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The evolutionary outcomes of high elevation adaptation have been extensively described. However, whether widely distributed high elevation endemic animals adopt uniform mechanisms during adaptation to different elevational environments remains unknown, especially with respect to extreme high elevation environments. To explore this, we analysed the phenotypic and genomic data of seven populations of plateau zokor (Myospalax baileyi) along elevations ranging from 2,700 to 4,300 m. Based on whole-genome sequencing data and demographic reconstruction of the evolutionary history, we show that two populations of plateau zokor living at elevations exceeding 3,700 m diverged from other populations nearly 10,000 years ago. Further, phenotypic comparisons reveal stress-dependent adaptation, as two populations living at elevations exceeding 3,700 m have elevated ratios of heart mass to body mass relative to other populations, and the highest population (4,300 m) displays alterations in erythrocytes. Correspondingly, genomic analysis of selective sweeps indicates that positive selection might contribute to the observed phenotypic alterations in these two extremely high elevation populations, with the adaptive cardiovascular phenotypes of both populations possibly evolving under the functional constrains of their common ancestral population. Taken together, phenotypic and genomic evidence demonstrates that heterogeneous stressors impact adaptations to extreme elevations and reveals stress-dependent and genetically constrained adaptation to hypoxia, collectively providing new insights into the high elevation adaptation., (© 2021 John Wiley & Sons Ltd.)

Objective: This study aimed to investigate the feasibility of blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) to evaluate visceral adipose tissue (VAT) oxygenation in Zucker diabetic fatty (ZDF) rats and its associations with systemic metaflammation., Methods: Five-week-old ZDF rats and Zucker lean (ZL) rats were fed a high-fat diet (HFD) for 18 weeks. A baseline BOLD-MRI scan of perirenal adipose tissue was performed after 8 weeks of HFD feeding, and then the rats were randomized to receive pioglitazone or a vehicle for the following 10 weeks. At sacrifice, BOLD-MRI scan, Hypoxyprobe-1 injection, and circulating T helper 17 (Th17), regulatory T (Treg) cells, and monocyte subtype flow cytometry analysis were performed., Results: HFD feeding led to a significant increase in VAT BOLD-MRI R2* signals (20.14 ± 0.23 per second vs. 21.53 ± 0.20 per second; P = 0.012), an indicator for decreased oxygenation. R2* signal was significantly correlated with VAT pimonidazole adduct-positive area, insulin resistance, Th17 and Treg cells, CD43 + and CD43+ + monocyte subtypes, and VAT macrophage infiltration. Pioglitazone treatment improved the insulin resistance and was associated with a delayed progression of VAT oxygenation., Conclusions: This work demonstrated the feasibility of BOLD-MRI for detecting the VAT oxygenation status in ZDF rats, and the BOLD-MRI signals were associated with insulin resistance and systemic metaflammation in ZDF rats during the development of obesity., (© 2018 The Obesity Society.)

Heme oxygenase-1 (HO-1) is an inducible and cytoprotective enzyme that provides a defense against oxidant damage. The present study screened 137 HO-1/interacting proteins using a profound co-immunoprecipitation (Co-IP) coupled with proteomics, and profiled the global HO-1 interactome network, including oxidative phosphorylation, endoplasmic reticulum and transport vesicle functions. Among these molecules, we observed that a novel interactor, emopamil-binding protein (EBP), is closely related to the cholesterol metabolism process. This study demonstrated that cholesterol promotes excessive oxidative stress and alters the energy metabolism in cardiomyocytes, further triggering numerous cardiovascular diseases. We observed that cholesterol caused the overexpression of EBP and HO-1 by the activation of AKT and Nrf2/mTOR pathways. In addition, HO-1 and EBP performed a myocardial protective function. The overexpression of HO-1 alleviated the cholesterol-induced excessive oxidative stress status by inhibition of the carbohydrate metabolism. Notably, we also confirmed that the loss of partial HO-1 activity aggravated the oxidative damage and cardiac systolic function induced by a high-fat diet in HO-1 heterozygous (HO-1+/-) mice. These findings indicate that the HO-1/EBP interaction plays a protective role in alleviating the dysfunction of oxidative stress and cardiac systolic function induced by cholesterol stimulation.

The blind mole rat (BMR), Spalax galili, is an excellent model for studying mammalian adaptation to life underground and medical applications. The BMR spends its entire life underground, protecting itself from predators and climatic fluctuations while challenging it with multiple stressors such as darkness, hypoxia, hypercapnia, energetics and high pathonecity. Here we sequence and analyse the BMR genome and transcriptome, highlighting the possible genomic adaptive responses to the underground stressors. Our results show high rates of RNA/DNA editing, reduced chromosome rearrangements, an over-representation of short interspersed elements (SINEs) probably linked to hypoxia tolerance, degeneration of vision and progression of photoperiodic perception, tolerance to hypercapnia and hypoxia and resistance to cancer. The remarkable traits of the BMR, together with its genomic and transcriptomic information, enhance our understanding of adaptation to extreme environments and will enable the utilization of BMR models for biomedical research in the fight against cancer, stroke and cardiovascular diseases.

Objective: To investigate the feasibility of blood oxygen level dependent magnetic resonance imaging (BOLD-MRI) in evaluating human visceral adipose tissue (AT) oxygenation induced by salt loading/depletion and its association with changes in circulating monocyte subsets., Methods: A dietary intervention study was performed in 23 healthy volunteers beginning with a 3-day usual diet followed by a 7-day high-salt diet (≥15 g NaCl/day) and a 7-day low-salt diet (≤5 g NaCl/day). BOLD-MRI was used to evaluate oxygenation in perirenal AT., Results: Salt loading led to a consistent AT hypoxia (increase in the R2* signal, 25.2 ± 0.90 s(-1) vs. baseline 21.5 ± 0.71 s(-1) , P < 0.001) and suppression of circulating renin-angiotensin-aldosterone system (RAAS), as well as an expansion of the CD14++CD16+ monocytes and monocyte pro-inflammatory activation. In salt depletion phase, the hypoxic state of AT and the expanded CD14++CD16+ monocyte pool were regressed to baseline levels, accompanied by a rebound activation of RAAS. Moreover, AT oxygenation level was positively correlated with the CD14++CD16+ monocytes (r = 0.419, P < 0.001)., Conclusions: This work provides proof-of-principle evidence supporting the feasibility of BOLD-MRI in monitoring visceral AT oxygenation in humans induced by dietary salt loading/depletion. In addition, the CD14++CD16+ monocytes may participate in the pathogenesis of high-salt intake induced AT hypoxia., (Copyright © 2014 The Obesity Society.)

Abnormal phosphorylation of microtubule-associated protein tau plays a critical role in Alzheimer's disease (AD), together with a distinct decrease of energy metabolism in the affected brain regions. To explore the effect of acute energy crisis on tau phosphorylation and the underlying mechanisms, we incubated rat brain slices in artificial cerebrospinal fluid (aCSF) at 37 degrees C with or without an oxygen supply, or in aCSF with low glucose concentrations. Then, the levels of total, phosphorylated and unphosphorylated tau, as well as the activities and levels of protein phosphatase (PP)-1, PP-2A, glycogen synthase kinase 3 (GSK-3), extracellular signal-regulated protein kinase (ERK) and C-jun amino terminal kinase (JNK), were measured. It was found, unexpectedly, that tau was significantly dephosphorylated at Ser396/Ser404 (PHF-1), Ser422 (R145), Ser199/Ser202 (Tau-1), Thr181 (AT270), Ser202/Thr205 (AT8) and Thr231 (AT180) by acute anoxia for 30 min or 120 min. The activity of PP-2A and the level of dephosphorylated PP-2A catalytic subunit at tyrosine 307 (Tyr307) were simultaneously increased. The active forms of ERK1/2 and JNK1/2 were decreased under anoxic incubation. The PP-2A inhibitor, okadaic acid (OA, 0.75 microm), completely prevented tau from acute anoxia-induced dephosphorylation and restored the active forms of ERK1/2 and JNK1/2 to the control level. The activities and protein levels of GSK-3 and PP-1 showed no change during acute anoxia. These data suggest that acute anoxia induces tau dephosphorylation, and that PP-2A may play a key role in tau dephosphorylation induced by acute anoxia.

To investigate the feasibility of blood oxygen level dependent magnetic resonance imaging (BOLD-MRI) in evaluating human subcutaneous and visceral adipose tissue (AT) oxygenation status, as well as their responses to dietary salt loading/depletion, we enrolled 16 healthy subjects [mean body mass index (BMI): 24.8 ± 2.7 kg/m(2)] to conduct a dietary intervention study, beginning with a 3-day run-in period for usual diet, followed by a 7-day high-salt diet (≥ 15 g NaCl/day) and a 7-day low-salt diet (≤ 5 g NaCl/day). Abdominal BOLD-MRI scan was performed to evaluate oxygenation in waist subcutaneous and perirenal (visceral) AT. Two subjects with lower BMI were excluded because of the difficulty to identify subcutaneous AT. High salt diet led to a consistent increase in R2* signal (a parameter for increased hypoxia) both in subcutaneous and visceral AT (all P < 0.0001), which was completely regressed to baseline levels by low salt diet. In addition, subcutaneous AT R2* values at any time points, were all higher than that of visceral AT (all P < 0.0001). Pearson correlation analysis revealed that the visceral AT R2* levels were negatively associated obesity indicators (waist circumference, waist-to-hip ratio and BMI). On the contrary, although a trend towards negative associations between the subcutaneous AT R2* and obesity indicators was observed, none of the associations reached statistical significances. Thus, our data demonstrate the possibility of simultaneous detection of human subcutaneous and visceral AT oxygenation status using BOLD-MRI. In addition, there is a more close relationship visceral AT oxygenation status and the development of obesity.

Nitroreductase (NTR) is an important biomarker widely used to evaluate the degree of tumor hypoxia. Although a few optical methods have been reported for detecting nitroreductase at low concentration ranges, an effective strategy for nitroreductase monitoring in vivo without limits to the imaging depth is still lacking. Herein, a novel dual‐mode NIR fluorescence and 19F MRI agent, FCy7‐NO2, is proposed for imaging tumor hypoxia. We show that FCy7‐NO2 serves as not only a rapid NIR fluorescence enhanced probe for monitoring and bioimaging of nitroreductase in tumors, but also a novel 19F MR chemical shift‐sensitive contrast agent for selectively detecting nitroreductase catalyzed reduction. Notably, integrating two complementary imaging technologies into FCy7‐NO2 enables sensitive detection of nitroreductase in a broad concentration range without tissue‐depth limit. In general, this agent has a remarkable response to nitroreductase, which provides a promising method for understanding tumor evolution and its physiological role in the hypoxic microenvironment. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Wound dressings with multiple functions are required to meet the complexity of the wound healing process. The multifunctionality often leads to an increase in the complexity and difficulty in dressing preparation. To surmount this problem, we used a facile preparation and fabrication process to fabricate a multi-functional dressing by integrating four widely accessible materials: plain gauze, sodium alginate (SA), Ca2+ and Co2+. Firstly, mixed Ca2+/Co2+ ion solutions with different concentration were applied to gauzes. After drying, SA solution was added to ionized gauze and Co2+-Ca2+/Gauze/SA (Ion-GSA) composite dressings were formed easily. In vitro results showed that all Ion-GSA dressings exhibited strong mechanical properties, uniform dispersion and sustained release of Ca2+ and Co2+, and the ability to retain moisture and absorb wound exudate. Besides the above advantages, dressings prepared with 0.25 g/L Co2+ and 4 g/L Ca2+ (Co2+0.25-Ca2+4 GSA composite dressings) exhibited the best overall effect for inducing a hypoxia-like response, and favorable cytocompatibility, hemostatic property and antibacterial activity. In vivo wound healing assays revealed that Co2+0.25-Ca2+4 GSA composite dressings inhibited bacterial growth, increased local Hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1) protein expression, and accelerated full-thickness skin wound healing in mouse bacterial-infected wound model. The quick healing wounds had improved angiogenesis, macrophages regulation, re-epithelialization and dense collagen deposition. Collectively, our results indicated that Co2+0.25-Ca2+4 GSA composite dressings promote wound healing. Statement of Significance Wound dressings with integrated functionalities are required to meet complex clinical requirements. However, there is often a trade-off between reducing preparation complexity and increasing the multifunctionality of the dressing's properties. In this study, we prepared multifunctional composite dressings by a facile preparation process using widely accessible materials. The composite dressings possessed the mechanical strength of gauze, had the effective wound exudate absorption, moisture maintenance and hemostatic property capacity of calcium alginate hydrogels, and had the hypoxia-like induction and the antimicrobial effects of Co2+. These functions all together promote bacteria-infected wound healing. Thus, we believed that the composite dressings can be widely applied in skin wound repair duo to their facile preparation method and good therapeutic effect. [ABSTRACT FROM AUTHOR]

After acute wound formation, the oxygen supply is reduced, which results in the formation of an acute hypoxic microenvironment; whether this hypoxic microenvironment enhances epidermal cell migration and the underlying regulatory molecular mechanism of this effect are unclear. In this study, HaCaT cells were maintained under hypoxic (1% oxygen) or normoxic conditions. Methods including immunofluorescence staining, wound scratch assays, transwell assays, Western blotting and high‐ and low‐expression lentiviral vector transfection were utilized to observe the changes in cell migration, microtubule dynamics and the expression levels of microtubule‐associated protein (MAP) 4 and the light chain protein DYNLT1 (Tctex‐1). The possible mechanisms were studied and discussed. The results showed that epidermal cell migration was enhanced during early hypoxia. Further experiments revealed that MAP4 regulates microtubule dynamics and promotes epidermal cell migration through Tctex‐1. MAP4 and Tctex‐1 play important roles in regulating the migration of epidermal cells under hypoxia. This evidence will provide a basis for further revealing the cellular and molecular mechanisms of local wound hypoxia and for promoting wound healing. [ABSTRACT FROM AUTHOR]

Introduction:Hypoxia, a common feature of tumor microenvironment, is known to accelerate tumor development and growth by promoting the formation of a neoplastic environment. Recent studies have provided a wealth of evidence that miRNAs are significant members of the adaptive response to low oxygen in tumors. miR-210 is one of the hypoxia-induced miRNAs, which has been reported extensively in cancer researches. However, there is no systematic discussion about the role of miR-210 in gastrointestinal cancer. We conducted a literature research in database including PubMed, Elsevier Science Direct and Medline before 16 September 2016, in order to collect articles of miR-210 in gastrointestinal cancer. Areas covered:In the present review, we mainly discuss the following aspects: hypoxia-induced dysregulation of miR-210, the expression of miR-210 and tumorigenesis, the resultant changes of miR-210 targets and its roles in different types of gastrointestinal cancer progression, the diagnostic, therapeutic and prognostic value of miR-210 in gastrointestinal cancer. Expert commentary:Numerous researches have demonstrated the values of miR-210 in cancer diagnosis, prognosis and targeted therapies, especially in gastrointestinal cancers. However, there are also some existing problems and challenges in translating the new research findings into clinical utility. Further investigations and studies are still urgently required. [ABSTRACT FROM PUBLISHER]

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A bimodal imaging probe FCy7‐NO2 was applied to image nitroreductase overexpressed by lung cancer in vivo, as reported by Xin Zhou and co‐workers in their Research Article (e202213495). Integrating two complementary imaging technologies into FCy7‐NO2 enables sensitive detection of nitroreductase over a broad concentration range without tissue‐depth limit. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor-BB (PDGF-BB) plays a critical role in cell proliferation, angiogenesis and fibrosis. However, its exact role in cardiomyocytes exposed to hypoxia is not well known. This study was therefore designed to detect whether PDGF-BB expression was changed in a hypoxic condition, then the possible role of endogenous PDGF-BB in cardiomyocytes was explored, with interference RNA in a lentiviral vector ex vivo. The results showed that cultured cardiomyocytes exhibited an optimal proliferation from 3 to 10 days. However, LDH level was significantly increased but the heart rhythm was not altered in cardiomyocytes exposed to hypoxia for 24 hours. PDGF-BB expression was substantially upregulated in hypoxic cardiomyocytes. In order to know the role of PDGF-BB, we performed PDGF-BB knockdown in cultured cardiomyocytes. The number of apoptotic cells and the level of LDH were significantly increased but the beat rhythm was reduced in cardiomyocytes with PDGF-BB knockdown. These findings suggest that endogenous PDGF-BB exerts a crucial protective effect to cultured cardiomyocytes exposed to hypoxia. [ABSTRACT FROM AUTHOR]

Objective To investigate the changes in the migration and motility of epidermal cells cultured under hypoxic conditions and the role of Gαi1 in promoting these changes. Methods A workstation for live cell imaging was used to observe the changes in the migration and motility of HaCaT cells cultured under hypoxic conditions for 24 h in comparison with cells in routine culture. Microarray chip technique was used to screen the differentially expressed genes that participated in the regulation of cell migration early after hypoxia exposure; Western blotting, immunofluorescence assay and lentivirus-mediated siRNA transfection were used to explore the role of Gαi1 protein in regulating the migration of HaCaT cells under hypoxic conditions. Results The migration ability of HaCaT cells was significantly enhanced under hypoxic conditions, and their movement rate and movement persistence were increased obviously early after hypoxic exposure (in the first 12 h) compared with the cells in normoxic culture. Western blotting and immunofluorescence assay showed that the exposure to hypoxia caused over-expression of Gαi1 protein in HaCaT cells. RNA interference of Gαi1 protein significantly lowered the migration ability of the cells irrespective of normoxic and hypoxic exposures and also resulted in obviously lowered cell motility and movement persistence. Conclusion Short-term hypoxic exposure significantly enhances the migration and movement of epidermal cells, and Gαi1 protein plays an important role in promoting the migration of epidermal cells under hypoxia.