ObjectiveTo investigate the effect of Rehmanniae Radix Praeparata on neurological function injury in ischemic stroke rats and explore its mechanism. MethodMale SD rats were randomized into sham operation， model， low- and high -dose （3.5 g·kg^-1 and 7 g·kg^-1） Rehmannia Radix Praeparata， and nimodipine （0.01 g·kg^-1） groups. The rat model of middle cerebral artery occlusion （MCAO） was established with the modified suture occlusion method. Zea-Longa 5-point scoring was employed to evaluate the neurological function of rats. The cerebral infarction volume was detected by 2，3，5-triphenyltetrazolium chloride （TTC） staining. Hematoxylin-eosin staining and Nissl staining were employed to observe the morphology and damage of the brain tissue. Meanwhile， the serum levels of lactate dehydrogenase （LDH）， oxidative stress-related indicators superoxide dismutase （SOD）， glutathione peroxidase 4 （GPX4）， and malondialdehyde （MDA）， and the iron （Fe） content in the brain tissue were determined. To explore the mechanism of Rehmanniae Radix Preparata in mitigating the neurological damage in ischemic stroke rats， Western blotting was employed to determine the expression levels of proteins in the ischemic brain tissue. The autophagy-associated proteins included autophagy effector （beclin-1）， microtubule-associated protein light chain 3 （LC3B）， and ubiquitin-binding protein p62 （p62）. The ferroptosis-associated proteins included transferrin （TF）， transferrin receptor 1 （TFR1）， ferritin heavy chain 1 （FTH1）， and ferropotin （FPN1）. The neurological function injury-associated proteins included brain-derived neurotrophic factor （BDNF） and tyrosine kinase receptor B （TrkB）. ResultCompared with the sham operation group， the model group showed increased neurological function score， cerebral infarction volume， and appearance of nuclear pyknosis and vacuole of cells in the cerebral cortex. In addition， the model group presented elevated levels of LDH， MDA， and Fe （P<0.01） and lowered levels of SOD and GPX4 （P<0.01）. Compared with the model group， Rehmanniae Radix Praeparata decreased the content of LDH， MDA， and Fe （P<0.05， P<0.01） and elevated the levels of SOD and GPX4 （P<0.05， P<0.01）. Compared with the sham operation group， the modeling promoted the expression of beclin-1，LC3B Ⅱ/Ⅰ， TF， and TFR1 and inhibited the expression of p62， FTH1， FPN1， BDNF， and TrkB （P<0.01）. The expression levels of these proteins were recovered after the treatment with Rehmanniae Radix Praeparata. ConclusionRehmanniae Radix Praeparata may inhibit ferroptosis and improve the neurological function in ischemic stroke rats by down-regulating the autophagy level in the brain tissue.

Objective:To explore the feasibility of bibliometric analysis of research papers on human metapneumovirus based on Web of Science database.Methods:The human metapneumovirus (HMPV) causes a serious disease burden worldwide. This article used bibliometric analysis method to search for papers using the keyword " metapneumovirus" , and searched for HMPV papers published from 2001 to 2023 in the Web of Science database. Statistical analysis of the distribution of papers on HMPV by year, country, journal, research institution, author, etc., in order to understand the current research status and development trends of HMPV in the international community.Results:A total of 3 282 papers were retrieved, of which 97% were in English. HMPV was first reported in 2001, and since then, research papers have been increasing year by year. The United States has the highest number of published papers, with China, the United Kingdom, France, and the Netherlands ranked 2nd, 3rd, 4th, and 5th respectively. The field of virology-general had the highest number of papers. In terms of research institution distribution, Vanderbilt University in the United States has published 135 papers, ranked the first. The journal which had the highest number of published papers was JOURNAL OF MEDICAL VIROLOGY, with a total of 143 papers. The author Williams JV of Vanderbilt University in the United States has published 92 papers, indicating its high international status in the field of HMPV research.Conclusions:Among the retrieved HMPV related papers, research institutions and universities in European and American countries have published more papers.

In traditional Chinese medicine， it is believed that the disease of tubal infertility is located in the uterus vessels， with stasis blocking uterus vessels as the core mechanism， and according to the characteristics of pathological changes in the course of treatment， the "three-stage advanced method" is proposed as the treatment plan. In the first stage of eliminating evil， the disease mechanism is characterized by externally-contracted heat toxin combined with endogenous dampness， stagnation and stasis in the uterus vessels， and the treatment is to clear heat and promote dampness， move qi and activate blood， and the self-prescribed Penyan Xiao Formula （盆炎消方）. In the second stage of dissolving fixed abdominal mass， the disease mechanism is characterized by qi and blood stagnation and uterus vessels obstruction， and the treatment is to break up the stagnation of blood and move qi， drive away blood stasis and clear the channels， with self-prescribed Tongguan Formula （通管方）. In the third stage of reinforcing healthy qi to support pregnancy， the disease mechanism is characterized by stasis of uterus vessels for a long period， and loss of kidney essence， therefore the treatment is to warm up the kidneys and eliminate the stasis， boost qi and nourish yin， with self-prescribed Yulin Zhuyun Formula （毓麟助孕方）. At the same time， attention should be paid to the synergistic diagnosis and treatment of traditional Chinese medicine and Western medicines， and combination of syndrome differentiation with the identification of diseases.

Advanced gastric cancer(AGC)includes locally unresectable gastric cancer(GC),metastatic GC,and postoperative recurrent GC.Due to delayed diagnosis and lack of effective treatment for AGC,the median survival time of AGC patients is only 6-12 months.At present,the main treatment goal of AGC is to improve symptoms and prolong the survival time of patients receiving sequential chemotherapy.Although the therapeutic effect of systemic therapy on AGC is gradually becoming apparent,the patient's prognosis is far from expected.In addition,targeted therapy and novel immunotherapy have drawbacks such as high incidence of drug resistance,high toxic side effects,and heavy economic burden on patients.Therefore,finding new therapeutic targets and developing anti-tumor drugs is a key issue that urgently needs to be addressed.According to reports,abnormal activation of the hepatocyte growth factor(HGF)/cellular-mesenchymal epithelial transition factor(c-MET)pathway plays a crucial role in the progression of GC and the occurrence of multi-line resistance and may be a potential therapeutic target for GC.In recent years,some HGF/c-MET-targeting small molecule tyrosine kinase inhibitors(TKIs)have been found to show good clinical effects in the treatment of GC.Meanwhile,new HGF/c-MET inhibitors(such as monoclonal antibodies,bispecific antibodies,antibody drug conjugates,etc.)have shown good anti-tumor activity in preclinical studies,but they are all at different stages of clinical research,and their efficacy and safety still need further confirmation.This review elaborates on the latest research progress of HGF/c-MET inhibitors in the treatment of AGC and discusses the main reasons and strategies for drug resistance,aiming to provide better guidance for the treatment of AGC and provide reference for future research.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Cognitive frailty is a state of weakness and mild cognitive impairment in patients without dementia.It directly affects the health of patients with cardiovascular disease, increasing disability risk and reducing quality of life.This article reviews the concept, assessment, epidemiology, prognosis, mechanisms and intervention of cognitive frailty in elderly patients with cardiovascular disease.

Objective:To assess whether cardiac structure and function are associated with frailty in elderly inpatients.Methods:This was a cross-sectional study.Inpatients aged 65 years or over, admitted to Beijing Hospital, Chinese PLA General Hospital and Beijing Tsinghua Changgeng Hospital, were consecutively recruited from September 2018 to April 2019.A total of 925 elderly inpatients were enrolled in the study, including 285 frailty patients and 640 non-frailty patients.Frailty was assessed with the Fried frailty phenotype.Clinical and echocardiographic data were collected.The association of cardiac structure and function with frailty was analyzed.Results:Compared with the non-frailty group, the frailty group was older, had lower body mass index, and had higher rates of heart failure, atrial fibrillation/atrial flutter, history of stroke/transient ischemic attack, renal insufficiency, and history of falls.N-terminal B-type natriuretic peptide(NT-proBNP)levels were higher while creatinine clearance and hemoglobin levels were lower(all P<0.05); The frailty group had a larger anterior-posterior left atrial diameter[(37.8±7.1)mm vs.(36.3±5.1)mm, t=-3.134, P=0.002]and a higher proportion with the left atrial anterior posterior diameter ≥45 mm[15.8%(45/285) vs.6.1%(39/640), χ2=22.452, P<0.001], a lower left ventricular ejection fraction[(60.1±9.5)% vs.(61.9±7.5)%, t=2.817, P=0.005]and a faster peak mitral inflow velocity[(0.8±0.3)cm/s vs.(0.7±0.2)cm/s, t=-2.675, P=0.003]. Multivariate logistic regression analysis showed that the left atrial anterior posterior diameter ≥45 mm was an independent correlation factor for frailty( OR=2.249, P=0.015). Increased age( OR=1.099, P<0.001), heart failure( OR=1.786, P=0.049), history of stroke/transient ischemic attack( OR=1.960, P=0.001)and decreased hemoglobin( OR=0.984, P=0.008)were independently associated with frailty. Conclusions:The left atrial anterior posterior diameter ≥45 mm and heart failure were independently associated with frailty.Assessing cardiac structure and function and screening for cardiovascular diseases in frailty patients should be emphasized.

Objective:To investigate expressions and clinical significance of plasma exosomal hsa_circ_0022417 in gastric cancer (GC).Methods:Sixty gastric cancer patients, 30 chronic gastritis patients (disease control group) and 30 healthy volunteers (healthy control group) were enrolled in this study. The expression levels of plasma exosomal hsa_circ_0022417 and serum CEA and CA19-9 were detected. The ROC curve and AUC were used to estimate the diagnostic capacity.Results:Compared with chronic gastritis patients and healthy control, the expression of plasma exosomal hsa_circ_0022417 was significantly upregulated in the gastric cancer group ( F=9.96, P<0.05). The expression level of hsa_circ_0022417 in GC tissue was significantly higher than that in adjacent tissue ( t=6.08, P<0.05). The AUC of hsa_circ_0022417, serum CEA and CA 19-9 was 0.79, 0.68 and 0.66, respectively. The combined detection of three indicators had the highest AUC (0.86) ( P<0.05). The expression level of exosomal hsa_circ_0022417 was significantly correlated with tumor size ( χ2=6.42, P<0.01), differentiation degree ( χ2=5.83, P=0.05), TNM stage ( χ2=7.14, P<0.05) and lymph node metastasis ( χ2=5.17, P<0.05). Conclusion:Exosome hsa_circ_0022417 is highly expressed in the plasma of GC patients, which is of great significance for clinical auxiliary diagnosis and early screening of GC.

Objective:This study aimed to investigate the expression of plasma exosomal hsa_circ_0064910 in gastric cancer (GC) patients, explore its correlation with the clinical pathological characteristics and evaluate its diagnostic efficacy in GC.Methods:Sixty patients with GC and 30 patients with Chronic Gastritis (disease control group) admitted to The First Affiliated Hospital of Henan University from October 2019 to December 2020 were selected. Meanwhile, 30 healthy subjects (healthy control group) who underwent physical examination were also enrolled. General data of GC patients were collected, including tumor size, degree of differentiation, TNM stage, lymph node metastasis, etc. Blood samples were collected before treatment and the expression levels of plasma exosomal hsa_circ_0064910 were detected via quantitative reverse transcription PCR (qRT-PCR). The serum concentrations of traditional biomarker (CEA and CA19-9) were measured via a chemiluminescent detection system. The receiver operating characteristic (ROC) curve and area under curve (AUC) were used to estimate the diagnostic capacity of different index in GC. Then, the expression difference of plasma exosomal hsa_circ_0064910 in GC patients before and after operation was analyzed, and its relationship with clinicopathological features of GC patients was also investigated.Results:RT-PCR results revealed that compared with Chronic gastritis patients and healthy control, the expression of plasma exosomal hsa_circ_0064910 was upregulated in the gastric cancer group(0.47±0.06, 0.43±0.05, 0.97±0.12, all P<0.001). The area under the ROC curve was 0.778, and AUC of the combination of CEA and CA19-9 for the diagnosis of gastric cancer was 0.841. which was higher than the diagnostic accuracies of CEA (AUC=0.673)and CA 19-9(AUC=0.653). The expression level of exosomal hsa_circ_0064910 was also significantly correlated with tumor size( χ2=7.545, P<0.01), TNM stage( χ2=4.571, P<0.05)and lymph node metastasis( χ2=6.907, P<0.01). The postoperative expression levels of exosomal hsa_circ_0064910 were lower compared with those of preoperative levels(1.21±0.21 vs 0.62±0.11, P<0.01). Conclusion:Our data demonstrated that exosomal hsa_circ_0064910 is highly expressed in GC patients and might be a potential noninvasive biomarker for the auxiliary diagnosis of GC.

ObjectiveThe pulmonary edema （PE） model where the disease was located in the viscera was established according to the treatment principle that patients with the disease location inside should be treated with descending and sinking medicine， combined with changes in the disease tendency， to verify the scientificity of descending and sinking properties of Descurainiae Semen Lepidii Semen （SD）， and to preliminarily elucidate the scientific connotation of descending， ascending， floating and sinking of Chinese medicine. MethodSixty male SD rats were randomly divided into normal control group， model group （20 mg·kg^-1）， positive drug group （dexamethasone， 0.075 mg·kg^-1） and SD low （1.167 g·kg^-1）， medium （2.334 g·kg^-1）and high （4.668 g·kg^-1） dose groups. The PE model was established by intrapleural injection of 1% carrageenan （2 mL·kg^-1）. The evaluation indexes （lung autopsy， amount of pleural effusion， number of white blood cells， lung wet/dry weight ratio， lung water content and lung permeability） were tested to determine the optimal dose of SD decoction for intervention of PE. The relevant indexes of the five major systems （central nervous system， respiratory system， circulatory system， digestive system and urinary system） closely related to the body's Qi movement were detected and changes in the disease tendency in PE rats were analyzed， to determine the descending， ascending， floating and sinking properties of SD. In addition， histopathological changes were investigated by hematoxylin-eosin （HE） staining， and types and numbers of inflammatory cells and mediators were detected to preliminarily explore the mechanism of SD in improving PE. ResultCompared with the conditions in the normal control group， the amount of pleural effusion， number of white blood cells in pleural effusion， lung wet/dry weight ratio， lung water content and lung permeability were increased （P<0.01） in the model group， where the rats presented cough， dyspnea， shortness of breath and arched back， and a small number of them had wet nose and bubble liquid in nostrils. In the autopsy of the rats in the model group， the lungs were enlarged or accompanied by congestion and plenty of pink bubble liquid appeared at the trachea. Compared with the conditions in the model group， SD reduced the amount of pleural effusion， number of white blood cells in pleural effusion， lung coefficient， lung wet/dry weight ratio and lung water content （P<0.01）， and improved pulmonary edema symptoms such as damage， inflammation and infiltration around the lumen， thickening of the trachea， and accumulation of edema fluid， and the SD medium dose group had the best effect on the treatment of PE. In terms of respiratory system， compared with the normal control group， the model group had reduced latent time of cough and asthma （P<0.05， P<0.01） and elevated number of cough and wheezing （P<0.01）. The three SD groups had increased latent time of cough and asthma and decreased number of cough and wheezing （P<0.01）. In terms of urinary system， compared with the normal control group， the model group presented decreased urine volume. The SD low， medium and high dose groups had increased urine volume （P<0.05， P<0.01）， but they had no effect on perspiration. In terms of digestive system， compared with the conditions in the normal control group， the gastric residual rate and gastrin （GT） level were increased （P<0.05， P<0.01）， and the gastric emptying rate and small intestine transit rate were decreased （P<0.01）. The SD low dose group had elevated small intestine transit rate （P<0.01）， and the SD high and medium groups had enhanced gastric emptying rate and small intestine transit rate （P<0.01）， reduced gastric residual rate， lowered GT level to promote gastrointestinal movement and transportation （P<0.01）， and increased motilin （MTL） level to promote gastric emptying in rats （P<0.05， P<0.01）. In terms of circulatory system， compared with the normal control group， the model group displayed reduced left ventricular ejection fraction （LVEF）， left ventricular short axis shortening rate （LVFS） and cardiac output （CO） （P<0.01）， and elevated tendency of heart rate， systolic blood pressure （SBP， P<0.01） and diastolic blood pressure （DBP， P<0.05）. Compared with the model group， the SD low dose group increased LVEF and decreased DBP （P<0.05）， while the SD medium dose group increased LVEF， LVFS， CO and SBP （P<0.01） and decreased DBP （P<0.05）， and the SD high dose group increased LVFS （P<0.01） and decreased SBP （P<0.01） and DBP （P<0.05）. In terms of central nervous system， compared with the conditions in the normal control group， the standing times dropped in the model group （P<0.01）. SD reduced the movement distance， movement time， standing times and activity time in the center of the open field， and increased the rest time and activity time at the edge of the open field （P<0.05， P<0.01）. Moreover， compared with the normal control group， the model group had serious inflammatory infiltration around the lung lumen， thickened trachea with accumulated edema fluid， seriously damaged lung tissue， increased number of white blood cells and percentage of neutrophils in blood （P<0.01）， elevated percentage of monocytes， interleukin-4 （IL-4）， immunoglobulin E （IgE） level and reactive oxygen species （ROS） level in lung tissue （P<0.05，P<0.01）， and decreased IFN-γ in alveolar lavage fluid （P<0.01）. Compared with the model group， SD decreased the number of white blood cells， neutrophil accumulation， pulmonary congestion and interstitial edema， IFN-γ and IL-4 levels in alveolar lavage fluid and ROS level in lung tissue， and increased IgE level （P<0.05， P<0.01）. ConclusionSD had a significant improvement effect on PE model where the disease was located in the viscera. It could regulate the excretion of water by purgation， regulate Qi movement and expel Qi stagnation by descending and sinking lung Qi， and promote purification and descent of lung qi to make Qi movement downward. This indicated SD had the descending and sinking properties. The medium dose of SD decoction exerted the best effect， and its mechanism of action might be through regulating the neutrophil inflammatory response.