The coronavirus disease 2019 (COVID-19) is an acute infectious disease caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which has led to serious worldwide economic burden. Due to the continuous emergence of variants, vaccines and monoclonal antibodies are only partial effective against infections caused by distinct strains of SARS-CoV-2. Therefore, it is still of great importance to call for the development of broad-spectrum and effective small molecule drugs to combat both current and future outbreaks triggered by SARS-CoV-2. Cathepsin L (CatL) cleaves the spike glycoprotein (S) of SARS-CoV-2, playing an indispensable role in enhancing virus entry into host cells. Therefore CatL is one of the ideal targets for the development of pan-coronavirus inhibitor-based drugs. In this study, a CatL enzyme inhibitor screening model was established based on fluorescein labeled substrate. Two CatL inhibitors IMB 6290 and IMB 8014 with low cytotoxicity were obtained through high-throughput screening, the half inhibition concentrations (IC₅₀) of which were 11.53 ± 0.68 and 1.56 ± 1.10 μmol·L^-1, respectively. SDS-PAGE and cell-cell fusion experiments confirmed that the compounds inhibited the hydrolysis of S protein by CatL in a concentration-dependent manner. Surface plasmon resonance (SPR) detection showed that both compounds exhibited moderate binding affinity with CatL. Molecular docking revealed the binding mode between the compound and the CatL active pocket. The pseudovirus experiment further confirmed the inhibitory effects of IMB 8014 on the S protein mediated entry process. In vitro pharmacokinetic evaluation indicated that the compounds had relatively good drug-likeness properties. Our research suggested that these two compounds have the potential to be further developed as antiviral drugs for COVID-19 treatment.

Child ; Electroacupuncture ; adverse effects ; instrumentation ; Electrolysis ; Equipment Failure ; Equipment and Supplies ; adverse effects ; Humans ; Male

Long-term endurance training or physical activity has been confirmed not only to improve physical performance, but to bring about an obvious beneficial effect on human health; however, the mechanism of this effect is not clear. The most studied health adaptations in skeletal muscle response to endurance exercise are increased muscle glycogen level and insulin sensitivity, fiber type transformation toward oxidative myofibers, and increased mitochondrial content/function. Mitochondria are dynamic organelles in eukaryotic cells critical in physical performance and disease occurrence. The mitochondrial life cycle spans biogenesis, maintenance, and clearance. Exercise training may promote each of these processes and confer positive impacts on skeletal muscle contractile and metabolic functions. This review focused on the regulation of these processes by endurance exercise and discussed its potential benefits in health and disease. We presented evidence suggesting that exercise training potentiates not only the biogenesis of mitochondria but also the removal of old and unhealthy mitochondria through mitochondrial quality control.
Adaptation, Physiological ; Exercise ; Humans ; Mitochondria ; physiology ; Muscle Contraction ; Muscle, Skeletal ; physiology

From the perspective of clinical doctors, in the teaching idea, national policy, school policies and different stages of clinicians cultivation , the article introduced the concept of translational medicine in the process of the clinical doctors tralning in the United States. It described US medical schools' (U.S. Virginia University School of medicine, for example) implementation ap-proach of translational medicine ideas in different stages, such as before entering school, during the period of school, practice exam and physician clinician tralning. It provided the reference for the de-velopment of translational medicine education in the process of China clinician education and tralning, including:medical students' integration into the related clinical research in preschool through volunteer service, the choice of multiple combination model of clinical science and basic research, interdisci-plinary examination of medical practitioners and the provisions of the research work in resident and specialist tralning stage.

Objective: To compare the efficacy of moxibustion with different doses for knee osteoarthritis (KOA), and explore the correlation between moxibustion dose and clinical efficacy. Methods: Sixty-eight patients with KOA who met the inclusion criteria were randomly divided into a 20-minute moxibustion group and a 40-minute moxibustion group by the random number table method, with 34 cases in each group. Dubi (ST 35), Neixiyan (EX-LE 4) and Heding (EX-LE 2) were used for moxibustion in the two groups. Each treatment lasted 20 min or 40 min for each point in the 20-minute moxibustion group and 40-minute moxibustion group, separately; the treatment was given 3 times a week and lasted for 4 weeks. The visual analog scale (VAS), Western Ontario and McMaster University osteoarthritis index (WOMAC) and traditional Chinese medicine (TCM) symptom scores were evaluated before and after treatment to compare the efficacy between different moxibustion doses for KOA. Results: After treatment, the total effective rate was 87.5％ in the 40-minute moxibustion group, versus 70.0％ in the 20-minute moxibustion group, and the difference in the total effective rate between the two groups was statistically significant (P<0.05). After treatment, the VAS scores, the total WOMAC scores and the component scores of pain, stiffness and dysfunction, and the TCM symptom scores in both groups all changed significantly when compared with those before treatment (all P<0.05). After treatment, the between-group differences in the VAS score, the total WOMAC score and the component scores of pain and dysfunction, and the TCM symptom score were statistically significant (all P<0.05), while the difference in the stiffness score in WOMAC showed no statistical significance (P>0.05). Conclusion: Either 20-minute moxibustion or 40-minute moxibustion can relieve pain, improve stiffness, dysfunction, and TCM symptoms for KOA; and 40-minute moxibustion is better in relieving pain, improving dysfunction and TCM symptoms.

Objective: To observe the effects of electroacupuncture (EA) on uterine prostaglandin F2α (PGF2α), cyclooxygenase 2 (COX-2) and nuclear factor κB (NF-κB) in rats with primary dysmenorrhea (PD) and to discuss the possible mechanism in EA intervening PD. Methods: Forty Sprague-Dawley female rats were randomly divided into a blank group, a model group, an EA group and an ibuprofen group, with 10 rats in each group. The PD model was established using estradiol benzoate combined with oxytocin in the model group, EA group and ibuprofen group. At the same time of modeling, rats in the EA group were given EA at Guanyuan (CV 4) and Sanyinjiao (SP 6) once a day for 20 min each time for 10 consecutive days. Ibuprofen was intragastrically administered once a day for 10 consecutive days in the ibuprofen group. The same amount of normal saline was intragastrically administered once a day for 10 consecutive days in the blank group and model group. The number of writhing of rats in each group within 30 min was compared on the 11th day just after the interventions. The uterine homogenate supernatant was separated and the PGF2α level was detected by enzyme-linked immunosorbent assay. Western blot was applied for the detection of the expression levels of COX-2, phospho-NF-κB p65 and NF-κB p65 proteins in uterine tissues. Results: Compared with the blank group, the number of writhing in the model group increased significantly (P<0.01), and the expression levels of PGF2α, COX-2, phospho-NF-κB p65 and NF-κB p65 proteins in uterine tissues were significantly increased (all P<0.01). Compared with the model group, the number of writhing in the EA group and ibuprofen group were significantly reduced (both P<0.01), and the expression levels of PGF2α and COX-2 protein in uterine tissues were significantly reduced (both P<0.01). Compared with the model group, the phospho-NF-κB p65 level in uterine tissues in the EA group was significantly reduced (P<0.01). Compared with the ibuprofen group, the phospho-NF-κB p65 level in the EA group was significantly reduced (P<0.01). Conclusion: The mechanism of EA for PD rats may be related to inhibiting the phosphorylation of NF-κB and reducing the levels of COX-2 and PGF2α in uterine tissues.

Apolipoprotein A5(ApoA5)level and other indices were determined in patients with type 2 diabetes mellitus and healthy individuals.Compared to control group,ApoA5 level in the diabetic group was lower (P

Transmembrane serine protease 2 (TMPRSS2) is a cell surface protease widely present in the human body. It is involved in the infection of various viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and in the cell invasion, tumor growth and metastasis processes of prostate cancer. This study used Boc-Gln-Ala-Arg-AMC as the fluorescent substrate to determine the cleavage activity of TMPRSS2 towards SARS-CoV-2 S protein. Then cell-based screening model for TMPRSS2 inhibitors was established in Vero E6 cells overexpressing TMPRSS2 (Vero E6/TMPRSS2). Seven compounds exhibiting TMPRSS2 inhibitory activities with low toxicity were obtained through high-throughput screening (HTS) from natural and synthetic compound pure product library of National Center for Screening Novel Microbial Drugs. Surface plasmon resonance (SPR) has shown that the obtained inhibitors could bind to TMPRSS2 with moderate affinity in a dose dependent manner. Cell-cell fusion experiments have shown that the obtained inhibitors can inhibit the occurrence of S protein mediated cell-cell fusion by inhibiting TMPRSS2 cleavage of SARS-CoV-2 S protein in a concentration dependent manner. Preliminary pseudovirus experiment showed that the inhibitors may reduce the pseudovirus infection into Opti-HEK-293T-ACE2 cells to varying degrees. In a word, this study successfully established a cell-based HTS model for TMPRSS2 inhibitor and preliminarily confirmed that the seven screened inhibitors possessed in vitro anti-TMPRSS2 activities, providing new structural scaffolds for the development of new drugs against SARS-CoV-2.

AIMTo analyze factors influencing the efficacy of hormonal suppression of spermatogenesis for male contraception.

METHODSA nested case-control study was conducted, involving 43 subjects, who did not achieve azoospermia or severe oligozoospermia when given monthly injections of 500 mg testosterone undecanoate (TU), defined as partial suppressors compared with 855 subjects who had suppressed spermatogenesis (complete suppressors). Sperm density, serum testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations at the baseline and the suppression phase were compared between partial and complete suppressors. Polymorphisms of androgen receptor (AR) and three single nucleotide variants and their haplotypes of FSH receptor (FSHR) genes determined by polymerase chain reaction (PCR) and DNA sequencing technique were compared between 29 partial and 34 complete suppressors.

RESULTSBaseline serum LH level was higher and serum LH as well as FSH level during the suppression phase was less suppressed in partial suppressors. Additionally, in a logistic regression analysis larger testis volume, higher serum FSH concentrations alone, or interaction of serum LH, FSH, testosterone and sperm concentrations were associated with degree of suppression. The distribution of polymorphisms of AR or FSH receptor genes did not differ between partial and complete suppressors. In cases with incomplete FSH suppression (FSH 0.2 IU/L), the chances of reaching azoospermia were 1.5 times higher in the subjects with more than 22 CAG triplet repeats.

CONCLUSIONPartial suppression of spermatogenesis induced by 500 mg TU monthly injections is weakly influenced by hormonal and clinical features but not polymorphism in AR and FSHR genes.

Adult ; Azoospermia ; chemically induced ; genetics ; Case-Control Studies ; Contraceptive Agents, Male ; administration & dosage ; Drug Resistance ; genetics ; Follicle Stimulating Hormone ; blood ; Haplotypes ; Humans ; Luteinizing Hormone ; blood ; Male ; Polymorphism, Single Nucleotide ; Predictive Value of Tests ; Promoter Regions, Genetic ; genetics ; Receptors, Androgen ; genetics ; Receptors, FSH ; genetics ; Sperm Count ; Spermatogenesis ; drug effects ; genetics ; Testosterone ; administration & dosage ; analogs & derivatives ; blood ; Trinucleotide Repeats

BACKGROUND:Increasingly studies report that the normal balance of bone metabolism may be destroyed in the case of postmenopausal osteoporosis or osteoarthritis. The concrete metabolic process of bone turnover could be revealed sensitively by measuring the bone turnover markers in the serum or urine.
OBJECTIVE:To study the bone density and bone metabolic index of knee osteoarthritis (KOA) and postmenopausal osteoporosis (PMO), and to discuss the characteristics of bone density and bone metabolic index in KOA and PMO.
METHODS:A total of 248 postmenopausal women were detected for bone mineral density and knee X-ray. Final y 180 patients were included in this study and were divided into three groups:KOA group, PMO group, and control group. The levels of bone turnover markers (bone alkaline phosphatase, bone gla protein, col agen type I cross-linked C-telopeptide, and tartrate-resistant acid phosphatase 5b) in serum from the participants were measured. The correlation between bone turnover markers and the disease progression was analyzed by Logistic regression analysis.
RESULTS AND CONCLUSION:The bone mineral density in the KOA group was higher than the control group but col agen type I cross-linked C-telopeptide was lower. The levels of bone gla protein, col agen type I cross-linked C-telopeptide, and tartrate-resistant acid phosphatase 5b in serum from PMO group were higher than the control group. The decrease of col agen type I cross-linked C-telopeptide was associated with the incidence of KOA, and the increases of bone gla protein, col agen type I cross-linked C-telopeptide, and tartrate-resistant acid phosphatase 5b were associated with the incidence of PMO. The lower bone absorption can be seen in postmenopausal women with KOA. PMO patients showed a higher bone turnover rate. The difference of bone metabolism between patients with KOA and PMO led to negative relationship of bone mineral density. The serum levels of bone gla protein, col agen type I cross-linked C-telopeptide, and tartrate-resistant acid phosphatase 5b can assist clinical diagnose and therapeutic effect detection of both KOA and PMO.