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Background Fatigue is one of the most frequent symptoms in patients with multiple sclerosis (MS), causing a major impact on quality-of-life. Non-pharmacological intervention strategies involve physical activity, which has been shown to reduce fatigue. Training under normobaric hypoxic conditions is thought to improve the response to endurance training and may, therefore, have an additional benefit over normoxic training conditions in MS patients. Objective To compare the effects of endurance training under hypoxic and normoxic conditions on fatigue, mobility and spasticity in patients with MS during inpatient rehabilitation. Methods Thirty-nine patients with MS were assigned within a randomized prospective longitudinal pilot study to (1) a routine clinical rehabilitation program, (2) a routine clinical rehabilitation program + normoxic endurance training and (3) a routine clinical rehabilitation program + hypoxic endurance training for 14 days. Fatigue (WEIMuS and MFIS), spasticity (MSSS-88) and walking endurance (6MinWT) were assessed at days 0, 7 and 14. Results Fatigue scores improved significantly in all groups, but these improvements were reached faster in the groups which additionally received endurance training (normoxic p = 0.004; hypoxic p = 0.002). Spasticity scores were significantly lower in endurance training groups at the end of the study compared to baseline (normoxic p = 0.048, hypoxic p = 0.012), while only the hypoxic group increased significantly in 6MinWT (p = 0.001). Conclusions Our findings demonstrate that endurance training provides substantial benefit to neurological rehabilitation programs. Endurance training under hypoxic conditions could positively influence walking endurance within a 2-week training intervention and warrants further investigations.

STUDY QUESTION Can markers of human endometrial hypoxia be detected at menstruation in vivo? SUMMARY ANSWER Our in vivo data support the presence of hypoxia in menstrual endometrium of women during physiological menstruation. WHAT IS KNOWN ALREADY Current evidence from animal models and human in vitro studies suggests endometrial hypoxia is present at menstruation and drives endometrial repair post menses. However, detection of human endometrial hypoxia in vivo remains elusive. STUDY DESIGN, SIZE, DURATION We performed a prospective case study of 16 women with normal menstrual bleeding. PARTICIPANTS/MATERIALS, SETTING, METHODS Reproductively aged female participants with a regular menstrual cycle underwent objective measurement of their menstrual blood loss using the alkaline haematin method to confirm a loss of 3 cm. Participants attended for two MRI scans; during days 1–3 of menstruation and the early/mid-secretory phase of their cycle. The MRI protocol included dynamic contrast-enhanced MRI and T2* quantification. At each visit, an endometrial sample was also collected and hypoxia-regulated repair factor mRNA levels (ADM, VEGFA, CXCR4) were quantified by RT-qPCR. MAIN RESULTS AND THE ROLE OF CHANCE Women had reduced T2* during menstrual scans versus non-menstrual scans (P = 0.005), consistent with menstrual hypoxia. Plasma flow (Fp) was increased at menstruation compared to the non-menstrual phase (P = 0.0005). Laboratory findings revealed increased ADM, VEGF-A and CXCR4 at menstruation on examination of paired endometrial biopsies from the menstrual and non-menstrual phase (P = 0.008; P = 0.03; P = 0.009). There was a significant correlation between T2* and these ex vivo hypoxic markers (P LIMITATIONS, REASONS FOR CAUTION This study examined the in vivo detection of endometrial hypoxic markers at specific timepoints in the menstrual cycle in women with a menstrual blood loss WIDER IMPLICATIONS OF THE FINDINGS Heavy menstrual bleeding (HMB) is a common, debilitating condition. Understanding menstrual physiology may improve therapeutics. To our knowledge, this is the first in vivo data supporting the presence of menstrual hypoxia in the endometrium of women with normal menstrual bleeding. If aberrant in those with HMB, these non-invasive tests may aid diagnosis and facilitate personalized treatments for HMB. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by Wellbeing of Women grant RG1820, Wellcome Trust Fellowship 209589/Z/17/Z and undertaken in the MRC Centre for Reproductive Health, funded by grants G1002033 and MR/N022556/1. H.O.D.C. has clinical research support for laboratory consumables and staff from Bayer AG and provides consultancy advice (but with no personal remuneration) for Bayer AG, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc; Myovant Sciences GmbH. H.O.D.C. receives royalties from UpToDate for articles on abnormal uterine bleeding. TRIAL REGISTRATION NUMBER N/A.

BACKGROUND: Intra-peritoneal adhesions (IPAs) common occurre in post abdominal surgical. Athough many methods have been developed for controlling IPAs, including mesenchymal stem cells (MSCs) application, however, there is none completely preventing in due to the mesothelial structure may promote the prolonged inflammations leading. Nevertheless hypoxia-MSCs (H-MSCs) have more potent in controlling the inflammation than normoxia-MSCs (N-MSCs) by releasing several anti-inflamation particularly IL-10, however the H-MSCs application to inhibit IPAs remain unclear. AIM: The aim of this study was to investigate the effectiveness of H-MSCs in preventing the AIPs event by releasing IL-10 on the ileum abrasion sutured omental patch as the animal model of peritoneal adhesion. METHODS: Using 24 IPAs animal model were randomly divided into 4 groups: Sham (Sh), Control (C), H-MSCs at high dose (T1) and H-MSCs at low dose (T2). H-MSCs were incubated under hypoxic conditions (5% O2), 37°C and 5% CO2 for 24 hours. The expression level of IL-10 was performed using RT-PCR analysis. The macroscopic appearance of IPAs was evaluated using Nair’s scale base on the absence/presence of adhesion, whereas the microscopic by Zuhlke’s scale at Hematoxylin and eosin (H&E) staining. RESULTS: This study showed a significanly increase in IL-10 expression (p < 0.05) at all T groups. In line with this, we also found a significant difference in IPAs between T groups and Control as well as a Sham (p < 0.05) either in the macroscopic or microscopic analysis. CONCLUSION: H-MSCs has a robust ability in inhibiting severe IPAs characterized by the decreased of adhesion formation and the enhanced expression of IL-10.

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.

New findings What is the central question of this study? What is the physiological interpretation of S p O 2 fluctuations observed during normobaric hypoxia in healthy individuals? What is the main finding and its importance? There is a significant flow of information between S p O 2 and other cardio-respiratory time series during graded hypoxia. Analysis of the pattern of S p O 2 variations has potential for non-invasive assessment of the engagement of respiratory control system in health and disease. Abstract Peripheral capillary oxygen saturation ( S p O 2 ) exhibits a complex pattern of fluctuations during hypoxia. The physiological interpretation of S p O 2 variability is not well understood. In this study, we tested the hypothesis that S p O 2 fluctuation carries information about integrated cardio-respiratory control in healthy individuals using a network physiology approach. We explored the use of transfer entropy in order to compute the flow of information between cardio-respiratory signals during hypoxia. Twelve healthy males (mean (SD) age 22 (4) years) were exposed to four simulated environments (fraction of inspired oxygen ( F I O 2 ): 0.12, 0.145, 0.17, and 0.2093) for 45 min, in a single blind randomized controlled design. The flow of information between different physiological parameters ( S p O 2 , respiratory frequency, tidal volume, minute ventilation, heart rate, end-tidal pressure of O2 and CO2 ) were analysed using transfer entropy. Normobaric hypoxia was associated with a significant increase in entropy of the S p O 2 time series. The transfer entropy analysis showed that, particularly at F I O 2 0.145 and 0.12, the flow of information between S p O 2 and other physiological variables exhibits a bidirectional relationship. While reciprocal interactions were observed between different cardio-respiratory parameters during hypoxia, S p O 2 remained the main hub of this network. S p O 2 fluctuations during graded hypoxia exposure carry information about cardio-respiratory control. Therefore, S p O 2 entropy analysis has the potential for non-invasive assessment of the functional connectivity of respiratory control system in various healthcare settings.

BackgroundNecrotizing enterocolitis (NEC) is a devastating disease that is relatively frequently diagnosed in term infants with congenital heart disease (CHD), compared with term infants without CHD, in whom NEC is rare. The exact pathogenesis of NEC in term infants with CHD is unknown, but it is hypothesized that ischemia of the intestines plays a pivotal role. We aimed to explore whether (near) term CHD infants, who develop NEC, exhibit more clinical signs of hypoxia/ischemia and low body perfusion directly after birth and during the first 48 hours after admission to the neonatal intensive care unit, when compared with (near) term CHD infants who did not develop NEC.Methods956 infants with CHD born after ≥ 35 weeks of gestational age were retrospectively reviewed for this case-control study between January 1999 and February 2020. We included infants with radiographically confirmed pneumatosis intestinalis and controls matched by type of CHD. Seven infants were diagnosed with transposition of the great arteries, six with left and four with right ventricular outflow tract obstruction. Several parameters suggestive of (relative) hypoxia/ischemia were used for analyses.ResultsWe included sixteen CHD infants with NEC and selected sixteen controls. There were no significant demographic differences between both groups. Apgar score at one and five minutes (median [IQR]) were lower in infants who developed NEC compared with control infants (8 [7-8]) vs. (9 [8-9],P = .011) and (8 [8-9]) vs. (9 [9-10],P = .009). A higher proportion of infants with NEC required respiratory support in the delivery room (11(69) vs. 2(13),P = .001). The (median [IQR]) diastolic blood pressure on the second day after admission (39 mmHg [34–42], vs. 43 mmHg [37–51],P = .112) and lowest (median [IQR]) pH in the 48 hours after admission (7.24 [7.17–7.35] vs. 7.38 ([7.27–7.43],P = .157) were not significantly lower in NEC infants but both demonstrated a similar direction towards (relative) hypoxia/ischemia in NEC infants.ConclusionsOur clinical results support a hypoxic/ischemic pathophysiology of NEC in (near) term CHD infants, with lower Apgar scores, more respiratory support in the delivery room and a tendency towards a lower diastolic blood pressure and pH in CHD infants who develop NEC.

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.

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.

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.

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.

Lung cancer is the most aggressive tumour afflicting patients on a global scale. Extracellular vesicle (EV)‐delivered microRNAs (miRs) have been reported to play critical roles in cancer development. The current study aimed to investigate the role of hypoxic bone marrow mesenchymal cell (BMSC)‐derived EVs containing miR‐328‐3p in lung cancer. miR‐328‐3p expression was determined in a set of lung cancer tissues by RT‐qPCR. BMSCs were infected with lentivirus‐mediated miR‐328‐3p knock‐down and then cultured in normoxic or hypoxic conditions, followed by isolation of EVs. Following ectopic expression and depletion experiments in lung cancer cells, the biological functions of miR‐328‐3p were analysed using CCK‐8 assay, flow cytometry and Transwell assay. Xenograft in nude mice was performed to test the in vivo effects of miR‐328‐3p delivered by hypoxic BMSC‐derived EVs on tumour growth of lung cancer. Finally, the expression of circulating miR‐328‐3p was detected in the serum of lung cancer patients. miR‐328‐3p was highly expressed in EVs derived from hypoxic BMSCs. miR‐328‐3p was delivered to lung cancer cells by hypoxic BMSC‐derived EVs, thereby promoting lung cancer cell proliferation, invasion, migration and epithelial‐mesenchymal transition. miR‐328‐3p targeted NF2 to inactivate the Hippo pathway. Moreover, EV‐delivered miR‐328‐3p increased tumour growth in vivo. Additionally, circulating miR‐328‐3p was bioactive in the serum of lung cancer patients. Taken together, our results demonstrated that hypoxic BMSC‐derived EVs could deliver miR‐328‐3p to lung cancer cells and that miR‐328‐3p targets the NF2 gene, thereby inhibiting the Hippo pathway to ultimately promote the occurrence and progression of lung cancer.

// Liang Pang 1 , Jing Qin 1 , Limei Han 1 , Wenjie Zhao 2 , Jianming Liang 1 , Zhongyi Xie 1 , Pei Yang 1 , Jianxin Wang 1 1 Key Laboratory of Smart Drug Delivery, Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai, 201203, China 2 Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China Correspondence to: Jianxin Wang, email: jxwang@fudan.edu.cn Keywords: macrophages, glioma, inflammation, hypoxic, nanoparticles Received: October 18, 2015 Accepted: April 24, 2016 Published: May 18, 2016 ABSTRACT The restriction of anti-cancer drugs entry to tumor sites in the brain is a major impediment to the development of new strategies for the treatment of glioma. Based on the finding that macrophages possess an intrinsic homing property enabling them to migrate to tumor sites across the endothelial barriers in response to the excretion of cytokines/chemokines in the diseased tissues, we exploited macrophages as ‘Trojan horses’ to carry drug-loading nanoparticles (NPs), pass through barriers, and offload them into brain tumor sites. Anticancer drugs were encapsulated in nanoparticles to avoid their damage to the cells. Drug loading NPs was then incubated with RAW264.7 cells in vitro to prepare macrophage-NPs (M-NPs). The release of NPs from M-NPs was very slow in medium of DMEM and 10% FBS and significantly accelerated when LPS and IFN-γ were added to mimic tumor inflammation microenvironment. The viability of macrophages was not affected when the concentration of doxorubicin lower than 25 μg/ml. The improvement of cellular uptake and penetration into the core of glioma spheroids of M-NPs compared with NPs was verified in in vitro studies. The tumor-targeting efficiency of NPs was also significantly enhanced after loading into macrophages in nude mice bearing intracranial U87 glioma. Our results provided great potential of macrophages as an active biocarrier to deliver anticancer drugs to the tumor sites in the brain and improve therapeutic effects of glioma.

The unique hypoxic inflammatory microenvironment observed in the spinal cord following spinal cord injury (SCI) limits the survival and efficacy of transplanted bone mesenchymal stem cells (BMSCs). The aim of the present study was to determine whether hypoxic preconditioning (HP) increased the therapeutic effects of BMSC on SCI. BMSCs were pretreated with cobalt chloride (CoCl2) in vitro, and the proliferative apoptotic and migratory abilities of these hypoxic BMSCs (H‑BMSCs) were assessed. BMSCs and H‑BMSCs derived from green fluorescent protein (GFP) rats were transplanted into SCI rats in vivo. The neurological function, histopathology, inflammation, and number and migration of transplanted cells were examined. HP significantly enhanced BMSC migration (increased hypoxia inducible factor 1α and C‑X‑C motif chemokine receptor 4 expression) and tolerance to apoptotic conditions (decreased caspase‑3 and increased B‑cell lymphoma 2 expression) in vitro. In vivo, H‑BMSC transplantation significantly improved neurological function, decreased spinal cord damage and suppressed the inflammatory response associated with microglial activation. The number of GFP‑positive cells in the SCI core and peripheral region of H‑BMSC animals was increased compared with that in those of BMSC animals, suggesting that HP may increase the survival and migratory abilities of BMSCs and highlights their therapeutic potential for SCI.

Background: Ectopic ossification and increased vascularization are two common phenomena in the chronic tendinopathic tendon. The increased vascularization usually leads to an elevated local oxygen tension which is one of micro-environments that can influence differentiate status of stem cells. Objective: This study aimed to investigate the osteogenesis capacity of rat tendon-derived stem cells TDSCs (rTDSCs) in normoxic and hypoxic cultures, and to study the role of ERK1/2 signaling pathway in this process. Methods: rTDSCs were subjected to osteogenesis inductive culture in hypoxic (3% O2) and normoxic (20% O2) conditions. The inhibitor U0126 was added along with culture medium to determine the role of ERK1/2 signaling pathway. Cell viability, cell proliferation, alizarin red staining, alkaline phosphatase (AKP) activity, gene expression (ALP, osteocalcin, collagen I and RUNX2) and protein expression (p-ERK1/2 and RUNX2) of osteogenic-cultured rTSDCs were analyzed in this study. Results: Hypoxic and normoxic culture had no effects on cell viability of rTDSCs, whereas the proliferation potential of rTDSCs was significantly increased in hypoxic culture. The osteogenesis capacity of rTDSCs in normoxic culture was significantly promoted compared with hypoxic culture, which was reflected by an increased alizarin red staining intensity, an elevated ALP activity, and the up-regulated gene (ALP, osteocalcin, collagen I and RUNX2) or protein (RUNX2) expression of osteogenic makers. However, the osteogenesis capacity of rTDSCs in both hypoxic and normoxic cultures was attenuated by the inhibitor U0126. Conclusion: Normoxic culture promotes osteogenic differentiation of rTDSCs compared with the hypoxic culture, and the ERK1/2 signaling pathway is involved in this process.

PURPOSE: The aim of this study was to analyze the effect of hypoxia on metabolic and acid-base balance, blood oxygenation, electrolyte, and half-squat performance variables during high-resistance circuit (HRC) training. METHODS: Twelve resistance-trained subjects participated in this study. After a 6RM testing session, participants performed three randomized trials of HRC: normoxia (NORM: FiO2 = 0.21), moderate hypoxia (MH: FiO2 = 0.16), or high hypoxia (HH: FiO2 = 0.13), separated by 72 h of recovery in normoxic conditions. HRC consisted of two blocks of three exercises (Block 1: bench press, deadlift and elbow flexion; Block 2: half-squat, triceps extension, and ankle extension). Each exercise was performed at 6RM. Rest periods lasted for 35 s between exercises, 3 min between sets, and 5 min between blocks. Peak and mean force and power were determined during half-squat. Metabolic, acid-base balance, blood oxygenation and electrolyte variables, arterial oxygen saturation (SaO2), and rating of perceived exertion (RPE) were measured following each block. RESULTS: During the first set, peak force and power were significantly lower in HH than MH and NORM; whereas in the second set, mean and peak force and power were significantly lower in HH than NORM. At the end of the HRC training session, blood lactate and RPE in HH were significantly higher than in MH and NORM. SaO2, pH, HCO3-, and pO2 values were significantly lower in all hypoxic conditions than in NORM. CONCLUSION: These results indicate that simulated hypoxia during HRC exercise reduce blood oxygenation, pH, and HCO3-, and increased blood lactate ultimately decreasing muscular performance. Actividad Física y Deporte

Objective To investigate the permeability of β-NGF through blood–brain-barrier (BBB) in neonatal and adult rats, and the spatial distribution of β-NGF in different brain regions in hypoxic-ischemic (HI) and normal neonatal rats. Methods To investigate the overall permeability of β-NGF through BBB, β-NGF labeled with I125 was injected into adult rats, neonatal rats and HI neonatal rats via tail vein. The radioactivity of brain tissue and blood was examined and analyzed 30 min after injection. Also, brain regions including the basal forebrain, frontal cortex, hippocampus, hypothalamus, cerebellum, bulbus olfactorius and hypophysis, of all the rats were dissected and radioactivity was examined to investigate the spatial specificity of NGF permeation through BBB. Results Statistically significant results were observed in I125-β-NGF contents in brain tissues of adult rats group, neonatal rats group and HI neonatal rats group (P

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.

Chronic hypoxia in the gestating fetus is a common occurrence which invariably leads to a variety of adverse events such as premature delivery, pulmonary hypertension, intrauterine growth restriction (IUGR) and fetal/adult cardiovascular dysfunction. This article is protected by copyright. All rights reserved

Purpose Hepatocellular carcinoma (HCC) is a common cancer worldwide. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a long noncoding RNA (lncRNA), has been reported to be aberrantly expressed in hypoxic cancer cells. MALAT1 plays a significant role in many malignancies, including HCC. The aim of this study was to explore the role of MALAT1 in hypoxic HCC cells and its underlying regulatory mechanism. Materials and methods Quantitative reverse transcription PCR (qRT-PCR) assay was performed to detect the mRNA levels of MALAT1 and microRNA-200a (miR-200a) in HCC cells. Cell invasion and migration ability were evaluated by Transwell assay. Starbase v2.0 and luciferase reporter assay were employed to identify the association between MALAT1 and miR-200a. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. Results MALAT1 levels were significantly upregulated in HCC cells under hypoxia. Hypoxia promoted proliferation, migration, and invasion, and blocked apoptosis in Hep3B cells, which were weakened by knockdown of MALAT1. Starbase v2.0 showed that MALAT1 and miR-200a have a complementarity region, and luciferase reporter assay verified that MALAT1 interacted with miR-200a in Hep3B cells. Moreover, MALAT1 negatively regulated the expression of miR-200a. miR-200a levels were dramatically downregulated in HCC cells under hypoxia. Upregulation of miR-200a inhibited proliferation, migration, and invasion, and induced apoptosis in Hep3B cells under hypoxia. Interestingly, downregulation of miR-200a partially reversed the tumor-suppressive effect of knockdown of MALAT1 on Hep3B cells in hypoxic condition. Conclusion LncRNA MALAT1 was involved in proliferation, migration, invasion, and apoptosis by interacting with miR-200a in hypoxic Hep3B cells, revealing a new mechanism of MALAT1 involved in hypoxic HCC progression.

The aim of the present study was to investigate regulatory relationships among hypoxia-inducible factor-1α (HIF-1α), microRNA and erythroid transcription factors. K562 cells were transfected with HIF-1α knockout or with overexpression lentivirus of plasmid (MOI 10). The cells were divided into 3 groups: the negative control, overexpressing and interference groups. The cells were cultured under normoxia and hypoxia. Expression of miR-17*, miR-363 and miR-574-5p in the three groups was determined by quantitative PCR. Expression levels of erythroid transcription factor mRNAs such as GATA-1/GATA-2 and nuclear factor-erythroid 2 (NF-E2) were measured using RT-qPCR while the protein expression was studied using western blot analysis. Under normoxia or hypoxia, the levels of miR-17*, miR-363 and miR-574-5p in the overexpression group were higher than those in the other groups. Differences were statistically significant (P

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.

Background Chronic low back pain due to disc degeneration represents a major social and economic burden worldwide. The current standard of care is limited to symptomatic relief and no current approved therapy promotes disc regeneration. Bone marrow-derived mesenchymal stem cells (MSCs) are easily accessible and well characterized. These MSCs are multipotent and exhibit great tissue regenerative potential including bone, cartilage, and fibrous tissue regeneration. The use of this cell-based biologic for treating protruding disc herniation and/or intervertebral disc degeneration is a promising therapeutic strategy, due to their known regenerative, immuno-modulatory and anti-inflammatory properties. Methods Five patients diagnosed with degenerative disc disease received an intra-discal injection of autologous, hypoxic cultured, bone marrow-derived mesenchymal stem cells (15.1–51.6 million cells) as part of a previous study. These patients were re-consented to participate in this study in order to assess long-term safety and feasibility of intra-discal injection of autologous, hypoxic cultured, bone marrow-derived mesenchymal stem cells 4–6 years post mesenchymal stem cell infusion. The follow-up study consisted of a physical examination, a low back MRI, and a quality of life questionnaire. Results Patients’ lower back MRI showed absence of neoplasms or abnormalities surrounding the treated region. Based on the physical examination and the quality of life questionnaire, no adverse events were reported due to the procedure or to the stem cell treatment 4–6 years post autologous, hypoxic cultured mesenchymal stem cell infusion. All patients self-reported overall improvement, as well as improvement in strength, post stem cell treatment, and four out of five patients reported improvement in mobility. Conclusion This early human clinical data suggests the safety and feasibility of the clinical use of hypoxic cultured bone marrow-derived mesenchymal stem cells for the treatment of lower back pain due to degenerative disc disorders and support further studies utilizing hypoxic cultured bone marrow-derived stem cells. The overall improvements reported are encouraging, but a larger double-blind, controlled, randomized clinical study with significant number of patients and implementation of validated endpoint measurements are next steps in order to demonstrate efficacy of this cell-based biologic.