Objective:To explore the mechanism of hypertension inducing erectile dysfunction(ED)using transcriptomics and network pharmacology.Methods:We randomly divided 12 male rats with spontaneous hypertension(SHT)into an L-arginine(LA)group(n=6)and an SHT model control(MC)group(n=6),took another 6 Wistar Kyoto male rats as normal controls(NC),and treated the animals in the LA group by intraperitoneal injection of LA at 400 mg/kg and those in the latter two groups with physio-logical saline,once a day,all for 7 days.Then we observed the blood pressure and penile erection of the rats,and determined the ex-pressions of the cGMP/PKG signaling pathway-related proteins and mRNAs in different groups using ELISA,Western blot and RT-qPCR.Results:Transcriptomics combined with network pharmacology showed that the cGMP/PKG signaling pathway played a key role in hypertension-induced ED.In vivo animal experiments revealed a significantly lower frequency of penile erections in the MC than in the NC group(1.33±0.52 vs 2.67±0.51,P＜0.05).The protein expressions of eNOS,PKG and sGC were markedly de-creased in the model controls compared with those the normal controls(P＜0.05),but remarkably upregulated in the LA group com-pared with those in the MC group(P＜0.05).Conclusion:Hypertension decreases the expressions of eNOS,NO,sGC,cGMP and PKG proteins and the level of testosterone by inhibiting the cGMP/PKG signaling pathway,which consequently suppresses the relaxa-tion of the penile vascular smooth muscle and reduces erectile function.

Interleukin 6 (IL-6), an important component of cardiac microenvironment, favors cardiac repair by improving cardiomyocyte regeneration in different models. This study aimed to investigate the effects of IL-6 on stemness maintenances and cardiac differentiation of mouse embryonic stem cells (mESCs). The mESCs were treated with IL-6 for two days, and then subjected to CCK-8 essay for proliferation analysis and quantitative real-time PCR (qPCR) to evaluate the mRNA expression of genes related to stemness and germinal layers differentiation. Phosphorylation levels of stem cell-related signal pathways were detected by Western blot. siRNA was used to interfere the function of STAT3 phosphorylation. Cardiac differentiation was investigated by the percentage of beating embryoid bodies (EBs) and qPCR analysis of cardiac progenitor markers and cardiac ion channels. IL-6 neutralization antibody was applied to block the endogenous IL-6 effects since the onset of cardiac differentiation (embryonic day of 0, EB0). The EBs were collected on EB7, EB10 and EB15 to investigate the cardiac differentiation by qPCR. On EB15, Western blot was applied to investigate the phosphorylation of several signaling pathways, and immunochemistry staining was adopted to trace the cardiomyocytes. IL-6 antibody was administered for two days (short term) on EB4, EB7, EB10 or EB15, and percentages of beating EBs at late developmental stage were recorded. The results showed that exogenous IL-6 promoted mESCs proliferation and favored maintenances of pluripotency, evidenced by up-regulated mRNA expression of oncogenes (c-fos, c-jun) and stemness markers (oct4, nanog), down-regulated mRNA expression of germ layer genes (branchyury, FLK-1, pecam, ncam, sox17), and increased phosphorylation of ERK1/2 and STAT3. siRNA targeting JAK/STAT3 partially attenuated the effects of IL-6 on cell proliferation and mRNA expression of c-fos and c-jun. During differentiation, long term IL-6 neutralization antibody application decreased the percentage of beating EBs, down-regulated mRNA expression of ISL1, GATA4, α-MHC, cTnT, kir2.1, cav1.2, and declined the fluorescence intensity of cardiac α actinin in EBs and single cell. Long term IL-6 antibody treatment decreased the phosphorylation of STAT3. In addition, short term (2 d) IL-6 antibody treatment starting from EB4 significantly reduced the percentage of beating EBs in late development stage, while short term IL-6 antibody treatment starting from EB10 significantly increased the percentage of beating EBs on EB16. These results suggest that exogenous IL-6 promotes mESCs proliferation and favors stemness maintenance. Endogenous IL-6 regulates mESC cardiac differentiation in a development-dependent manner. These findings provide important basis for the study of microenvironment on cell replacement therapy, as well as a new perspective for understanding the pathophysiology of heart diseases.
Animals ; Mice ; Interleukin-6 ; Mouse Embryonic Stem Cells ; Cell Differentiation ; Proto-Oncogene Proteins c-fos ; RNA, Messenger

Plasma nontargeted metabolomics technology was developed for investigating the effect and mechanism of improving kidney deficient in mice of Polygoni Multiflori Radix Praeparata. Thirty-five ICR mice were randomly divided into the control group, the model group, the BB24 h (braising with black bean sauce for 24 hours) group, the BB32 h group, and the BB40 h group. Biochemical indices in blood plasma of mice were measured by collecting eye blood after modeling. Changes in plasma endogenous metabolites of mice from each group were determined by ultra-performance liquid chromatography-linear trap quadrupole-orbitrap XL (UPLC-LTQ-orbitrap XL), and differential metabolites were screened. The results of pharmacodynamic investigation showed that compared to the model group, the levels of estradiol increased obviously in the BB24 h (P < 0.05), and the levels of cortisol increased obviously in BB32 h (P < 0.05). The hormone level of mice with kidney deficiency was significantly improved after taking processed Polygonum multiflorum. A total of 70 differential endogenous metabolites in blood plasma of mice were identified from all treatment groups, which mainly involved glycerophospholipid meta-bolism, arachidonic acid metabolism, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and linoleic acid metabolism. The study indicated that Polygoni Multiflori Radix Praeparata may play the role of tonifying liver and kidney by improving the disorder of hypothalamic-pituitary-adrenal axis and regulating lipid metabolism in mice. Correlation analysis on differential metabolites in blood plasma and the chemical constituents showed that stilbene glycosides and saccharides may be the key pharmacodynamic material basis. The present study provides a new reference and theoretical foundation for revealing the potential pharmacodynamic material basis and mechanism investigation on tonifying liver and kidney of Polygoni Multiflori Radix Praeparata. This study was carried out following the ethical guidelines and regulations for the use of laboratory animals of the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences and passed the animal experimental ethical review [No. SYXK (Jing) 2019-0003].

Objective: To compare the effects of two administration time strategies for rabbit antihuman thymocyte immunoglobulin (rATG) of 5mg/kg total dose in matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) . Methods: This study retrospectively analyzed the clinical data of 32 patients who received MSD-HSCT with 5 mg/kg rATG conditioning regimen at the Department of Hematology of the First Medical Center of the People's Liberation Army General Hospital from October 2020 to April 2022. The patients were classified into two groups: the 4d-rATG group (16 cases), who received antithymocyte globulin (ATG) from day -5 to day -2, and the 2d-rATG group (16 cases), who received ATG from day -5 to day -4. Between the two groups, the transplantation outcomes, serum concentrations of active antithymocyte globulin (ATG) in patients from -4 days to 28 days after graft infusion (+28 days), and the reconstitution of lymphocyte subsets on days +30, +60, and +90 were compared. Results: The cumulative incidences of acute graft-versus-host disease at 100 days after graft infusion were 25.0% (95% CI 7.8% -47.2% ) and 18.8% (95% CI 4.6% -40.2% ) (P=0.605) in the 4d-rATG group and 2d-rATG group, respectively. The 1-year cumulative incidences of chronic graft-versus-host disease were 25.9% (95% CI 8.0% -48.6% ) and 21.8% (95% CI 5.2% -45.7% ) (P=0.896). The 1-year cumulative incidence of relapse was 37.5% (95% CI 18.9% -65.1% ) and 14.6% (95% CI 3.6% -46.0% ) (P=0.135), and the 1-year probabilities of overall survival were 75.0% (95% CI 46.3% -89.8% ) and 100% (P=0.062). The total area under the curve (AUC) of serum active ATG was 36.11 UE/ml·d and 35.89 UE/ml·d in the 4d-rATG and 2d-rATG groups, respectively (P=0.984). The AUC was higher in the 4d-rATG group than that in the 2d-rATG group (20.76 UE/ml·d vs 15.95 UE/ml·d, P=0.047). Three months after graft infusion, the average absolute count of CD8(+) T lymphocytes in the 4d-rATG group was lower than that in the 2d-rATG group (623 cells/μl vs 852 cells/μl, P=0.037) . Conclusion: The efficiencies of GVHD prophylaxis in MSD-PBSCT receiving 4d-ATG regimen and the 2d-rATG regimen were found to be similar. The reconstruction of CD8(+)T lymphocytes in the 2d-rATG group was better than that in the 4d-rATG group, which is related to the lower AUC of active ATG after transplantation.
Animals ; Rabbits ; Humans ; Antilymphocyte Serum/therapeutic use* ; Siblings ; Retrospective Studies ; Hematopoietic Stem Cell Transplantation ; Tissue Donors ; Graft vs Host Disease/drug therapy* ; Transplantation Conditioning

Aconiti Lateralis Radix Praeparata polysaccharides(AP) are a class of bioactive macromolecules extracted from the herbs of Aconiti Lateralis Radix Praeparata and its various processed products. Since the AP was first separated in 1986, its pharmacological effects include immune regulation, anti-tumor, anti-depression, organ protection, hypoglycemia, and anti-inflammatory had been found. In recent years, with the development of polysaccharide extraction, separation, and structure identification technologies, more than 20 kinds of AP have been separated from Aconiti Lateralis Radix Praeparata and its processed products, and they have ob-vious differences in relative molecular weight, monosaccharide composition, glycosidic bond, structural characteristics, and biological activities. In particular, AP may be dissolved, degraded, or allosteric under the complex processing environment of fermentation, soaking, cooking, etc., leading to the diversified structure of AP, which provides a possibility for further understanding of the structure-activity relationship of AP. Therefore, this study systematically reviewed the research progress on the structure and structure-activity relationship of AP, summarized the biological activity and potential action mechanism of AP, and discussed the technical challenges in the development and application of AP, so as to promote the quality control and further development and utilization of AP.
Drugs, Chinese Herbal/chemistry* ; Aconitum/chemistry* ; Polysaccharides/pharmacology* ; Structure-Activity Relationship ; Technology

Objective: To analyze the occurrence of recompensation conditions in patients with chronic hepatitis B virus-related decompensated cirrhosis after entecavir antiviral therapy. Methods: Patients with hepatitis B virus-related decompensated cirrhosis with ascites as the initial manifestation were prospectively enrolled. Patients who received entecavir treatment for 120 weeks and were followed up every 24 weeks (including clinical endpoint events, hematological and imaging indicators, and others) were calculated for recompensation rates according to the Baveno VII criteria. Measurement data were compared using the Student t-test or Mann-Whitney U test between groups. Categorical data were compared by the χ (2) test or Fisher's exact probability method between groups. Results: 283 of the 320 enrolled cases completed the 120-week follow-up, and 92.2% (261/283) achieved a virological response (HBV DNA 20 IU/ml). Child-Pugh and MELD scores were significantly improved after treatment (8.33 ± 1.90 vs. 5.77 ± 1.37, t = 12.70, P < 0.001; 13.37 ± 4.44 vs. 10.45 ± 4.58, t = 5.963, P < 0.001). During the 120-week follow-up period, 14 cases died, two received liver transplants, 19 developed hepatocellular cancer, 11 developed gastroesophageal variceal bleeding, and four developed hepatic encephalopathy. 60.4% (171/283) (no decompensation events occurred for 12 months) and 56.2% (159/283) (no decompensation events occurred for 12 months and improved liver function) of the patients had achieved clinical recompensation within 120 weeks. Patients with baseline MELD scores > 15 after active antiviral therapy achieved higher recompensation than patients with baseline MELD scores ≤15 [50/74 (67.6%) vs. 109/209 (52.2%), χ (2) = 5.275, P = 0.029]. Conclusion: Antiviral therapy can significantly improve the prognosis of patients with hepatitis B virus-related decompensated cirrhosis. The majority of patients (56.2%) had achieved recompensation. Patients with severe disease did not have a lower probability of recompensation at baseline than other patients.
Humans ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic/drug therapy* ; Antiviral Agents/adverse effects* ; Esophageal and Gastric Varices/complications* ; Liver Cirrhosis/complications* ; Treatment Outcome ; Gastrointestinal Hemorrhage/complications* ; Hepatitis B/drug therapy*

Objective: To investigate the clinical manifestations and genetic features of 2 children with Smith-Kingsmore syndrome caused by MTOR gene variation and review the literature. Methods: The clinical data of 2 children carrying MTOR gene variant, diagnosed at Xi'an Children's Hospital from April 2018 to April 2021, were retrospectively summarized."MTOR"and"Smith-Kingsmore syndrome"were used as key words to search at China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, PubMed and OMIM up to August 2021. The characteristics of MTOR gene variation and the clinical phenotype of children with Smith-Kingsmore syndrome were summarized. Results: Two children were both females, aged 1.5 years and 2 years respectively, the onset age were both in infancy. They both had developmental delay, megalencephaly and abnormal face. Both whole exome sequencing revealed a de novo heterozygous missense variant in MTOR gene. One case carried c.5395G>A (p.Glu1799Lys) and the other case carried c.7234G>C (p.Asp2412His). There was no literature of MTOR gene variation in Chinese. So far, a total of 45 cases were reported worldwide with detailed clinical information. Eleven variations in MTOR gene were involved, which were all heterozygous missense mutations. Among them, p.Glu1799Lys was the most common sites (28 cases,62%). Another case carried c.7234G>C (p.Asp2412His) was not reported before. Summarizing the 47 cases (including these 2 cases), 46 cases had developmental delay or intellectual disability, 9 cases had developmental regression,42 cases had megalencephaly, 30 cases had facial malformation,16 cases had hypotonia, 17 cases had autism spectrum disorders, 3 cases had hyperactivity, 3 cases had obsessive compulsive disorder, 13 cases had eye diseases, 11 cases had cutaneous vascular malformation, and 9 cases had hypoglycemia. Conclusions: The main clinical features of Smith-Kingsmore syndrome include megalencephaly, developmental delay or intellectual disability, and facial malformation, which can be combined with epilepsy, autism spectrum disorder, hypotonia, hypoglycemia and so on. The variation of MTOR gene is the cause of Smith-Kingsmore syndrome.
Autism Spectrum Disorder ; Female ; Humans ; Hypoglycemia ; Intellectual Disability/genetics* ; Megalencephaly/genetics* ; Muscle Hypotonia ; Mutation ; Retrospective Studies ; TOR Serine-Threonine Kinases/genetics*

The present study collected, collated, analyzed, and evaluated randomized controlled trial(RCT) of Chinese patent medicine published in Chinese and English journals in 2020, and summarized clinical evidence of Chinese patent medicine in stages, providing references for follow-up clinical research and evidence transformation and application. On the basis of the collection in the Traditional Chinese Medicine(TCM) Clinical Evidence Database System(EVDS), CNKI, Wanfang, SinoMed, Cochrane Library, PubMed, and EMbase were searched for RCTs of Chinese patent medicine published in 2020, and their research characteristics and methodological quality were analyzed and evaluated. A total of 1 285 research papers on Chinese patent medicine(1 257 in Chinese/28 in English) were included, involving 146 054 patients and 639 Chinese patent medicines, including 526 oral drugs, 68 injections, and 45 external drugs. A total of 412 diseases in 23 types were involved, which were dominated by circulatory system diseases and respiratory system diseases, specifically, cerebral infarction and angina pectoris. The sample size ranged from 20 cases to 2 673 cases, and 57.67% of RCTs had samples sizes less than 100. Single-center trials were the main ones, and multi-center trials only accounted for 4.75%(n=61). In terms of methodological quality, 52.91% of the RCTs had unclear descriptions or incorrect application of randomization methods, and the implementation of allocation concealment and blinding methods has not been paid much attention. In conclusion, compared with the conditions in 2019, the number of RCTs published in 2020 has decreased, and the research interest in respiratory diseases has increased, while the quality control in the process of research design and implementation has not been improved. Therefore, it is necessary to strengthen the methodological training of researchers and promote the output of high-quality research evidence.
China ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Medicine, Chinese Traditional ; Nonprescription Drugs ; Quality Control

The present study systematically collected, analyzed, and evaluated randomized controlled trial(RCT) of Chinese patent medicine in the treatment of heart failure to provide references for follow-up clinical research design, guideline update, and policy formulation, and promote the improvement of clinical evidence quality. On the basis of the collection in the Traditional Chinese Medicine(TCM) Clinical Evidence Database System(EVDS), CNKI, VIP, Wanfang, SinoMed, PubMed, and Web of Science were searched for RCTs of Chinese patent medicine in the treatment of heart failure from database inception to December 31, 2020. The di-sease type, publication time, sample size, intervention/control setting, course of treatment, evaluation indexes, and methodological quality were analyzed and evaluated. A total of 1 631 RCTs were included, including 1 622 in Chinese and 9 in English. It was first published in 1995, with the largest number of publications in 2016. There were only 56 RCTs(3.43%) with a sample size≥200. Seventy-eight types of Chinese patent medicines were involved, including 49 types of oral drugs and 29 types of injections. There were 34 intervention/control protocols, which were dominated by Chinese patent medicine+conventional treatment vs conventional treatment, accounting for 28.51%(n=465). About 94.0% of RCTs reported the course of treatment, mainly 14-56 days. The evaluation indexes were mainly physical and chemical tests and symptoms/signs, and left ventricular ejection fraction(LVEF) was the most frequently used measurement index. In enumeration indexes, clinical efficacy(response rate) was used the most frequently. Methodologically, 92.0% of the research subjects were rated as high risk of blindness. There were only 13 RCTs(0.80%) reporting registered information. It is necessary to further standardize the design, implementation, and quality control of clinical studies in order to improve the quality of evidence and avoid research waste.
China ; Drugs, Chinese Herbal/therapeutic use* ; Heart Failure/drug therapy* ; Humans ; Medicine, Chinese Traditional ; Nonprescription Drugs/therapeutic use* ; Randomized Controlled Trials as Topic ; Stroke Volume ; Ventricular Function, Left

To systematically collect and analyze clinical randomized controlled trial(RCT) of Chinese patent medicine treatment for stroke in 2020, in order to provide basic information for clinical decision-making and related research. On the basis of the collection in the Traditional Chinese Medicine(TCM) Clinical Evidence Database System(EVDS), CNKI, Wanfang, SinoMed, Cochrane Library, PubMed, EMbase were searched for RCTs of Chinese patent medicine for stroke in 2020. The publication, sample size, intervention and control measures, course of treatment, outcome indicators, methodological quality and other contents were statistically analyzed.A total of 68 RCTs studies on Chinese patent medicine for stroke were included in 2020, of which 29(42.60%) were RCTs with sample size>100 cases. A total of 41 kinds of proprietary Chinese medicines were involved, including 23 kinds of oral proprietary Chinese medicines and 18 kinds of injections. A total of 18 intervention/control cases were included in RCTs, and 19 cases(Chinese patent medicine+Western medicine vs Western medicine) were applied in RCTs, accounting for 27.90%. The duration of treatment was reported in 91.18% of the studies, and the intervention duration was 8-14 days in 50.00% of the studies. Evaluation indexes were widely used, among which physical and chemical testing indexes(49.36%) were the most widely used. According to the methodological quality evaluation, the overall methodological quality of the study is not high, especially the implementation of the allocation hidden, blind method is not accurate, and the registration, ethics and other links are often missing. In conclusion, 2020 implementation of proprietary Chinese medicine in the treatment of stroke research methodology problems is outstanding, the similar function scale large range of optional, no specification selection criteria, reliability and practicability of the impact study, need to further standardize the proprietary Chinese medicine in the treatment of stroke study design, implementation and quality control, and highlight the value of proprietary Chinese medicine in the treatment of stroke and improve the quality of the evidence.
China ; Clinical Trials as Topic ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Medicine, Chinese Traditional ; Nonprescription Drugs/therapeutic use* ; Reproducibility of Results ; Stroke/drug therapy*