Research progress of ferroptosis in hypoxia-associated brain injury / 生理学报

Cerebral hypoxia often brings irreversible damage to the central nervous system, which seriously endangers human health. It is of great significance to further explore the mechanism of hypoxia-associated brain injury. As a programmed cell death, ferroptosis mainly manifests as cell death caused by excessive accumulation of iron-dependent lipid peroxides. It is associated with abnormal glutathione metabolism, lipid peroxidation and iron metabolism, and is involved in the occurrence and development of various diseases. Studies have found that ferroptosis plays an important role in hypoxia-associated brain injury. This review summarizes the mechanism of ferroptosis, and describes its research progress in cerebral ischemia reperfusion injury, neonatal hypoxic-ischemic brain damage, obstructive sleep apnea-induced brain injury and high-altitude hypoxic brain injury.

The protective effect of betelnut polyphenols on exercise-induced fatigue at high altitude and its network pharmacology in rats / 中国药理学通报

Aim: To explore the protective effect of betelnut polyphenols on high altitude exercise-induced fatigue in rats, and to select the main targets to carry out network pharmacology research to preliminarily explore its protective mechanism. Methods: We compared the protective effects of areca catechu polyphenols on high altitude exercise fatigue in rats in low, medium and high dose groups (400, 800, and 1600 mg·kg

The protective effect of catechin on acute high-altitude hypoxic injury / 中国药理学通报

Aim To study the protective effect of catechin on acute altitude injury in rats. Methods Rats were randomly divided into six groups: control group, altitude hypoxia model group, rhodiola capsule group, low -, middle-and high dose of catechin groups. After three days of preventive administration, animals were rushed to 4 010 m altitude. After five days of continuous administration, abdominal aortic blood of rats was collected for blood gas detection. Cardiac, brain and lung tissues were collected for HE staining to observe the pathological changes. MDA content, GSH content, NO content, SOD activity of myocardial, brain and lung tissues were detected, so were IL-6 and TNF-α content in serum. Results Compared with the control group, blood oxygen saturation of rats of altitud hypoxia model group was significantly reduced, while myocardial, brain and lung tissues were damaged to different degrees. MDA and NO content increased, while GSH content and SOD activity decreased. The serum inflammatory factors TNF-α and IL-6 levels were elevated significantly. After catechin treatment, blood oxygen saturation of hypoxia rats significantly increased (P < 0. 05). HE staining results showed that myocardial, brain and lung tissue injury was alleviated to some extent. MDA, NO, IL-6 and TNF-α content were down-regulated, while GSH content and SOD activity were up-regulated respectively. Conclusions Catechin can resist high altitude hypoxia and protect the main organs from hypoxia injury in rats acute exposed to altitude, which is related to alleviating oxidative stress and inflammation caused by acute hypoxia exposure.

Study on the protective effect of salidroside on memory impairment in mice under high altitude hypoxia / 中国药理学通报

Aim To explore the effect of salidroside on the learning and memory ability of mice under high altitude hypoxia. Methods Forty-eight C57BL/6J male mice were randomly divided into plain control group, plateau model group and salidroside group according to their body weight, with 16 mice in each group. The animals in each group were given prophylactic doses for three days and then rushed to a plateau with an altitude of 4 010 m. After one day of hypoxia exposure, Morris water maze was performed to test the learning and memory ability of mice; malondialdehyde(MDA), hydrogen peroxide(H

Effects of plateau hypoxia on the pharmacokinetics and pharmacodynamics of atorvastatin calcium in hyperlipidemic rats / 中国药理学通报

Objective To study the effect of simulated high altitude hypoxia on the pharmacokinetics and pharmacodynamics of atorvastatin calcium in hyperlipidemia rats. Methods The wistar rats with hyperlipidemia induced by high-fat diet were divided into normoxia group and hypoxia group. Rats in the hypoxia group received a 14-day chronic hypoxia exposure at simulated an altitude of 5, 500 m. The two groups were given atorvastatin calcium(20 mg•kg

The research progress of high altitude environment-associated chronic obstructive pulmonary disease and therapeutic drugs / 生理学报

The plateau environment is characterized by low oxygen, low air pressure, low temperature, and strong ultraviolet rays, etc. Chronic obstructive pulmonary disease (COPD) is a preventable and treatable chronic lung disease. High altitude environment increases COPD prevalence, clinical manifestation and mortality. The therapeutic window of theophylline drugs for COPD is narrow, and the high altitude environment has an influence on the pharmacokinetics of the drugs. This review summarizes the differences in the prevalence, mortality, clinical manifestation and clinical symptoms of COPD in the plateau and plain, providing a basis for identifying the risk factors of COPD in the plateau areas. The effects of plateau hypoxic environment on the pharmacokinetics of COPD drugs were also discussed. It can provide a rationale for more effective prevention and treatment of COPD at high altitude.

The protective effect of fluoxetine hydrochloride on brain tissues of rats with high altitude cerebral edema / 中国药理学通报

Aim To study the protective effect of fluoxetine hydrochloride on brain tissues of rats with simulated high altitude cerebral edema(HACE)and its mechanism.Methods The optimal dosage and time of fluoxetine hydrochloride were determined by the hypoxia tolerance test of mice under normal pressure.The rat model of brain edema at high altitude was established by large-scale low-pressure oxygen chamber.HE staining was used to observe the pathological changes of brain tissues in rats.Microplate reader was used to detect the corresponding indexes of oxidative stress such as malondialdehyde(MDA)level and superoxide dismutase(SOD)activity.The expressions of hypoxia-related proteins HIF-1α,VEGF,MMP-9,AQP4 and SERT were detected by Western blot.Results Compared with the hypoxia model group,after the intervention of fluoxetine hydrochloride,the survival time of mice was prolonged,and the middle dose of fluoxetine(14 mg·kg-1)had the best effect,with an extension rate of 17.78%.The pathological damage of brain was improved,the water content of brain decreased,and the permeability of blood-brain barrier decreased.MDA content in rat brain decreased and SOD activity increased.Western blot results showed that HIF-1α,VEGF,MMP-9,AQP4,SERT protein were significantly down-regulated.Conclusions Fluoxetine has protective effect on rats with brain edema at high altitude,and its mechanism may be related to improving oxidative stress,activating HIF-1α/VEGF/MMP-9 signaling pathway and affecting the expression of SERT protein.SERT may be a potential target for treating brain edema at high altitude.

The effect of acute hypobaric hypoxia on bile acid composition in the small intestine of rats / 药学学报

In order to clarify the influence of acute hypobaric hypoxia on the bile acids of the rat small intestine, we used ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to identify bile acids in the contents of the small intestine from untreated and acute hypobaric hypoxia-treated rats. Thirty-nine bile acids were detected; PCA and OPLS-DA analysis revealed marked differences in the composition of bile acids between the untreated and the acute hypobaric hypoxia groups. Bile acids were screened with VIP > 1, |log2FC| ≥ 1, P < 0.05, and a total of 7 bile acids with significant differences in content between the two groups were obtained, including 5 conjugated bile acids, 2 unconjugated bile acids; in addition, the content of conjugated bile acids has risen in the treated group. This study demonstrated the influence of high-altitude hypoxic environment on bile acid composition and metabolism in rats. All the animal experiments in this study were approved by the 940th Hospital Ethics Committee (approval No: 2020KYLL012).

Efficacy of low frequency pulsed electromagnetic field therapy in treatment of peritumoral edema of glioma / 上海预防医学

Objective To evaluate the efficacy of low frequency pulsed electromagnetic field (LFPEMF) on peritumoral edema in patients with glioma, providing a theoretical basis for clinical treatment of peritumoral edema. Methods This study included 32 patients with recurrent cerebral glioma with peritumoral edema after the operation of glioma in department of glioma, Beijing Shijitan Hospital, Capital Medical University from March 2017 to December 2018.The period of LFPEMF treatment was 10-14 days.The clinical symptoms related to brain edema were recorded before and after treatment.The National Institutes of Health Stroke Scale (National Institute of health stroke scale, NIHSS), Karnofsky quality of life score (KPS), brain edema and tumor range in cranial MRI, T lymphocyte subgroup CD4+/CD8+, superoxide dismutase (SOD) were recorded.The SPSS21.0 statistical analysis software was used to carry out analysis by using self controlled study.P < 0.05 was statistically significant. Results After the treatment of LFPEMF, the results showed that LFPEMF was effective in 25 patients, invalid in 7 patients, and the total effective percentage was 78.13%.The area of brain edema was significantly improved after using LFPEMF(P < 0.05).There was no significant improvement in the area of brain tumor after using LFPEMF therapy (P>0.05).KPS and NIHSS scores improved significantly after using LFPEMF (P < 0.05). Conclusion In the patients with peritumoral edema of glioma, the application of LFPEMF in the patients′ Yongquan point and Lao Gong point can reduce peritumoral edema, and improve clinical symptoms.

Efficacy of low frequency pulsed electromagnetic field therapy in treatment of peritumoral edema of glioma / 上海预防医学

Objective To evaluate the efficacy of low frequency pulsed electromagnetic field (LFPEMF) on peritumoral edema in patients with glioma, providing a theoretical basis for clinical treatment of peritumoral edema. Methods This study included 32 patients with recurrent cerebral glioma with peritumoral edema after the operation of glioma in department of glioma, Beijing Shijitan Hospital, Capital Medical University from March 2017 to December 2018.The period of LFPEMF treatment was 10-14 days.The clinical symptoms related to brain edema were recorded before and after treatment.The National Institutes of Health Stroke Scale (National Institute of health stroke scale, NIHSS), Karnofsky quality of life score (KPS), brain edema and tumor range in cranial MRI, T lymphocyte subgroup CD4+/CD8+, superoxide dismutase (SOD) were recorded.The SPSS21.0 statistical analysis software was used to carry out analysis by using self controlled study.P < 0.05 was statistically significant. Results After the treatment of LFPEMF, the results showed that LFPEMF was effective in 25 patients, invalid in 7 patients, and the total effective percentage was 78.13%.The area of brain edema was significantly improved after using LFPEMF(P < 0.05).There was no significant improvement in the area of brain tumor after using LFPEMF therapy (P>0.05).KPS and NIHSS scores improved significantly after using LFPEMF (P < 0.05). Conclusion In the patients with peritumoral edema of glioma, the application of LFPEMF in the patients′ Yongquan point and Lao Gong point can reduce peritumoral edema, and improve clinical symptoms.

Advances in the study of gut pharmacomicrobiomics / 药学学报

The intestinal flora is a diverse microbial community living in the digestive tract of humans and animals. This microbial community can modify drugs in unpredictable ways, leading to changes in the pharmacokinetics of drugs in vivo and affecting their clinical efficacy. Here we review drug metabolism mediated by intestinal flora from three aspects: prodrug activation, drug inactivation, and toxicity. The effect of the stable hypoxic environment on the composition and quantity of intestinal flora and the effect on drug metabolism are discussed. Understanding the influence of intestinal flora on drug metabolism is not only conducive to individualized medication, but also conducive to rational drug design, allowing us to predict and understand individual drug response and regulate the intestinal microbiome to improve drug efficacy, thus promoting personalized medicine.

Efficacy and safety of chimeric antigen receptor-T cells in the treatment of B cell lymphoma: a systematic review and meta-analysis / 中华医学杂志(英文版)

BACKGROUND@#Conventional treatment has limited efficacy in relapsed/refractory B-cell lymphoma. Since chimeric antigen receptor T-cell (CAR-T) technology has shown high safety and results in high remission rates, we investigated its efficacy and safety in B-cell lymphoma treatment and analyzed potential affecting factors to provide evidence for therapeutic strategies and applications.@*METHODS@#We searched databases including PubMed, Embase, and Cochrane up to July 2019. Meta-analysis 1 was conducted to study the efficacy of CAR-T cell for treating B-cell lymphoma, measuring the response rate and complete remission rate as outcomes. Sub-group analysis was performed for age, pathological type, target antigen, co-stimulatory molecule, and conditioning chemotherapy. Meta-analysis 2 was undertaken on the safety of the treatment with the incidence rate of toxicity (cytokine-releasing syndrome [CRS], neurotoxicity) as an outcome.@*RESULTS@#Seventeen studies were included in the systematic review and meta-analysis. It was found that CAR-T cells had good therapeutic effects in the following cases: B-cell lymphoma (patients ≥65 years old); diffuse large B-cell lymphoma pathological type; patients with treatment target antigen other than CD19; patients treated with co-stimulatory molecules other than CD28, including 4-1BB+CD28 or 4-1BB; and patients treated with cyclophosphamide/fludarabine pre-treatment protocol conditioning chemotherapy. Although the CRS and neurotoxicity incidences were high, most were reversible with minimal risk of death.@*CONCLUSION@#CAR-T cell treatment is safe for clinical application; however, toxicity effects should be monitored.

Features and therapeutic potential of T-cell receptors in high-grade glioma / 中华医学杂志(英文版)

Background@#Previous studies have shown that endogenous T cells play an important role in the prolonged survival time of highgrade glioma (HGG) patients. Our objectives were to investigate the features of T-cell receptor (TCR) repertoires in HGG patients and to elucidate any potential therapeutic value.@*Methods@#During November 2011 and December 2018, tumor tissues and blood samples of 35 patients with HGG who underwent surgery at Beijing Tiantan Hospital or Beijing Shijitan Hospital were selected after surgery. After isolating DNA from samples, multiple rounds of PCR were performed to establish a DNA immune repertoire (IR). Then, the sequences and frequencies of the complementarity-determining 3 (CDR3) region in TCR beta chain (TRB) were identified by high-throughput sequencing and IR analysis. A survival follow-up was conducted monthly thereafter until December 2018. Finally, the t test and Mann-Whitney test were used to compare statistical differences between two sets of data.@*Results@#The Shannon diversity index (SHDI) of TRB sequences of HGG patients was significantly lower than that of healthy individuals (7.34 vs. 8.45, P = 0.001). The SHDI of TRB sequences of glioblastoma (GBM) patients with more than 16 months survival time was much higher than that of GBM patients with shorter survival times in both tumor tissues (3.48 ± 0.31 vs. 6.21 ± 0.33, t = -5.49, P = 0.002) and blood cells (6.02 ± 0.66 vs. 7.44 ± 0.32, t = -2.20, P = 0.036). In addition, patients achieved a distinctly higher proportion compared to that of healthy individuals in the proportion of TRBV9 and TRBV5 functional regions (9.83% vs. 6.83%, P = 0.001). Surgical tissue from patients who survived more than 16 months yielded a much higher proportion of TRBV4 and TRBV9 regions (7.14% vs. 3.28%, t = 3.18, P = 0.019). In surgical tissues from two GBM patients who survived for longer than 46 months, we found a potentially therapeutic TCR sequence.@*Conclusions@#HGG patients have less species diversity of TCR repertoires compared with that of healthy individuals. TRBV9 regions in TCRs may be protective factors for long-term survival of GBM patients.

Investigation and analysis on difference of cultivation technique situation of Salvia miltiorrhiza / 中国中药杂志

Salvia miltiorrhiza is one of the commonly used bulk medicinal materials, which has significant effect on cardiovascular disease, and are heavy demanded in Asia, Europe, North America, Russia and Africa. Consequently, increasing the yield and quality of S. miltiorrhiza has become a major concern worldwide. With the current wild resources of S. miltiorrhiza gradually decreasing, cultivated products occupy most of the markets. However, the cultivation area is widely distributed and the cultivation techniques is different, which lead to the quality and yield of S. miltiorrhiza in consistent. This paper combined visiting survey with document analysis to carry out the cultivation situation of S. miltiorrhiza in main cultivation areas of Shandong, Henan, Sichuan, Shanxi and Hebei provinces. There exist big differences of the ecological environment, mode of cultivation, fertilization, pest control, harvesting processing among the producing areas. We should carry on the ecological suitability zoning analysis and suitable cultivation of each area study to form a pattern of high quality and high yield for the sustainable development of S. miltiorrhiza cultivation.

Therapeutic Effect of Ershen Pill () Extract on Pi (Spleen)-Shen (Kidney) Yang Deficiency-Induced Diarrhea in Rat Model / 中国结合医学杂志

OBJECTIVE@#To investigate whether Ershen Pill (ESP, ) could alleviate the symptom of Pi (Spleen)-Shen (Kidney) yang deficiency (PSYD)-induced diarrhea in rat model and explore its anti-diarrhea mechanism.@*METHODS@#Seventy-five Sprague-Dawley rats were divided into 5 groups by a random number table, including control, positive, model, low-dose (LD) and high-dose (HD) ESP groups, 15 rats in each group. All the rats, except those in the control group, were developed PSYD induced-diarrhea based on its pathology and etiology. The rats in positive, LD and HD ESP groups were treated with Shenling Baizhu Pill (), LD (1.05 g/kg) or HD (3.50 g/kg) ESP petroleum ether extract once a day for 2 weeks, respectively. Body weight change and diarrhea index were measured. The histology scores of the kidney were evaluated via hematoxylin and eosin (HE) staining. Aquaporin-3 (AQP3) expression in the colon was analyzed by immunofluorescence, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, respectively.@*RESULTS@#Compared with the model group, oral administration of LD and HD ESP prevented body weight loss and inhibited diarrhea after 2-week treatment (P<0.05). Kidney deterioration was impeded, and the histology score in LD and HD ESP groups were 8.2 and 10.5, respectively, which were both higher than those in the model group (P<0.05). In addition, ESP treatment alleviated rat colitis, and HD ESP significantly improved the AQP3 positive staining intensity in the colon tissue compared with the model group. The result from Western blot revealed that AQP3 protein synthesis in colon tissue of LD and HD ESP groups increased by 2.1- and 5.9-fold compared with the model group (P<0.05). qRT-PCR result showed that AQP3 gene expression in the HD ESP group was also up-regulated by 2.5-fold normalized to the model group (P<0.05).@*CONCLUSION@#ESP extract effectively alleviates the symptoms of PSYD and relieves PSYD-induced diarrhea by improving AQP3 synthesis in the colon.

Features and therapeutic potential of T-cell receptors in high-grade glioma / 中华医学杂志(英文版)

BACKGROUND@#Previous studies have shown that endogenous T cells play an important role in the prolonged survival time of high-grade glioma (HGG) patients. Our objectives were to investigate the features of T-cell receptor (TCR) repertoires in HGG patients and to elucidate any potential therapeutic value.@*METHODS@#During November 2011 and December 2018, tumor tissues and blood samples of 35 patients with HGG who underwent surgery at Beijing Tiantan Hospital or Beijing Shijitan Hospital were selected after surgery. After isolating DNA from samples, multiple rounds of PCR were performed to establish a DNA immune repertoire (IR). Then, the sequences and frequencies of the complementarity-determining 3 (CDR3) region in TCR beta chain (TRB) were identified by high-throughput sequencing and IR analysis. A survival follow-up was conducted monthly thereafter until December 2018. Finally, the t test and Mann-Whitney test were used to compare statistical differences between two sets of data.@*RESULTS@#The Shannon diversity index (SHDI) of TRB sequences of HGG patients was significantly lower than that of healthy individuals (7.34 vs. 8.45, P = 0.001). The SHDI of TRB sequences of glioblastoma (GBM) patients with more than 16 months survival time was much higher than that of GBM patients with shorter survival times in both tumor tissues (3.48 ± 0.31 vs. 6.21 ± 0.33, t = -5.49, P = 0.002) and blood cells (6.02 ± 0.66 vs. 7.44 ± 0.32, t = -2.20, P = 0.036). In addition, patients achieved a distinctly higher proportion compared to that of healthy individuals in the proportion of TRBV9 and TRBV5 functional regions (9.83% vs. 6.83%, P = 0.001). Surgical tissue from patients who survived more than 16 months yielded a much higher proportion of TRBV4 and TRBV9 regions (7.14% vs. 3.28%, t = 3.18, P = 0.019). In surgical tissues from two GBM patients who survived for longer than 46 months, we found a potentially therapeutic TCR sequence.@*CONCLUSIONS@#HGG patients have less species diversity of TCR repertoires compared with that of healthy individuals. TRBV9 regions in TCRs may be protective factors for long-term survival of GBM patients.

Diagnostic value of multidetector CT in acute and chronic mesenteric venous thrombosis / 上海交通大学学报（医学版）

Objective · To analyze the multidetector CT (MDCT) manifestations of mesenteric venous thrombosis (MVT) and further explore the diagnostic value of MDCT in acute and chronic MVT. Methods · MDCT findings of 47 MVT patients clinically confirmed in Shanghai Sixth People's Hospital, Shanghai Jiao Tong University and Second People's Hospital in Kashgar from January 2012 to October 2018 were retrospectively analyzed. The mean CT value of thrombus on CT axial images of acute and chronic MVT was measured and calculated. According to CT values and CT manifestations, differences between the two groups were statistically analyzed. Results · Among 47 patients with MVT, there were 46 (97.87％) with filling defect of mesenteric vein and its branches, 34 (72.34％) with dilatation of blood vessels at the thrombosis site, 30 (63.82％) with intestinal wall thickening, 9 (19.15％) with enhanced delamination of intestinal wall, 11 (23.40％) with intestinal dilatation, 21 (44.68％) with ascites, and 25 (53.19％) with mesenteric edema. The mean CT value of MVT thrombus in acute group [ (42.88±17.77) HU] was higher than that in chronic group [ (31.80±6.18) HU] (P＜0.05). The proportion of MVT with vasodilation and target sign in acute group was higher than that in chronic group (P＜0.05). There was no difference in the ratio of other signs between the two groups. Conclusion · The MDCT findings of MVT patients are characteristic. CT value of thrombus, vasodilation and target sign are valuable in evaluating acute and chronic MVT.

Modulation of drug-metabolizing enzymes and transporters under hypoxia environment / 生理学报

Drug metabolism is significantly affected under hypoxia environment with changes of pharmacokinetics, expression and function of drug-metabolizing enzymes and transporters. Studies have shown that hypoxia increases the release of a series of inflammatory cytokines which can modulate drug metabolism. Besides, both hypoxia inducible factor 1α (HIF-1α) and microRNA-mediated pathways play a role in regulating drug metabolism. This article reviewed the impact and single-factor modulating mechanisms of drug metabolism under hypoxia, and put forward the speculation and prospects of multi-factor modulating mechanisms.

Impact of Weight Relief Raise on Acromiohumeral Distance in Patients with Thoracolumbar Spinal Cord Injury / 中国康复理论与实践

Objective:To study the effect of weight relief raise on acromiohumeral distance in patients with thoracolumbar spinal cord injury. Methods:The acromiohumeral distance of 20 patients with thoracolumbar spinal cord injury was measured by ultrasonic diagnostic system, respectively in the resting position and the supporting decompression position. Results:The acromiohumeral distance was significantly larger in the resting position than in the supporting decompression position (t = 6.933, P < 0.001). Conclusion:Support could reduce the subacromial space in patients with spinal cord injury and become a potential factor for subacromial tissue injury.

Analysis of genetic diversity of main morphological traits and chemical components in Glycyrrhiza uralensis germplasms / 中草药

Objective Based on the main morphological traits and chemical constituents of 42 Glycyrrhiza uralensis germplasm in China, the genetic diversity of them was analyzed comprehensively. Methods Twelve morphological traits and five kinds of chemical components of G. uralensis germplasm transplanted in the same place were collected. The genetic diversity index and coefficient of variation were calculated, using cluster analysis and principal component analysis for statistical analysis. Results Among the five chemical constituents, the highest genetic diversity index of liquiritin content was 2.05; The maximum coefficient of variation of isoliquiritin content was 99.50%; The content of liquiritin was moderately correlated with the content of isoliquiritin. Among 12 morphological traits, the highest genetic diversity index of plant height was 2.08, and the maximum coefficient of variation of actual fruit sequence was 37.09%. The variation of fruit type and plant type was greater than that of leaf type. Cluster analysis divided 42 germplasms into three types, and the second group had better germplasm quality. The principal component analysis reduced 17 indicators to six factors, with a cumulative contribution rate of 72.96%. Factor 6 was a factor that represents glycyrrhizic acid, liquiritin, and isoliquiritin. Conclusion The genetic diversity of the main morphological traits and chemical constituents of 42 G. uralensis germplasms is rich, and six excellent germplasms are V08, V10, V17, V34, V36, and V38.