Research progress on the effect of mitochondrial and endoplasmic reticulum stress caused by hypoxia during pregnancy on preeclampsia and intrauterine growth restriction / 生理学报

Preeclampsia and intrauterine growth restriction (IUGR) of the fetus are the two most common pregnancy complications worldwide, affecting 5%-10% of pregnant women. Preeclampsia is associated with significantly increased maternal and fetal morbidity and mortality. Hypoxia-induced uteroplacental dysfunction is now recognized as a key pathological factor in preeclampsia and IUGR. Reduced oxygen supply (hypoxia) disrupts mitochondrial and endoplasmic reticulum (ER) function. Hypoxia has been shown to alter mitochondrial reactive oxygen species (ROS) homeostasis and induce ER stress. Hypoxia during pregnancy is associated with excessive production of ROS in the placenta, leading to oxidative stress. Oxidative stress occurs in a number of human diseases, including high blood pressure during pregnancy. Studies have shown that uterine placental tissue/cells in preeclampsia and IUGR show high levels of oxidative stress, which plays an important role in the pathogenesis of both the complications. This review summarizes the role of hypoxia-induced mitochondrial oxidative stress and ER stress in the pathogenesis of preeclampsia/IUGR and discusses the potential therapeutic strategies targeting oxidative stress to treat both the pregnancy complications.

Factors affecting pulmonary arterial pressure in response to high-altitude hypoxic stress / 生理学报

The alteration of pulmonary artery pressure is an important physiological indicator to reflect the organism's adaptation to acclimatization or the pathological injury in response to high-altitude hypoxic environment. The effects of hypoxic stress at different altitudes for different time on pulmonary artery pressure are different. There are many factors involved in the changes of pulmonary artery pressure, such as the contraction of pulmonary arterial smooth muscle, hemodynamic changes, abnormal regulation of vascular activity and abnormal changes of cardiopulmonary function. Understanding of the regulatory factors of pulmonary artery pressure in hypoxic environment is crucial in clarifying the relevant mechanisms of hypoxic adaptation, acclimatization, prevention, diagnosis, treatment and prognosis of acute and chronic high-altitude diseases. In recent years, great progress has been made in the study regarding the factors affecting pulmonary artery pressure in response to high-altitude hypoxic stress. In this review, we discuss the regulatory factors and intervention measures of pulmonary arterial hypertension induced by hypoxia from the aspects of hemodynamics of circulatory system, vasoactive state and changes of cardiopulmonary function.

Laparoscopic-assisted vs open transhiatal gastrectomy for Siewert type II adenocarcinoma of the esophagogastric junction: A retrospective cohort study.

BACKGROUND: The studies of laparoscopic-assisted transhiatal gastrectomy (LTG) in patients with Siewert type II adenocarcinoma of the esophagogastric junction (AEG) are scarce. AIM: To compare the surgical efficiency of LTG with the open transhiatal gastrectomy (OTG) for patients with Siewert type II AEG. METHODS: We retrospectively evaluated a total of 578 patients with Siewert type II AEG who have undergone LTG or OTG at the First Medical Center of the Chinese People's Liberation Army General Hospital from January 2014 to December 2019. The short-term and long-term outcomes were compared between the LTG (n = 382) and OTG (n = 196) groups. RESULTS: Compared with the OTG group, the LTG group had a longer operative time but less blood loss, shorter length of abdominal incision and an increased number of harvested lymph nodes (P < 0.05). Patients in the LTG group were able to eat liquid food, ambulate, expel flatus and discharge sooner than the OTG group (P < 0.05). No significant differences were found in postoperative complications and R0 resection. The 3-year overall survival and disease-free survival performed better in the LTG group compared with that in the OTG group (88.2% vs 79.2%, P = 0.011; 79.7% vs 73.0%, P = 0.002, respectively). In the stratified analysis, both overall survival and disease-free survival were better in the LTG group than those in the OTG group for stage II/III patients (P < 0.05) but not for stage I patients. CONCLUSION: For patients with Siewert type II AEG, LTG is associated with better short-term outcomes and similar oncology safety. In addition, patients with advanced stage AEG may benefit more from LTG in the long-term outcomes.

Protective Effects from the Ischemic/Hypoxic Stress Induced by Labor in the High-Altitude Tibetan Placenta.

Labor and vaginal delivery cause acute ischemic/hypoxic insult to the placenta. Previous studies demonstrate that placentas from high altitude non-natives showed blunted responses to ischemic/hypoxic insult caused by labor and vaginal birth, and there were some differences in the ATP/ADP production ratio. We hypothesized that adapted highlanders would not have a stress response to the acute hypoxia/ischemia of labor. Tibetan laboring (n = 10) and non-laboring (n = 5) and European descendants laboring (n = 10) and non-laboring (n = 5) high-altitude placentas were analyzed using genome-wide expression array analysis. There was no evidence for ischemic/hypoxic stress in high-altitude Tibetan laboring as compared with non-laboring placentas, while there were differences in gene expression between laboring and non-laboring placentas from high-altitude European descendants. Our results provide evidence for adaptation to acute hypoxic ischemic insult caused by labor and vaginal birth in placentas in a high-altitude native Tibetan population.

A Case of Human Hepatic Alveolar Echinococcosis Accompanied by Lung and Brain Metastases

Alveolar echinococcosis (AE) is considered as a fatal zoonosis caused by the larvae of Echinococcus multilocularis. The lungs and brain are the most common metastatic organs. We report a human case of hepatic alveolar echinococcosis accompanied by lung and brain metastasis. In particular, the patient had a history of tuberculosis and the lung lesions were easily misdiagnosed as lung abscesses. The lesions of liver and lung underwent radical resection and confirmed as alveolar echinococcosis by pathological examination. The patient had no surgical complications after operation and was discharged after symptomatic treatment. Unfortunately, the patient later developed multiple intracerebral AE metastases. We required the patient to take albendazole orally for life and follow up.

A Case of Human Hepatic Alveolar Echinococcosis Accompanied by Lung and Brain Metastases

Alveolar echinococcosis (AE) is considered as a fatal zoonosis caused by the larvae of Echinococcus multilocularis. The lungs and brain are the most common metastatic organs. We report a human case of hepatic alveolar echinococcosis accompanied by lung and brain metastasis. In particular, the patient had a history of tuberculosis and the lung lesions were easily misdiagnosed as lung abscesses. The lesions of liver and lung underwent radical resection and confirmed as alveolar echinococcosis by pathological examination. The patient had no surgical complications after operation and was discharged after symptomatic treatment. Unfortunately, the patient later developed multiple intracerebral AE metastases. We required the patient to take albendazole orally for life and follow up.

Hypoxia inducing factor related genetic adaptation in high-altitude and pharmacological modulation / 药学学报

Adaptation to hypoxia of the plateau environment has been a focus of scientific research in decades. The geographical distributions of such living environment include the Qinghai-Tibet Plateau, Andean Plateau in South America and Ethiopian Plateau. Over the past century, the unique features of physiological adaptation to high-altitude chronic hypoxia have been documented scientifically. The genetic studies of hypoxic adaptation in the past decade have revealed genetic bases of human high-altitude adaptation, with a close relationship to the hypoxia inducible factor (HIF) pathway and hypoxia response elements (HREs). Interestingly, the genetic pattern of adaptation to hypoxia is not the same among the three plateau populations. Tibetan has developed the best high-altitude adaptation, with modification of the HIF pathway as the key genetic element. Due to the wide range of HIF pathways, HIFs could regulate hundreds of downstream genes and are closely related to various diseases such as cancer, inflammation, ischemia, acute organ damage and infection, etc. The treatment researches of these diseases through HIFs-related regulations have led to the development of stabilizers and inhibitors of HIF pathway. We review here the adaptive responses of the three plateau populations to the hypoxic environment, and the genetic mechanism of HIF and HREs in the different ethnic high-altitude populations. Classes of HIF inhibitors, such as PI3K and/or mammalian target of rapamycin (mTOR) inhibitors, DNA-binding inhibitors, histone deacetylase inhibitors, heat-shock protein 90 inhibitors, cardiac glycosides, transcription inhibitors, topoisomerase inhibitors, and HIF activators including 2-OG mimics, Fe2+ chelators, prolyl hydroxylase (PHD) active-site blockers and CUL2 deneddylators have been presented with the drug examples. In addition, the top 3 chemical-disease and chemical-gene (protein) co-occurrences have been presented from the Pubmed literature search. The review could serve as references for research of hypoxia adaptation and HIF-related diseases.

Research Advance on Promoting Angiogenesis of Mesenchymal Stem Cells-Review / 中国实验血液学杂志

Mesenchymal stem cells (MSC) possess important biological characteristics of tissue repair and regeneration. MSC exert the properties promoting endogenous angiogenesis and have been widely applied in treatment of ischemia diseases. The therapeutic potency of MSC for ischemia diseases is owing to their secretion of angiogenic growth factors and release of exosomes. MSC promote angiogenesis stronger in hypoxia environment, and their miRNA played an important role in mediating regulation. This review summarizes recent advances in treatment of angiogenesis using MSC and their mechanisms. The angiogenic activities of MSC under hypoxia condition and their regulation by a miRNA network were discussed.

MiR-486 Regulates the Glycometabolism of Hematopoietic Cells by Targeting Sirt1 / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To investigate the effect and mechanism of miR-486 on glycometabolism of hematopoietic cells.</p><p><b>METHODS</b>qRT-PCR was applied to detect the expression of miR-486 or Sirt1 on TF-1 cells under hypoxia. Lentivirus was used to mediate the overexpression or inhibition of miR-486 on TF-1 cells and qRT-PCR was used to detect the expressions of Sirt1, glucose transporter 1(Glut1) and glucose transporter 4(Glut4). Lentivirus-mediated Sirt1-shRNA transduction was used to knockdown Sirt1 expression which was detected by qRT-PCR and Western blot. The expressions of Glut1 and Glut4 were determined by qRT-PCR.</p><p><b>RESULTS</b>Hypoxia promoted the expression of miR-486 and inhibited the expression of Sirt1. MiR-486 overexpression could inhibit the expression of Sirt1 and promote the expressions of Glut1 and Glut4, whereas miR-486 silencing upregulated the sirt1 expression and inhibited the expressions of Glut1 and Glut4. And inhibition of Sirt1 expression increased the expressions of Glut1 and Glut4.</p><p><b>CONCLUSION</b>MiR-486 can regulate the glycometabolism of hematopoietic cells by targeting Sirt1.</p>

Roles of SPK in Regulation of Hypoxia Induced Proliferation and Glucose Consume of Leukemia Cells / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To clarify the roles of SPK pathway in the regulation of proliferation, survival and glucose consume of human erythroleukemia TF-1 cells.</p><p><b>METHODS</b>The interfering in SPK expression of TF-1 cells was performed using leutivirus vector-mediated shRNA, the interference efficacy of SPK in TF-1 cells was detected by RT-qPCR and Western blot, the viability of TF-1 cell proliferation was detected by using CCK-8 method, the apoptosis of TF-1 cells was determined by flow cytmetry with Annexin V staining.</p><p><b>RESULTS</b>Hypoxia up-regulated the expression of HIF-1α, HIF-2α, and SPK in TF-1 cells. SPK treatment resulted in reduced proliferation and induced apoptosis in TF-1 cells. Furthermore, knockdown of the SPK significantly reduced utilization and consumption of glucose.</p><p><b>CONCLUSION</b>The SPK is key signalling molecule involved in regulation of hypoxia-induced proliferation and glucose metabolism in TF-1 cells, and plays an important rote in proliferation and energy metabolism of leukemia cells.</p>

Joint detection of ERCC1, TUBB3, and TYMS guidance selection of docetaxel, 5-fluorouracil and cisplatin (DDP) individual chemotherapy in advanced gastric cancer patients.

BACKGROUND: To investigate the guidance selection of docetaxel (D), cisplatin (DDP) (C), and 5-fluorouracil (5-FU) (F) as individual chemotherapy agents via joint detection of ERCC1, TUBB3, and TYMS genes in patients with advanced gastric cancer (AGC). METHOD: Clinical data of 120 patients with AGC who enrolled in our hospital between May 2009 and May 2012 were analyzed. These patients were randomly assigned to experimental and control groups. The mRNA expression of ERCC1, TUBB3, and TYMS was measured by DNA chip technology in the experimental group. Different chemotherapies were administered according to the mRNA expression levels of the three genes, while DCF chemotherapy was directly applied to the control group. Correlation between the three genes' mRNA levels, efficiency rate, the median time to progression (MTP), median survival time (MST) and adverse reactions was evaluated. RESULTS: As a result, there was a significant correlation between ERCC1 and TUBB3 mRNA expression (P = 0.005), but no obvious correlation between TUBB3 and TYMS or ERCC1 and TYMS. There was also no significant difference in the efficiency rate of chemotherapy (50% versus 55%; P = 0.357) and the MTP (10 months versus 7 months; P = 0.091) between the two groups. However, there was obvious significance in MST (13.7 months versus 11.6 months; P = 0.004). Additionally, the experimental group provided us with a more effective way for controlling adverse reactions to chemotherapy. CONCLUSION: Combination regimen of D, C, and F in AGC patients according to their ERCC1, TUBB3, and TYMS mRNA expression level may reduce adverse reactions and improve MST.

A genetic mechanism for Tibetan high-altitude adaptation.

Tibetans do not exhibit increased hemoglobin concentration at high altitude. We describe a high-frequency missense mutation in the EGLN1 gene, which encodes prolyl hydroxylase 2 (PHD2), that contributes to this adaptive response. We show that a variant in EGLN1, c.[12C>G; 380G>C], contributes functionally to the Tibetan high-altitude phenotype. PHD2 triggers the degradation of hypoxia-inducible factors (HIFs), which mediate many physiological responses to hypoxia, including erythropoiesis. The PHD2 p.[Asp4Glu; Cys127Ser] variant exhibits a lower K(m) value for oxygen, suggesting that it promotes increased HIF degradation under hypoxic conditions. Whereas hypoxia stimulates the proliferation of wild-type erythroid progenitors, the proliferation of progenitors with the c.[12C>G; 380G>C] mutation in EGLN1 is significantly impaired under hypoxic culture conditions. We show that the c.[12C>G; 380G>C] mutation originated ∼8,000 years ago on the same haplotype previously associated with adaptation to high altitude. The c.[12C>G; 380G>C] mutation abrogates hypoxia-induced and HIF-mediated augmentation of erythropoiesis, which provides a molecular mechanism for the observed protection of Tibetans from polycythemia at high altitude.

Contraction responses of isolated aortic rings of pika (Ochotona curzoniae) and Sprague-Dawley rat to hypoxia / 生理学报

The aim of the present study was to observe the effects of hypoxia on tensions of aortic rings of pika (Ochotona curzoniae) and Sprague-Dawley (SD) rat. The aortic rings were prepared, and in vitro vascular ring perfusion was used to assay the effects of hypoxia or different drugs on contraction responses of the rings with or without endothelium. The results showed that, there was no difference of the contractions to KCl (80 mmol/L) between the aortic rings of the pikas and SD rats. After pre-contraction with NE (1 μmol/L), the aortic rings with endothelium of the SD rats showed obvious relaxation to ACh (1 μmol/L), whereas the aortic rings of the pikas, no matter with or without endothelium, showed significant and unusual contraction to ACh. The aortic rings of pikas, no matter with or without endothelium, exhibited greater contraction when treated by 1 h of hypoxia, compared with those in SD rats; The similar result was showed under hypoxia in combination with Ca(2+) removal. These results suggest that the contraction response to hypoxia in pika is more sensitive compared to that in SD rat, which is dependent on the release of calcium from intracellular calcium store.

Effect of different altitudes on telomere length of rat peripheral blood leukocyte / 生理学报

The present study was aimed to investigate the effect of different altitudes on telomere length of rat peripheral blood leukocyte and possible mechanism. Sixty male rats were randomly divided into three groups, lower altitude control group (10 m), moderate altitude group (2 260 m) and very high altitude group (simulated 5 000 m). The moderate altitude group and very high altitude group rats were transported to Xining and hypobaric chamber in Qinghai University, respectively. The peripheral blood specimens were extracted 30 d after the transportation. By means of real-time PCR, automatic blood cell analyzer, ELISA, TBA and WST-1 methods, the telomere lengths of blood leukocyte, the hemoglobin (Hb) contents, the plasma levels of telomerase reverse transcriptase (TERT) and hypoxia-inducible factor 1α (HIF-1α), the plasma content of malondialdehyde (MDA) and superoxide dismutase (SOD) activity were measured, respectively. The results showed that the telomere lengths of peripheral blood leukocyte in moderate altitude group were longer than those in control group and very high altitude group. The changes of TERT were compatible with the telomere length of peripheral blood leukocyte under different altitudes. The levels of HIF-1α in moderate altitude group and very high altitude group were higher than that of control group. The very high altitude group showed decreased SOD activities and increased level of MDA, compared with the other two groups. These results suggest that the telomere lengths of rat peripheral blood leukocyte in moderate altitude are elongated, and that the telomere-elongating effect is lost under very high altitude. The changes of HIF-1α, TERT and oxidative stress damage are the main mechanisms of telomere length changes. Moderate altitude living might be beneficial to increasing the life span in mammals.

No relation between ACE-I/D polymorphism and high altitude pulmonary edema in the Han Chinese / 中国应用生理学杂志

<p><b>OBJECTIVES</b>To explore whether the angiotensin I -converting enzyme (ACE) I/D (insertion/ deletion) polymorphism is associated with the susceptibility to high altitude pulmonary edema (HAPE) in the Han Chinese.</p><p><b>METHODS</b>One hundred and forty-seven HAPE-p (HAPE patients) and 193 HAPE-r (HAPE resistants) were enrolled from the Yushu earthquake reconstruction workers in Qinghai province where the altitude is over 3 500 m above sea level. Blood samples were collected from each of the HAPE-p and HAPE-r groups. Information about physiological phenotypes was obtained via fieldwork investigation. The ACE-I/D polymorphism in HAPE-p and HAPE-r was detected by polymerase chain reaction (PCR).</p><p><b>RESULTS</b>The SaO2 was significantly lower while HR was significantly higher in HAPE-p group than those in HAPE-r group. The genotype frequencies of ACE-I/D for II, ID, DD in HAPE-r and HAPE-p groups were 0.430, 0.446, 0.124 and 0.435, 0.469, 0.095, respectively, the allelic frequencies of I and D were 0.650, 0.350 and 0.670, 0.330, respectively. The OR of ID, DD and D alleles relative to II for HAPE was 0.961 (0.610-1.514), 1.322 (0.634-2.758) and 1.080 (0.783-1.489). There was no significant difference of the genotypic and the allelic frequencies in ACE-I/D polymorphism between HAPE-p and HAPE-r groups.</p><p><b>CONCLUSIONS</b>There is no relation between ACE-I/D polymorphism and HAPE in the Han Chinese.</p>

Energy power in mountains: difference in metabolism pattern results in different adaption traits in Tibetans / 中国应用生理学杂志

Energy metabolism plays an important role in life survival for species living in high altitude hypoxia condition. Air-breathing organisms require oxygen to create energy. Tibetans are the well-adapted highlanders in Qinghai-Tibetan Plateau. It was thought that different metabolic approaches could lead to different adaptation traits to high altitude hypoxia. Recently identified hypoxia inducible factors pathway regulators, endothelial PAS domain protein1 (EPAS1)/HIF-2a and PPARA, were involved in decreasing hemoglobin concentrations in Tibetans. Because EPAS1 and PPARA also modulated the energy metabolism during hypoxia, we hypothesized that positive selected EPAS1 and PPARA genes were also involved in unique energy metabolisms in Tibetans. In this brief review, we take a look into genetic determinations to energy metabolisms for hypoxia adaptations traits in Tibetans and mal-adaptive conditions such as high altitude diseases.

Neurological adaptations to hypoxia in Tibetan antelope (Pantholops hodgsonii) with a view of molecular biology of respiratory globin-neuroglobin / 中国应用生理学杂志

Neuroglobin (Ngb) is a respiratory protein that is preferentially expressed in brain of mouse and man. In this article, Tibetan antelope, living at altitude of 3 000-5 000 m for millions of years, was selected as the model of hypoxia-tolerant adaptation species. Using reverse transcription polymerase chain reaction (RT-PCR) and Western blot techniques, expression of Ngb gene was amplified and analyzed in antelope brain tissue. Our results showed that Ngb homology protein in Tibetan antelope was identified with more sequence similarity with cattle (96%), sheep (95%), and human (95%). We detected that there were some mutations occurred in the Open Reading Frame of Ngb in Tibetan antelope compared with sheep. Phylogenetic analysis of Ngb chain showed that it was closer to cattle than the others. This study suggests possible roles of central nervous system enriched Ngb in adaptation of Tibetan antelope to extremely high altitude.

Study on the content of myoglobin and the activity of lactate dehydrogenase and malate dehydrogenase in skeletal muscle of tibetan antelope / 中国应用生理学杂志

<p><b>OBJECTIVE</b>To explore the adaptive mechanism to hypoxia in skeletal muscle of tibetan antelope.</p><p><b>METHODS</b>Tibetan sheep which living at the same altitude (4 300 m) with tibetan antelope and low altitude (1 800 m) sheep as control, the content of myoglobin (Mb) and lactic acid (LA), the activity of lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) in skeletal muscles among three animals were analyzed by spectrophotometer.</p><p><b>RESULTS</b>The content of myoglobin in skeletal muscle of tibetan antelope significantly higher than that of tibetan sheep and low altitude sheep (P < 0.05). And the content of LA in skeletal muscle of tibetan antelope significantly lower than that of tibetan sheep and low altitude sheep (P < 0.05), activity of LDH and MDH in skeletal muscle was significantly lower and higher respectively than that of tibetan sheep and low altitude sheep (P < 0.05). There was no significant difference between tibetan sheep and low altitude sheep.</p><p><b>CONCLUSION</b>Tibetan antelope may improve their ability to get oxygen under hypoxia by increasing the content of myoglobin in skeletal muscle, and the proportion of aerobic metabolism is high in skeletal muscle, it may be relate that with high myoglobin content in skeletal muscle, we suppose that high myoglobin content in skeletal muscle of tibetan antelope might be one of the molecular basis to adapt hypoxia.</p>

Comparisons of endocrine hormones levels between Tibetan antelope and Tibetan sheep / 生理学报

The Tibetan antelope, a prototype mammal, has developed a unique adaptation to extreme high altitude-associated hypoxia. To investigate the role of the endocrine system in adaptation to high altitude in the Tibetan antelope, comparisons of endocrine hormones levels between Tibetan antelope (n = 9) and Tibetan sheep (n = 10) were performed. Both two kinds of animals were captured at an altitude of 4 300 m and then transported to experimental base at 2 800 m altitude. The blood samples were drawn from right external jugular vein in the next morning, and the 20 hormones in hypothalamus-adenohypophysis-peripheral hormonal axis were measured with radioimmunoassay or enzyme-linked immunosorbent assay. Heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean pulmonary arterial pressure (mPAP) were recorded using catheterization. Moreover, hemoglobin (Hb) content was measured by blood analyser. The results showed that, the levels of FT(3), FT(4) and Ang II in Tibetan antelope were significantly lower than those in Tibetan sheep, whereas TRH, CRH, GHRH, F, E(2), Ald, ACTH and CGRP levels were significantly greater in Tibetan antelope than those in the Tibetan sheep. Compared with Tibetan sheep, Tibetan antelope showed lower HR, mPAP, SBP, DBP and Hb content. In Tibetan antelope and Tibetan sheep, both Hb and Ang II were correlated positively with respective mPAP. In Tibetan antelope, FT(3) level was correlated positively with GH and negatively with ACTH. These results suggest that the endocrine system of Tibetan antelope is characterized by low energy expenditure and high stress, which may be one of the mechanisms underlying the Tibetan antelope adaptation to chronic hypoxia.