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ECH was observed to inhibit [Ca2+]cyt increase in NE-induced PASMCs in a concentration-dependent manner, effectively reducing abnormal cell proliferation. It also reduced the expression of Transient receptor potential channel (TRPC) 1 (TRPC1), TRPC4, TRPC6, and calmodulin in PASMCs. In vivo studies demonstrated that ECH lowered the expression of these proteins in lung tissues of HPH rats, significantly decreased mean pulmonary artery pressure, and mitigated PVR.

Objective To explore the differences in mRNA expression profiles of ovarian cancer cells cultured in normoxic and hypoxic environments. Methods The ovarian cancer SKOV3 cells were cultured separately in low oxygen(2% oxygen) and normal oxygen(21% oxygen) environments.Oxygen probes were used to detect cellular hypoxia status.The whole mRNAs expressed within cells were detected using high-through RNA sequencing,and bioinformatics analysis tools were used to analyze gene expression differences and functional enrichment of the genes,and reverse transcription quantitative real-time PCR was used to further verify the related differential gene expression. Results Compared with cells cultured under normal oxygen,cells cultured under low oxygen environment showed a total of 999 significantly upregulated gene expressions and 646 significantly downregulated gene expressions.These differentially expressed genes were involved in biological processes such as extracellular matrix formation,cell adhesion,glycolysis,ciliary assembly,as well as signaling pathways such as cancer signaling,PI3K-AKT signaling,RNA transport,and tumor choline metabolism.The reverse transcription quantitative real-time PCR results confirmed that the expression of HILPDA,MT1B,CA9,MT1X and LOX-L2 genes in the hypoxic group were significantly higher than those in the normoxic group,while the expression of WARS1,CHAC1,PSAT1,UPP1 and DDX5 genes in the hypoxic group were significantly lower than those in the normoxic group. Conclusion This study revealed the differentially expressed genes and molecular pathways of mRNA transcription levels in ovarian cancer cells under different oxygen concentrations environments,providing an experimental basis for further exploring the potential molecular mechanisms of the impact of low oxygen environments on the growth of ovarian cancer.

Abstract Real‐time tracking of drug release from nanomedicine in vivo is crucial for optimizing its therapeutic efficacy in clinical settings, particularly in dosage control and determining the optimal therapeutic window. However, most current real‐time tracking systems require a tedious synthesis and purification process. Herein, a supramolecular nano‐tracker (SNT) capable of real‐time tracking of drug release in vivo based on non‐covalent host‐guest interactions is presented. By integrating multiple cavities into a single nanoparticle, SNT achieves co‐loading of drugs and probes while efficiently quenching the photophysical properties of the probe through host‐guest complexation. Moreover, SNT is readily degraded under hypoxic tumor tissues, leading to the simultaneous release of drugs and probes and the fluorescence recovery of probes. With this spatial and temporal consistency in drug loading and fluorescence quenching, as well as drug release and fluorescence recovery, SNT successfully achieves real‐time tracking of drug release in vivo (Pearson r = 0.9166, R2 = 0.8247). Furthermore, the released drugs can synergize effectively with fluorescent probes upon light irradiation, achieving potent chemo‐photodynamic combination therapy in 4T1‐bearing mice with a significantly improved survival rate (33%), providing a potential platform to significantly advance the development of nanomedicine and achieve optimal therapeutic effects in the clinic.

Haopeng Wang,1,* Hua Zhao,1,* Zheng Chen,1,* Xiaomin Cai,1 Xuhui Wang,1 Ping Zhou,1 Yinda Tang,1 Tingting Ying,1 Xin Zhang,1 Yiman Shen,1 Baimiao Wang,1 Wanchun Zhu,1 Jin Zhu,1 Xinjun Wang,2 Shiting Li1 1Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, People’s Republic of China; 2Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shiting Li, Department of Neurosurgery, Xinhua Hospital Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, 200092, People’s Republic of China, Email lishiting@xinhuamed.com.cn Xinjun Wang, Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China, Email wangxj@zzu.edu.cnBackground: Facial nerves have the potential for regeneration following injury, but this process is often challenging and slow. Schwann cells (SCs) are pivotal in this process. Bone mesenchymal stem cells (BMSC)-derived exosomes promote tissue repair through paracrine action, with hypoxic preconditioning enhancing their effects. The main purpose of this study was to determine whether hypoxia-preconditioned BMSC-derived exosomes (Hypo-Exos) exhibit a greater therapeutic effect on facial nerve repair/regeneration and reveal the mechanism.Methods: CCK-8, EdU, Transwell, and ELISA assays were used to evaluate the functions of Hypo-Exos in SCs. Histological analysis and Vibrissae Movements (VMs) recovery were used to evaluate the therapeutic effects of Hypo-Exos in rat model. circRNA array was used to identify the significantly differentially expressed exosomal circRNAs between normoxia-preconditioned BMSC-derived exosomes (Nor-Exos) and Hypo-Exos. miRDB, TargetScan, double luciferase assay, qRT-PCR and WB were used to predict and identify potential exosomal cirRNA_Nkd2-complementary miRNAs and its target gene. The function of exosomal circRNA_Nkd2 in facial nerve repair/regeneration was evaluated by cell and animal experiments.Results: This study confirmed that Hypo-Exos more effectively promote SCs proliferation, migration, and paracrine function, accelerating facial nerve repair following facial nerve injury (FNI) compared with Nor-Exos. Furthermore, circRNA analysis identified significant enrichment of circRNA_Nkd2 in Hypo-Exos compared with Nor-Exos. Exosomal circRNA_Nkd2 positively regulates mediator complex subunit 19 (MED19) expression by sponging rno-miR-214-3p.Conclusion: Our results demonstrated a mechanism by which Hypo-Exos enhanced SCs proliferation, migration, and paracrine function and facial nerve repair and regeneration following FNI through the circRNA_Nkd2/miR-214-3p/Med19 axis. Hypoxic preconditioning is an effective and promising method for optimizing the therapeutic action of BMSC-derived exosomes in FNI. Keywords: hypoxic, BMSCs, exosomes, Schwann cells, facial nerve injury

Objectives: To analyze the impact of exercise under hypoxic exposure versus normoxic exposure on blood glucose level, insulin level, and insulin sensitivity in people at risk of Type 2 diabetes mellitus (T2DM). Materials and Methods: We systematically performed electronic searching on PubMed, Web of Science, ProQuest, and Scopus. Primary studies that met the inclusion criteria were analyzed using Revman 5.4.1. Results: Nine randomized controlled trials were included in this meta-analysis. We found that physical exercise under hypoxic exposure had no significant effect on improving blood glucose levels, insulin levels, and insulin sensitivity in the elderly and sedentary people compared to normoxic condition. However, physical exercise during hypoxic exposure had a significant effect on lowering blood glucose levels in overweight/obese individuals (pooled Standardized Mean Difference = 0.29; 95% confidence interval = 0.01–0.57; P = 0.04). Conclusions: Exercising under hypoxic exposure can be an alternative strategy for reducing blood glucose levels in overweight/obese people. Nevertheless, in other populations at risk of T2DM, exercising in hypoxic conditions gives similar results to normoxic conditions.

Background: As an important monitoring index for adaptation to hypoxia, sleep may reflect the adaptive state of the body at high altitudes. The literature has shown a link between altitude and sleep problems, and sleep changes have become a common problem for individuals at high altitudes, negatively impacting their physical and mental health. As research on high-altitude sleep has gained attention in recent years, the publishing volume has increased worldwide, necessitating a more comprehensive understanding of this field. This manuscript evaluates the key themes and emerging trends in high-altitude sleep over the past few decades and predicts future research directions. Methods: Articles related to high-altitude sleep published from 1992 to 2022 were retrieved from the Web of Science Core Collection, and the relevant literature characteristics were extracted after the screening. Then, bibliometric analyses and visualizations were performed using Microsoft Excel, CiteSpace, VOSviewer, and an online analysis platform (http://bibliometric.com). Results: A total of 1151 articles were retrieved, of which 368 were included in the analysis, indicating a gradually increasing trend. The United States, Switzerland, and China have made significant contributions in this field. Bloch KE from the University of Zurich was determined to be the most productive and academically influential author in this field. The highest-yielding journal was High Altitude Medicine & Biology. Initially, altitude training was the primary research topic. Currently, research focuses on sleep disorders and sleep apnea. In the coming years, keywords such as “sleep quality,” “prevalence,” and “obstructive sleep apnea” will attract more attention. Conclusion: Our findings will assist scholars to better understand the intellectual structure and emerging trends in this field. Future developments in high-altitude sleep research are highly anticipated, particularly in terms of sleep quality at high altitudes and its associated prevalence. This research is also crucial for the improvement and treatment of symptoms during nocturnal sleep in patients with chronic hypoxia due to cardiopulmonary diseases at high altitudes.

IntroductionThe Caspian Sea is the world’s largest landlocked saline lake which lies between Europe and Asia. This region is particularly known for its large-scale oil reserves, pipelines, and drilling activities, which have contributed to the environmental decline of this lake. In addition to pollution from the petroleum industry, drainage from various river basins brings an influx of residential, industrial, and agricultural effluents that induce eutrophication and hypoxic conditions in deeper, colder waters, creating an oxygen gradient. The temperature and oxygen stratification in this environment has presented a unique opportunity to investigate the potential of the biodegradative processes carried out by the indigenous microbial community. We believe these indigenous microbes possess different metabolic capabilities to degrade oil as they adapted to declining oxygen concentrations and temperatures with increasing depths over a prolonged period. Hence, community structure and composition will vary with depth.MethodsMicrocosms were set up to observe the indigenous microbial reaction after a 60 ppm native crude oil amendment over 115 days. Surface water microcosms were incubated at 28ºC and aerated while deep water microcosms were incubated at 8ºC under anaerobic conditions. These two environmental conditions represent the temperature and oxygen extremes along the gradient and were selected as we try to simulate the indigenous community’s response to this oil contamination. DNA was extracted and amplified from these microcosms and sequenced. Bioinformatic analysis was performed to track changes in the abundance of taxa present and biodiversity over different time points to show the progression of community structure.ResultsAll microcosms showed the presence of hydrocarbon-degrading phyla, whose presence is consistent with other reports from oil-enriched environments. However, distinct communities were observed in oxic versus hypoxic microcosms.ConclusionOrders of Bacteria related to sulfate and nitrogen cycling were found in hypoxic microcosms, indicating a possible mechanism for the anaerobic biodegradation of crude oil. GC-MS analysis of initial and final microcosms also provided evidence of degradation of hydrocarbon fractions in both warm, oxic and cold, hypoxic conditions.

Hypoxia, a primary stimulus for angiogenesis, is important for tumour proliferation and survival. The effects of hypoxia on parathyroid tumour cells, which may also be important for parathyroid autotransplantation in patients, are, however, unknown. We, therefore, assessed the effects of hypoxia on gene expression in parathyroid adenoma (PA) cells from patients with primary hyperparathyroidism. Cell suspensions from human PAs were cultured under normoxic or hypoxic conditions and then subjected to cDNA expression analysis. In total, 549 genes were significantly upregulated and 873 significantly downregulated. The most highly upregulated genes (carbonic anhydrase 9 (CA9), Solute carrier family 2A1 (SLC2A1) and hypoxia-inducible lipid droplet-associated protein (HIG2)) had known involvement in hypoxia responses. Dysregulation of oxidative phosphorylation and glycolysis pathway genes were also observed, consistent with data indicating that cells shift metabolic strategy of ATP production in hypoxic conditions and that tumour cells predominantly utilise anaerobic glycolysis for energy production. Proliferation- and angiogenesis-associated genes linked with growth factor signalling, such as mitogen-activated protein kinase kinase 1 (MAP2K1), Jun proto-oncogene (JUN) and ETS proto-oncogene 1 (ETS1), were increased, however, Ras association domain family member 1 (RASSF1), an inhibitor of proliferation was also upregulated, indicating these pathways are unlikely to be biased towards proliferation. Overall, there appeared to be a shift in growth factor signalling pathways from Jak-Stat and Ras signaling to extracellular signal-regulated kinases (ERKs) and hypoxia-inducible factor (HIF)-1α signalling. Thus, our data demonstrate that PAs, under hypoxic conditions, promote the expression of genes known to stimulate angiogenesis, as well as undergoing a metabolic switch.

Hypoxia in disease describes persistent low oxygen conditions, observed in a range of pathologies, including cancer. In the discovery of biomarkers in biological models, pathophysiological traits present a source of translatable metabolic products for the diagnosis of disease in humans. Part of the metabolome is represented by its volatile, gaseous fraction; the volatilome. Human volatile profiles, such as those found in breath, are able to diagnose disease, however accurate volatile biomarker discovery is required to target reliable biomarkers to develop new diagnostic tools. Using custom chambers to control oxygen levels and facilitate headspace sampling, the MDA-MB-231 breast cancer cell line was exposed to hypoxia (1% oxygen) for 24 h. The maintenance of hypoxic conditions in the system was successfully validated over this time period. Targeted and untargeted gas chromatography mass spectrometry approaches revealed four significantly altered volatile organic compounds when compared to control cells. Three compounds were actively consumed by cells: methyl chloride, acetone and n-Hexane. Cells under hypoxia also produced significant amounts of styrene. This work presents a novel methodology for identification of volatile metabolisms under controlled gas conditions with novel observations of volatile metabolisms by breast cancer cells.

Objective To explore the changes in the transcription levels of microRNAs(miRNAs) in endometrial glandular epithelial cells (EECs) under hypoxia and their effects on apoptosis. Methods EECs were seeded into six-well plates in logarithmic growth phase(1×105 cells/well), and divided into two groups: hypoxia group and control group. The cells in both hypoxia group and the control group were placed in a hypoxic environment (the volume ratio of O2∶N2∶CO2 was 1∶94∶5) and cultured in normoxic environment (O2∶CO2 volume ratio of 95∶5). All cells were collected after they were cultured 4 h, and Trizol was added into the cells and total RNAs were extracted. High-throughput sequencing was used to detect the changes of miRNAs expression profiles in the two groups of EECs. Subsequently, realtime fluorescence quantitative polymerase chain reaction (RT-PCR) was used to detect the gene expression of miR-7704 and miR-7974. Flow cytometry was used to detect the apoptosis of EECs. The protein expression changes of p53 and apoptosis-related proteins were detected by Western blot. Results High-throughput sequencing detected the expression levels of 21 common miRNAs. Compared with the control group, 16 miRNAs were up-regulated and 5 miRNAs were down-regulated in the EECs of the hypoxia group; the expression of miR-7704 and miR-7974 decreased most significantly in the hypoxia group(all P < 0.05). RT-PCR results showed that compared with the control group, the relative expression levels of miR-7704 and miR-7974 in EECs of the hypoxia group decreased by 20% and 80%, respectively. The results of flow cytometry showed that the ratio of early apoptotic cells and late apoptotic cells in the hypoxia group was higher than that in the control group (all P < 0.001). The results of Western blot showed that the expression of p53 in EECs in the hypoxia group increased, and the expression of the anti-apoptotic protein B-cell lymphoma-2 decreased compared with the control group(all P < 0.05). Conclusions Hypoxic environment can induce changes in the expression profile of miRNAs in EECs, among which the down-regulation of miR-7974 is the most significant. p53 may be the target protein of miR-7974, and hypoxia-induced EEC apoptosis may be achieved by down-regulating the level of miR-7974 and promoting the expression of p53.

Abstract Background Renal fibrosis is a common pathological process of chronic kidney diseases induced by multiple factors. Hypoxic pretreatment of mesenchymal stem cells can enhance the efficacy of secreted extracellular vesicles (MSC-EVs) on various diseases, but it is not clear whether they can better improve renal fibrosis. The latest research showed that recovery of fatty acid oxidation (FAO) can reduce renal fibrosis. In this study, we aimed to examine whether hypoxic pretreatment with MSC extracellular vesicles (Hypo-EVs) can improve FAO to restore renal fibrosis and to investigate the underlying mechanism. Methods Hypo-EVs were isolated from hypoxia-pretreated human placenta-derived MSC (hP-MSC), and Norm-EVs were isolated from hP-MSC cultured under normal conditions. We used ischemia–reperfusion (I/R)-induced renal fibrosis model in vivo. The mice were injected with PBS, Hypo-EVs, or Norm-EVs immediately after the surgery and day 1 postsurgery. Renal function, kidney pathology, and renal fibrosis were assessed for kidney damage evaluation. For mechanistic exploration, fatty acid oxidation (FAO), mitochondrial morphological alterations, ATP production and mitochondrial mass proteins were detected in vivo. Mitochondrial membrane potential and reactive oxygen species (ROS) production were investigated in vitro. Results We found that Hypo-EVs confer a superior therapeutic effect on recovery of renal structure damage, restoration of renal function and reduction in renal fibrosis. Meanwhile, Hypo-EVs enhanced mitochondrial FAO in kidney by restoring the expression of a FAO key rate-limiting enzyme carnitine palmitoyl-transferase 1A (CPT1A). Mechanistically, the improvement of mitochondrial homeostasis, characterized by repaired mitochondrial structure, restoration of mitochondrial mass and ATP production, inhibition of oxidative stress, and increased mitochondrial membrane potential, partially explains the effect of Hypo-EVs on improving mitochondrial FAO and thus attenuating I/R damage. Conclusions Hypo-EVs suppress the renal fibrosis by restoring CPT1A-mediated mitochondrial FAO, which effects may be achieved through regulation of mitochondrial homeostasis. Our findings provide further mechanism support for development cell-free therapy of renal fibrosis.

Hypoxia, or dissolved oxygen (DO) at low enough levels to impair organisms, is a particularly useful indicator of the health of freshwater ecosystems. However, due to limited sampling in headwater networks, the degree, distribution, and timing of hypoxia events are not known across the vast majority of most river networks. We thus sought to clarify the extent of hypoxia in headwater networks through three years of instrumentation of 78 sites across eight temperate, agricultural watersheds. We observed broadly distributed hypoxia, occurring 4 % of the time across 51 of the 78 sites over 20 months. The hypoxia was driven by three mechanisms: storm events, drying, and rewetting, with drying as the most common driver of hypoxia (55 % of all hypoxic event types). Drying induced hypoxia was most severe in smaller streams (Strahler orders ≤ 3), whereas storm events preferentially induced hypoxia in the larger streams (Strahler orders 3–5). A large diversity in DO trajectories towards hypoxia depended on hydrologic event type, with subsequent expected differences in mortality profiles of a sensitive species. Predictive models showed the most vulnerable sites to hypoxia were small streams with low slope, particularly during hot, low discharge periods. Despite variation among hypoxic events, there was remarkable similarity in the rate of DO drawdown during hypoxia events (ca. 1 mg O2 L−1 d−1). This drawdown similarity may be a useful rule-of-thumb for managers, and we hypothesize that it is either a signal of increasing lateral inflow of low DO water or a signal of increasing downstream oxygen demand. Overall, we posit that hypoxia is likely a common feature of most headwater networks that often goes undetected. Headwater hypoxia may become more common under increasingly dry conditions associated with climate and water resource management changes, with important implications for biological communities and biogeochemical processes.

Background: Severe acute respiratory illness caused by SARS-CoV-2 has been a health emergency of great concern in the year 2020. This study was undertaken to identify characteristics of hospitalized patients with Coronavirus Disease 19 (COVID-19) and hypoxia in the form of disease course and outcome with special reference to the presence or absence of comorbidities. Materials and Methods: A prospective observational study was conducted at a tertiary hospital recognized as Dedicated COVID Hospital during the period of June 2020 to September 2020. The study included a total of 249 patients of COVID-19 with hypoxia who required oxygen or noninvasive ventilation/invasive ventilation. Patients were divided into two groups as per the presence or absence of comorbidity (175 and 74 patients, respectively). Their clinical and laboratory findings, course in the hospital, and outcomes were noted. Data were analyzed using SPSS software. Results: Among all the study patients, more patients from comorbidity group presented with a N:L ratio >3.5 and raised inflammatory markers (like serum ferritin) than patients in the no comorbidity group. In patients with comorbidities, 47.43% required noninvasive or invasive ventilation as against 18.92% in those without any comorbidities. Development of deranged renal function was noted in 32.57% of patients in the comorbidity group and only 9.46% in the noncomorbid group. All except one death during the study period were in the patients with comorbidities. Conclusion: COVID-19 patients with hypoxia and the presence of comorbidities in this study had more complications and a worse outcome.

Abstract Background The study was performed to evaluate the feasibility of utilizing small intestinal submucosa (SIS) scaffolds seeded with adipose-derived mesenchymal stem cells (ADMSCs) for engineered tendon repairing rat Achilles tendon defects and to compare the effects of preconditioning treatments (hypoxic vs. normoxic) on the tendon healing. Methods Fifty SD rats were randomized into five groups. Group A received sham operation (blank control). In other groups, the Achilles tendon was resected and filled with the original tendon (Group B, autograft), cell-free SIS (Group C), or SIS seeded with ADMSCs preconditioned under normoxic conditions (Group D) or hypoxic conditions (Group E). Samples were collected 4 weeks after operation and analyzed by histology, immunohistochemistry, and tensile testing. Results Histologically, compared with Groups C and D, Group E showed a significant improvement in extracellular matrix production and a higher compactness of collagen fibers. Group E also exhibited a significantly higher peak tensile load than Groups D and C. Additionally, Group D had a significantly higher peak load than Group C. Immunohistochemically, Group E exhibited a significantly higher percentage of MKX + cells than Group D. The proportion of ADMSCs simultaneously positive for both MKX and CM-Dil observed from Group E was also greater than that in Group D. Conclusions In this animal model, the engineered tendon grafts created by seeding ADMSCs on SIS were superior to cell-free SIS. The hypoxic precondition further improved the expression of tendon-related genes in the seeded cells and increased the rupture load after grafting in the Achilles tendon defects.

Abstract Background The administration of mesenchymal stem cells (MSCs) remains the most promising approach for cardiac repair after myocardial infarct (MI). However, their poor survival and potential in the ischemic environment limit their therapeutic efficacy for heart repair after MI. The purpose of this study was to investigate the influence of FoxC1-induced vascular niche on the activation of octamer-binding protein 4 (Oct4) and the fate of MSCs under hypoxic/ischemic conditions. Methods Vascular microenvironment/niche was induced by efficient delivery of FoxC1 transfection into hypoxic endothelial cells (ECs) or infarcted hearts. MSCs were cultured or injected into this niche by utilizing an in vitro coculture model and a rat MI model. Survival and neovascularization of MSCs regulated by Oct4 were explored using gene transfer and functional studies. Results Here, using gene expression heatmap, we demonstrated that cardiac ECs rapidly upregulated FoxC1 after acute ischemic cardiac injury, contributing to an intrinsic angiogenesis. In vitro, FoxC1 accelerated tube-like structure formation and increased survival of ECs, resulting in inducing a vascular microenvironment. Overexpression of FoxC1 in ECs promoted survival and neovascularization of MSCs under hypoxic coculture. Overexpression of Oct4, a FoxC1 target gene, in MSCs enhanced their mesenchymal-to-endothelial transition (MEndoT) while knockdown of Oct4 by siRNA altering vascularization. In a rat MI model, overexpression of FoxC1 in ischemic hearts increased post-infarct vascular density and improved cardiac function. The transplantation of adOct4-pretreated MSCs into these ischemic niches augments MEndoT, enhanced vascularity, and further improved cardiac function. Consistently, these cardioprotective effects of FoxC1 was abrogated when Oct4 was depleted in the MSCs and was mimicked by overexpression of Oct4. Conclusions Together, these studies demonstrate that the FoxC1/Oct4 axis is an essential aspect for survival and neovascularization of MSCs in the ischemic conditions and represents a potential therapeutic target for enhancing cardiac repair.

ABSTRACT Mice are frequently used as animal models for mechanistic studies of infection and obstetrical disease, yet characterization of the murine microbiota during pregnancy is lacking. The objective of this study was to characterize the microbiotas of distinct body sites of the pregnant mouse—vagina, oral cavity, intestine, and lung—that harbor microorganisms that could potentially invade the murine amniotic cavity, thus leading to adverse pregnancy outcomes. The microbiotas of these body sites were characterized through anoxic, hypoxic, and oxic culture as well as through 16S rRNA gene sequencing. With the exception of the vagina, the cultured microbiotas of each body site varied by atmosphere, with the greatest diversity in the cultured microbiota appearing under anoxic conditions. Only cultures of the vagina were comprehensively representative of the microbiota observed through direct DNA sequencing of body site samples, primarily due to the predominance of two Rodentibacter strains. Identified as Rodentibacter pneumotropicus and Rodentibacter heylii, these isolates exhibited predominance patterns similar to those of Lactobacillus crispatus and Lactobacillus iners in the human vagina. Whole-genome sequencing of these Rodentibacter strains revealed shared genomic features, including the ability to degrade glycogen, an abundant polysaccharide in the vagina. In summary, we report body site-specific microbiotas in the pregnant mouse with potential ecological parallels to those of humans. Importantly, our findings indicate that the vaginal microbiotas of pregnant mice can be readily cultured, suggesting that mock vaginal microbiotas can be tractably generated and maintained for experimental manipulation in future mechanistic studies of host vaginal-microbiome interactions. IMPORTANCE Mice are widely utilized as animal models of obstetrical complications; however, the characterization of the murine microbiota during pregnancy has been neglected. Microorganisms from the vagina, oral cavity, intestine, and lung have been found in the intra-amniotic space, where their presence threatens the progression of gestation. Here, we characterized the microbiotas of pregnant mice and established the appropriateness of culture in capturing the microbiota at each site. The high relative abundance of Rodentibacter observed in the vagina is similar to that of Lactobacillus in humans, suggesting potential ecological parallels. Importantly, we report that the vaginal microbiota of the pregnant mouse can be readily cultured under hypoxic conditions, demonstrating that mock microbial communities can be utilized to test the potential ecological parallels between microbiotas in human and murine pregnancy and to evaluate the relevance of the structure of these microbiotas for adverse pregnancy outcomes, especially intra-amniotic infection and preterm birth.

Abstract Background Lupus nephritis is one of the most common and severe complications of systemic lupus erythematosus, of which poor prognosis is indicated by aggravated renal hypoxia and tubulointerstitial fibrosis. Cell adhesion molecules play a key role in the progression of lupus nephritis tubulointerstitial lesion, including P-selectin, which mediates the rolling of leukocytes and subsequent adhesion and infiltration and then initiates the inflammatory immune response and ischemia and hypoxia injury. However, the effects and mechanisms of P-selectin in lupus nephritis remain to be investigated, and a noninvasive measurement of lupus nephritis tubulointerstitial hypoxia and fibrosis remains to be explored. Methods Thirty-four MRL/lpr mice were randomly divided into the following three groups: MRL/lpr, saline, and anti-P-selectin, which consisted of no treatment, treatment with normal saline, and treatment with anti-P-selectin monoclonal antibody (mAb) from 12 to 16 weeks of age, respectively. Ten male C57BL/6 mice of the same age served as normal controls. 24-h urinary protein, urinary albumin–creatinine ratio, and periodic acid–Schiff were used to assess kidney damage; Western blot or immunohistochemical staining of the hypoxia probe Hypoxyprobe™-1, hypoxia-inducible factor 1α (HIF-1α), and CD31 were used to evaluate hypoxia in renal tissue; and NADPH oxidase subunit gp91phox and p22phox were used to examine renal oxidative stress. The correlation between kidney injury and blood oxygen level–dependent magnetic resonance imaging (BOLD-MRI) was calculated to assess the clinical value of BOLD-MRI. Results P-selectin is upregulated in lupus nephritis. Blocking P-selectin with mAb alleviated renal tubulointerstitial fibrosis, renal hypoxia, and peritubular capillary loss, without alteration of the levels of lupus activity indicators, anti-dsDNA antibody, or complement C3. BOLD-MRI showed that the reduced R2* values in the renal cortex and medulla of lupus mice were increased when treated with anti-P-selectin mAb as compared with those treated with normal saline, which were negatively correlated with Hypoxyprobe™-1 hypoxia probe and the expression of HIF-1α. Conclusions Early intervention of lupus nephritis with anti-P-selectin mAb can significantly improve the hypoxic state of the kidney and reduce the severity of tubulointerstitial lesions. BOLD-MRI techniques are noninvasive and can dynamically evaluate the changes in renal lesions and intrarenal oxygenation levels before and after treatment in lupus nephritis.

The global epidemic of obesity is tightly associated with numerous comorbidities, such as type II diabetes, cardiovascular diseases and the metabolic syndrome. Among the key features of obesity, some studies have suggested the abnormal expansion of adipose-tissue-induced local endogenous hypoxic, while other studies indicated endogenous hyperoxia as the opposite trend. Endogenous hypoxic aggravates dysfunction in adipose tissue and stimulates secretion of inflammatory molecules, which contribute to obesity. In contrast, hypoxic exposure combined with training effectively generate exogenous hypoxic to reduce body weight and downregulate metabolic risks. The (patho)physiological effects in adipose tissue are distinct from those of endogenous hypoxic. We critically assess the latest advances on the molecular mediators of endogenous hypoxic that regulate the dysfunction in adipose tissue. Subsequently we propose potential therapeutic targets in adipose tissues and the small molecules that may reverse the detrimental effect of local endogenous hypoxic. More importantly, we discuss alterations of metabolic pathways in adipose tissue and the metabolic benefits brought by hypoxic exercise. In terms of therapeutic intervention, numerous approaches have been developed to treat obesity, nevertheless durability and safety remain the major concern. Thus, a combination of the therapies that suppress endogenous hypoxic with exercise plans that augment exogenous hypoxic may accelerate the development of more effective and durable medications to treat obesity and comorbidities.

Gliomas are characterized by high incidence, recurrence and mortality all of which are significant challenges to efficacious clinical treatment. The hypoxic microenvironment in the inner core and intermediate layer of the tumor mass of gliomas is a critical contributor to glioma pathogenesis. In this study, we identified an upregulated lncRNA, OR7E156P, in glioma was identified. The silencing of OR7E156P inhibited cell invasion and DNA synthesis in vitro and tumor growth in vivo. OR7E156P was intricately linked to the HIF1A pathway. Hypoxia could induce OR7E156P expression, whereas OR7E156P silencing decreased HIF1A protein levels under hypoxic conditions. Hypoxia promoted glioma cell invasion and DNA synthesis, and HUVEC tube formation, whereas OR7E156P silencing partially reversed the cellular effects of hypoxia. HIF1A overexpression promoted, whereas OR7E156P silencing inhibited tumor growth; the inhibitory effects of OR7E156P silencing on tumor growth were partially reversed by HIF1A overexpression. miR-143 directly targeted OR7E156P and HIF1A, respectively. miR-143 inhibition increased HIF1A protein levels, promoted glioma cell invasion and DNA synthesis. Moreover, they enhanced HUVEC tube formation, whereas OR7E156P silencing partially reversed the cellular effects of miR-143 inhibition. HIF1A targeted the promoter region of miR-143 and inhibited miR-143 expression. Altogether a regulatory axis consisting of OR7E156P, miR-143, and HIF1A, was identified which is deregulated in glioma, and the process of the OR7E156P/miR-143/HIF1A axis modulating glioma cell invasion through ZEB1 and HUVEC tube formation through VEGF was demonstrated.

Aim: High-flow nasal cannulas (HFNCs) show potential in the application of positive pressure, improving gas exchange, and decreasing work of breathing in patients with acute respiratory distress. The aims of this study were to elucidate the indications for HFNC therapy in children of all ages and diagnoses, and to evaluate the efficacy and risk factors for failure of HFNC therapy in children with acute respiratory distress with hypoxia in a pediatric intensive care unit.Methods: We conducted this retrospective cohort study at a tertiary pediatric intensive care unit between January 1, 2018 and December 31, 2020. All children, from 1 month to 18 years of age, with acute respiratory distress with hypoxia and HFNC therapy were eligible. The clinical data were reviewed.Results: One hundred and two children met the eligibility criteria for the study, of whom 57 (55.9%) were male, and the mean age was 7.00 ± 6.79 years. Seventy-eight (76.5%) of the children had underlying disorders. The most common indications for the use of HFNC therapy were pneumonia (40, 39.2%), sepsis-related respiratory distress (17, 16.7%), and bronchiolitis (16, 15.7%). The failure rate was 15.7% (16 of 102 children). Higher initial and maximum fraction of inspiration O2 levels and lower initial and lowest SpO2/FiO2 (S/F) ratio were early and possible signs of failure requiring escalation of respiratory support.Conclusion: In our population, we found that HFNC therapy could be initiated as the first-line therapy for various etiologies of acute respiratory distress with hypoxia in a pediatric intensive care unit and for all age groups.

Hypoxia has become a universal environmental and ecological problem in recent decades. The Pearl River estuary (PRE), the largest estuary in Southern China, is hypoxic year-round in the upper estuary. This study reports the inter-annual variation between 2005 and 2019 in the carbonate system of the hypoxic upper PRE in winter. In January 2005, both dissolved inorganic carbon (DIC) and total alkalinity (TA) concentrations were >3000 μmol kg–1 at the upstream-most station and decreased sharply downstream. However, DIC and TA were lower, with concentrations of 2300 and 1950 μmol kg–1, respectively, at the upstream-most in January 2019. At salinities >15, both DIC and TA were conservative and reached steady values at the downstream seawater end-member. The upstream-most station was taken as an example to quantify the influences of biogeochemical processes on DIC and TA, including CO2 degassing, organic carbon oxidation, pelagic nitrification, CaCO3 dissolution and benthic release. Among the biogeochemical process, a decrease in CaCO3 dissolution (from 734.4 μmol kg–1 in 2005 to 168.9 μmol kg–1 in 2019) was the major factor driving the decreases of DIC and TA in 2019. In the context of global change, inter-annual variability in biogeochemical process should receive more attention.

There are a growing number of people entering underground spaces. However, underground spaces have unique environmental characteristics, and little is known about their effects on human health. It is crucial to elucidate the effects of the underground space environment on the health of humans and other organisms. This paper reviews the effects of hypoxia, toxic atmospheric particles, and low background radiation in the underground space environment on living organisms from the perspective of oxidative stress. Most studies have revealed that living organisms maintained in underground space environments exhibit obvious oxidative stress, which manifests as changes in oxidants, antioxidant enzyme activity, genetic damage, and even disease status. However, there are few relevant studies, and the pathophysiological mechanisms have not been fully elucidated. There remains an urgent need to focus on the biological effects of other underground environmental factors on humans and other organisms as well as the underlying mechanisms. In addition, based on biological research, exploring means to protect humans and living organisms in underground environments is also essential.

Pathological vascular endothelial damage caused by hypoxia is the basis of many vascular-related diseases. However, the role of circular RNA in hypoxic vascular injury is still poorly understood. Here, we found that hypoxia induced AFF1 circular RNA (circAFF1) can activate the SAV1/YAP1 and lead to the dysfunction of vascular endothelial cells. In HUV-EC-C and HBEC-5i cells, circAFF1 was upregulated under CoCl2 induced hypoxic conditions. The abnormal expression of circAFF1 inhibited the proliferation, tube formation, migration of vascular endothelial cells. The effect of circAFF1 is achieved by the adsorption of miR-516b to release SAV1, which in turn causes the phosphorylation of YAP1. Moreover, we found that the upregulation of circAFF1 in 235 Patients with subarachnoid hemorrhage. Taken together, we clarify the role of circAFF1/miR-516b/SAV1/YAP1 axis in vascular endothelial dysfunction and its potential early diagnostic value of disease caused by hypoxia injury in blood vessels.

Oxidative stress is an important mechanism of neonatal hypoxic-ischemic brain damage. Sirtuin1 (Sirt1) is a deacetylase that depends on NAD+, which has an important role in antioxidant metabolism. Furthermore, peroxisome proliferator-activated receptor γ-co-activator 1α (PGC-1α) is a key regulator of mitochondrial oxidative stress, which is regulated by Sirt1. Here, we investigated the role of Sirt1 in the pathogenesis of brain injuries after modulating its activity in primary cultured hippocampal neurons. Our study shows that the expression of Sirt1 was downregulated after oxygen-glucose deprivation. Activation of Sirt1 with resveratrol improved cell's resistance to oxidative stress, whereas inhibition of Sirt1 with EX527 significantly reduced cell viability after cellular oxidative stress. Our study also shows that activation of Sirt1 with resveratrol exerts its antioxidant effect by regulating the expression of PGC-1α. In contrast, application of EX527 decreased the expression of PGC-1α. In summary, these results confirmed that Sirt1 is a potent protective factor for neurons subjected to oxidative stress, and the protective effect of Sirt1 is attributed to its regulation of PGC-1α.

Background/Aims: The phosphatidylinositol-3-kinase -AKT (PI3K-AKT) is an important intracellular signal pathway in regulating cell proliferation, differentiation and apoptosis. In previous studies, we’ve demonstrated that PI3K–AKT pathway protects cardiomyocytes from ischemic and hypoxic apoptosis through mitochondrial function. However, the molecular mechanisms underlying hypoxia-induced cardiomyocyte apoptosis via PI3K-AKT pathway remain ill-defined. Here, we addressed this question. Methods: Cardiomyocytes were exposed to hypoxia, with/without different inhibitors and then protein levels were assessed by Western blotting. Results: We found that the PI3K–AKT pathway was activated in cardiomyocytes that were exposed to hypoxia. Moreover, the phospho-AKT (pAKT) translocated from cytosol to mitochondria via mitochondrial adenosine triphosphate-dependent potassium (mitoKATP), leading to an increase in cytochrome c oxidase (CcO) activity to suppress apoptosis. On the other hand, the mitoKATP specific blocker, 5-hydroxydecanote (5-HD), or suppression of CcO using siRNA, inhibited the pAKT mitochondrial translocation to maintain the CcO activity, resulting in mitochondrial dysfunction and cellular apoptosis induced by hypoxia. Conclusion: These findings suggest that the anti-apoptotic effect of the PI3K-AKT pathway through pAKT translocation to mitochondrial via mitoKATP may be conducted through modification of CcO activity.

Nitroreductase as a potential biomarker for aggressive tumors has received extensive attention. In this work, a novel NIR fluorescent probe for nitroreductase detection was synthesized. The probe Py-SiRh-NTR displayed excellent sensitivity and selectivity. Most importantly, the confocal fluorescence imaging demonstrated that HepG-2 cells treated with Py-SiRh-NTR under hypoxic conditions showed obvious enhanced fluorescence, which means that the NTR was overexpressed under hypoxic conditions. Moreover, the probe showed great promise that could help us to study related anticancer mechanisms research.

Enteropathogenic Escherichia coli (EPEC) is a major pathogen for diarrheal diseases among children. Antibiotics, when used appropriately, are effective; however, their overuse and misuse have led to the rise of antibiotic resistance worldwide. Thus, there are renewed efforts into the development of phage therapy as an alternative antibacterial therapy. Because EPEC in vivo models have shortcomings, a surrogate is used to study the mouse pathogen Citrobacter rodentium in animal models. In this study, two new phages CrRp3 and CrRp10, which infect C. rodentium, were isolated and characterized. CrRp3 was found to be a new species within the genus Vectrevirus, and CrRp10 is a new strain within the species Escherichia virus Ime09, in the genus Tequatrovirus. Both phages appear to have independently evolved from E. coli phages, rather than other Citrobacter spp. phages. Neither phage strain carries known genes associated with bacterial virulence, antibiotic resistance, or lysogeny. CrRp3 is more potent, having a 24-fold faster adsorption rate and shorter lytic cycle when compared to the same properties of CrRp10. However, a lysis curve analysis revealed that CrRp10 prevented growth of C. rodentium for 18 h, whereas resistance developed against CrRp3 within 9 h. We also show that hypoxic (5% oxygen) conditions decreased CrRp3 ability to control bacterial densities in culture. In contrast, low oxygen conditions did not affect CrRp10 ability to replicate on C. rodentium. Together, CrRp10 is likely to be the better candidate for future phage therapy investigations.

History of present illness: A 46-year-old female was sent to the emergency department from clinic with an oxygen saturation of 86%. She endorsed fevers with cough and generalized weakness for one week. She had been evaluated by her primary care provider on day two of illness and was started empirically on Oseltamivir without improvement of her symptoms. The patient arrived febrile, tachycardic, tachypneic, and hypoxic on room air with left-sided crackles on exam. Significant findings: Point-of-care ultrasound of the left lower lobe demonstrates lung hepatization, a classic finding for pneumonia. In addition, a shred sign is present with both air bronchograms and focal B-lines—all suggestive of poorly aerated, consolidated lung.1 The patient was started on antibiotics and admitted to the hospital with a diagnosis of community-acquired pneumonia. Discussion: With a systematic approach, a skilled clinician can distinguish patterns on point-of-care ultrasound to evaluate for underlying pathology of the lung. Such findings include focal B-lines, an artifact that results from altered fluid-air compositions in the alveoli.2,3 Studies show, that when referenced with the gold standard of computed tomography, ultrasound is more sensitive than chest X-ray in diagnosing pneumonia. Nazerian et al.4 conducted a 190-patient study in which ultrasound had a higher sensitivity—81% compared to a dismal 65% by chest X-ray. Similarly, Cortellaro et al.5 concluded bedside ultrasound (96% sensitivity) is a reliable and superior tool for timely diagnosis of pneumonia compared to chest X-ray (69% sensitivity). Bourcier et al.6 drew conclusions on the effectiveness of ultrasound over chest X-ray on two groups of patients. In the group who exhibited symptoms for less than 24 hours, ultrasound outperformed chest X-ray, where the PPV of ultrasound was 76% and chest X-ray 23%. For those who exhibited symptoms for more than 24 hours, ultrasound demonstrated a PPV of 93% while chest X-ray only 77%. Thus, the use of point-of-care ultrasound in the diagnosis of pneumonia can improve sensitivity while minimizing radiation.

Carbon-ion radiotherapy (CIRT) has progressed rapidly in technological delivery, indications, and efficacy. Owing to a focused dose distribution in addition to high linear energy transfer and subsequently high relative biological effect, CIRT is uniquely able to target otherwise untreatable hypoxic and radioresistant disease, while opening the door for substantially hypofractionated treatment of normal and radiosensitive disease. CIRT has increasingly garnered international attention, and is nearing the tipping point for international adoption.

The matters of the hypoxic training for highly qualified swimmers as extra means of improving level for sports achievements were considered. A method of artificial hypoxic training that increase indexes of cardiorespiratory system of tested people was developed. Twelve students from the university swimming combined team took part in the experiment. In the experiment were used pedagogical testing methods, biochemistry analysis of blood, cardiorespiratory indexes rating, methods of mathematical statistics. It was determined that offered methodology of hypoxic training allows to reach higher sports achievements. It is set that the use of irregular hypoxic influences is considerably modified dependence a «dose is an effect» in regard to loadings of anaerobic alactic influence

Bone marrow mesenchymal stem cells (BM-MSCs) are used to repair hypoxic or ischemic tissue. After hypoxic the level of ATP is decreases, cellular functions do not continue and apoptosis or necrosis occur. Apoptosis is a progress of programmed cell death that occurs in normal or pathological conditions. In this study, we were investigated the hypoxic effect on apoptosis in mesenchymal stem cell. Bone marrow-derived stem cells were cultured in hypoxic (1% or 3%) or normoxic conditions 24, 96 well plates for 36 h. Cell viability was shown by MTT assay on 36 h. After fixation of cells with 4% paraformaldehyde, distributions of caspase-3, Bcl-2 and Bax with indirect immunoperoxidase technique, apoptotic cells with TUNEL assay were investigated. All staining results were evaluated using H-score analyses method with ANOVA, statistically. As a result, hypoxic condition was toxic for human mesenchymal stem cells and the number of death cell was higher in that than normoxic condition.

The present study was carried out to evaluate the cerebroprotective effect of the aqueous extract of the roots of Glycyrrhiza glabra Linn. (250 and 500 mg/kg) in hypoxic rats. Hypoxia was induced by providing sodium nitrite drinking water to rats for 14 days. Extract at the tested doses promoted the locomotor activity and spatial behavior significantly, which was impaired in hypoxic rats. The extract administration restored the decreased levels of brain enzymes such as glutamate and dopamine and decreased acetylcholinesterase (AchE) activity significantly. Levels of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase were reduced due to hypoxia and were restored to near normalcy by administration of ethanol extract of G. glabra. Increased lipid peroxidation in hypoxic rats was also restored significantly by extract treatment. Thus, this study suggests that ethanol extract of G. glabra possess a cerebroprotective effect in hypoxic rats, which may be mediated by its antioxidant effects.

En peces, para el control homeostático, se necesita un adecuado suministro de oxígeno desde el medio acuático hasta los sitios de metabolismo aeróbico. Muchos peces están bien adaptados para soportar condiciones hipoxicas en su ambiente por ajustes respiratorios y cardiovasculares. Sin embargo no existe suficiente información sobre la respuesta homeostática de parámetros sanguíneos a hipoxia aguda. En los peces de cultivo es común que ellos sean expuestos a cortos periodos de hipoxia o anoxia a causa de fallas en las rutinas de manejo. Se determinó hematocrito, hemoglobina, recuento de eritrocitos, tamaño de los eritrocitos y cantidad de hemoglobina por eritrocito en truchas (Oncorhynchus mikyss) llevadas a hipoxia progresiva por mantención de los peces en respirómetros estáticos por 5, 10, 20 y 30 minutos; también se determinó el Indice Bazo-Somático (IBS) y la tasa de consumo de oxígeno. Los resultados mostraron que los peces fueron expuestos a condiciones hipoxicas de 2 mg O2/L al final de los 30 minutos. En respuesta al estrés hipoxico las truchas reaccionaron con disminución del consumo de oxigeno y del (IBS) e incrementos simultáneos en el número de eritrocitos, hematocrito y policromatófilos (eritrocitos inmaduros). Sin embargo el tamaño celular y la concentración de hemoglobina en los eritrocitos disminuyeron. Estos resultados sugieren que los peces se adaptan al estrés hipóxico reduciendo el consumo de oxígeno (respuesta oxiconformadora) e incrementando el número de eritrocitos en circulación. Sin embargo muchas de estas células son fisiológicamente poco funcionales debido a la poca hemoglobina que poseenAn adequate transfer of oxygen from the aquatic environment to the oxidative sites at fish tissues is needed to supply the methabolic requeriments for the homeostatic control. Many fish are well adapted to survive hipoxic conditions in their environments by respiratory and cardiovascular adjustments. However, there are not sufficient information on the homeostatic responses in blood parameters to acute hipoxia. In fish aquacultures, it is common that fishes are exposed to short periods of hypoxia or anoxia because failing in the management routines. To examine the physiological responses in the blood comparment to short-time increasing hypoxic conditions, laboratory experiments were done with rainbow trout (Oncorhynchus mikyss). Blood parameters assessed were hematocrit, hemoglobin concentration, erythrocyte total number, erythrocyte size and hemoglobin content in red cells, together wih fish oxygen consumption and variations in the Somatic-Spleen Index (IBS). Fish were exposed to increasing hypoxic conditions (0, 5, 10, 20 and 30 minutes) inside glass-sealed respirometers. The results showed that fish were exposed to hypoxic conditions as such as 2 mg O2/lt at the end of 30 minutes. In response to the hypoxic stress, trouts showed diminished oxygen consumption together with a decreasing IBS with simultaneous increasing values in number of erythrocytes, hematocrite and poly-chromatophils red cells. However, cellular size and hemoglobin content in the red cells, were decreased. These results suggest that stressed fish adapted to increasing hypoxic conditions with reduction in the oxygen consumption (oxyconformation response) and increasing number of red cells in blood circulation. However most of the red cells were physiological non-functional since the on hemoglobin contents did not increase with hypoxia

Ionizing radiation (IR) is a non-specific but highly effective way to kill malignant cells. However, tumor recurrence sustained by a minor fraction of surviving tumor cells is a commonplace phenomenon caused by the activation of both cancer cell intrinsic resistance mechanisms, and also extrinsic intermediaries of therapy resistance, represented by non-malignant cells and structural components of the tumor stroma. The improved accuracy offered by advanced radiotherapy (RT)-technology permits reduced volume of healthy tissue in the irradiated field, and has been triggering an increase in the prescription of high-dose oligo-fractionated regimens in the clinics. Given the remarkable clinical success of high-dose RT and the current therapeutic shift occurring in the field, in this review we revise the existing knowledge on the effects that different radiation regimens exert on the different compartments of the tumor microenvironment, and highlight the importance of anti-tumor immunity and other tumor cell extrinsic mechanisms influencing therapeutic responses to high-dose radiation.

Fermentation or anoxic metabolism allows unicellular organisms to colonize environments that become anoxic. Free-living unicellular algae capable of a photoautotrophic lifestyle can also use a range of metabolic circuitry associated with different branches of fermentation metabolism. While algae that perform mixed-acid fermentation are widespread, the use of anaerobic respiration is more typical of eukaryotic heterotrophs. The occurrence of a core set of fermentation pathways among the algae provides insights into the evolutionary origins of these pathways, which were likely derived from a common ancestral eukaryote. Based on genomic, transcriptomic, and biochemical studies, anaerobic energy metabolism has been examined in more detail in Chlamydomonas reinhardtii (Chlamydomonas) than in any other photosynthetic protist. This green alga is metabolically flexible and can sustain energy generation and maintain cellular redox balance under a variety of different environmental conditions. Fermentation metabolism in Chlamydomonas appears to be highly controlled, and the flexible use of the different branches of fermentation metabolism has been demonstrated in studies of various metabolic mutants. Additionally, when Chlamydomonas ferments polysaccharides, it has the ability to eliminate part of the reductant (to sustain glycolysis) through the production of H2, a molecule that can be developed as a source of renewable energy. To date, little is known about the specific role(s) of the different branches of fermentation metabolism, how photosynthetic eukaryotes sense changes in environmental O2 levels, and the mechanisms involved in controlling these responses, at both the transcriptional and post-transcriptional levels. In this review, we focus on fermentation metabolism in Chlamydomonas and other protists, with only a brief discussion of plant fermentation when relevant, since it is thoroughly discussed in other articles in this volume.

There is evidence suggesting that herbal extracts demonstrate greater bioactivities than their isolated constituents at an equivalent dose. This phenomenon could be attributed to the absence of interacting substances present in the extracts. By measuring the pharmacokinetic parameters of paeoniflorin (PF) and albiflorin (AF) after being orally administered to rats in isolated form, in combination with each other and within total peony glucosides (TPG), respectively, the current study aimed to identify positive pharmacokinetic interactions between components of peony radix extracts. Moreover, the pharmacokinetic profiles of PF and AF under normoxia and hypoxia were also investigated and compared. In order to achieve these goals, a highly sensitive and reproducible ultra-peformance liquid chromatography–mass spectrometry (UPLC-MS) method was developed and validated for simultaneously quantitation of PF and AF in rat plasma. This study found that compared with that of single component (PF/AF), the exposure of PF in rat plasma after combination administration or TPG administration was significantly increased, meanwhile the elimination of PF/AF was remarkably reduced. It was also noticed that AUC and Cmax of PF in hypoxia rats were significantly decreased compared with that of normaxia rats, suggesting that there was a decreased exposure of PF in rats under hypoxia. The current study, for the first time, revealed the pharmacokinetic interactions between PF/AF and other constitutes in TGP and the pharmacokinetic profiles of PF and AF under hypoxia. In view of the current findings, it could be supposed that the clinical performance of total peony glucosides would be better than that of single constitute (PF/AF). The outcomes of this animal study are expected to serve as a basis for development of clinical guidelines on total peony glucosides usage.