activates plant survival and acclimation responses. Transcriptional responses to low oxygen are generally associated with the activation of group VII ETHYLENE-RESPONSE FACTOR (ERFVII) transcription factors. However, the exact mechanisms and molecular components by which ERFVII factors initiate gene expression are not fully elucidated. Here, we show that the ERFVII factors RELATED TO APETALA 2.2 (RAP2.2) and RAP2.12 cooperate with the Mediator complex subunit AtMED25 to coordinate gene expression under hypoxia in Arabidopsis thaliana. Respective med25 knock-out mutants display reduced low-oxygen stress tolerance. AtMED25 physically associates with a distinct set of hypoxia core genes and its loss partially impairs transcription under hypoxia due to decreased RNA polymerase II recruitment. Association of AtMED25 with target genes requires the presence of ERFVII transcription factors. Next to ERFVII protein stabilisation, also the composition of the Mediator complex including AtMED25 is potentially affected by hypoxia stress as shown by protein-complex pulldown assays. The dynamic response of the Mediator complex to hypoxia is furthermore supported by the fact that two subunits, AtMED8 and AtMED16, are not involved in the establishment of hypoxia tolerance, whilst both act in coordination with AtMED25 under other environmental conditions. We furthermore show that AtMED25 function under hypoxia is independent of ethylene signalling. Finally, functional conservation at the molecular level was found for the MED25-ERFVII module between A. thaliana and the monocot species Oryza sativa, pointing to a potentially universal role of MED25 in coordinating ERFVII-dependent transcript responses to hypoxia in plants.