Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure-activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC₅₀ = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC₅₀ = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy-lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.

Objective To investigate the incidence rate,clinical characteristics,and prognosis of neonatal stroke in Shenzhen,China.Methods Led by Shenzhen Children's Hospital,the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022.The incidence,clinical characteristics,treatment,and prognosis of neonatal stroke in Shenzhen were analyzed.Results The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137,1/6 060,and 1/7 704,respectively.Ischemic stroke accounted for 75％(27/36);boys accounted for 64％(23/36).Among the 36 neonates,31(86％)had disease onset within 3 days after birth,and 19(53％)had convulsion as the initial presentation.Cerebral MRI showed that 22 neonates(61％)had left cerebral infarction and 13(36％)had basal ganglia infarction.Magnetic resonance angiography was performed for 12 neonates,among whom 9(75％)had involvement of the middle cerebral artery.Electroencephalography was performed for 29 neonates,with sharp waves in 21 neonates(72％)and seizures in 10 neonates(34％).Symptomatic/supportive treatment varied across different hospitals.Neonatal Behavioral Neurological Assessment was performed for 12 neonates(33％,12/36),with a mean score of(32±4)points.The prognosis of 27 neonates was followed up to around 12 months of age,with 44％(12/27)of the neonates having a good prognosis.Conclusions Ischemic stroke is the main type of neonatal stroke,often with convulsions as the initial presentation,involvement of the middle cerebral artery,sharp waves on electroencephalography,and a relatively low neurodevelopment score.Symptomatic/supportive treatment is the main treatment method,and some neonates tend to have a poor prognosis.

Objective To evaluate the effects of high-fat diet on the pharmacokinetics of metronidazole in Chinese healthy adult subjects.Methods This program is designed according to a single-center,randomized,open,single-dose trial.Forty-seven healthy subjects were assigned to receive single dose of metronidazole tablets 200 mg in either fasting and high-fat diet state,and blood samples were taken at different time points,respectively.The concentrations of metronidazole in plasma were determined by high performance liquid chromatography-mass spectromentry.Results The main pharmacokinetic parameters of metronidazole in fasting state and high-fat diet state were as follows:Cmax were(4 799.13±1 195.32)and(4 044.17±773.98)ng·mL-1;tmax were 1.00 and 2.25 h;t1/2 were(9.11±1.73)and(9.37±1.79)h;AUC0_t were(5.59±1.19)x 104 and(5.51±1.18)x 104 ng·mL-1·h;AUC0_∞ were(5.79±1.33)x 104 and(5.74±1.32)× 104 ng·mL-1·h.Compared to the fasting state,the tmaxof the drug taken after a high fat diet was delayed by 1.25 h(P＜0.01),Cmax,AUC0_t,AUC0-∞ were less or decreased in different degrees,but the effects were small(all P＞0.05).Conclusion High-fat diet has little effects on the pharmacokinetic parameters of metronidazole,which does not significantly change the degree of drug absorption,but can significantly delay the time to peak.

Abstract: Objective　To analyze the laboratory indexes of patients infected with malaria patients and COVID-19, so as to provide reliable evidence for the diagnosis of mixed infection of both. Methods　The routine clinical laboratory items such as routine blood, biochemistry and lymphocyte subsets were tested in three cases of COVID-19 complicated with falciparum malaria who admitted to Guangzhou Eighth People's Hospital Affiliated to Guangzhou Medical University from July to December 2020 were tested. Laboratory data were stage-wise analyzed in conjunction with changes in the course of disease. Results　Three patients confirmed COVID-19 infection recruited all had malaria infection history. Fever, headache, and other symptoms emerged on the 4rd to 11th day after admission. Malaria parasite was detected by malaria parasite antigen testing and blood smear testing, and all three patients had re-ignition of malaria after being confirmed COVID-19 infection. In the early stage of malaria relapse, lymphocytes decreased, CRP and SAA increased, and gradually returned to normal level after antimalarial treatment. Interestingly, we only found one patient at the initial stage of malaria detection showed PLT decreased, no other unnormal changes in other routine blood results (WBC, ESO) and liver function results (ALT, AST, GGT, TBIL, DBIL, CG) were found from the beginning to end course of the disease. Conclusion　COVID-19 infection may promote the resurgence of malaria, so the relapse of malaria should be monitored especially for the patient with malaria infection history who begin to develop fever and other symptoms a few days after the diagnosis of COVID-19. The inflammatory indicators would be worth able as an auxiliary judgment basis for the effective treatment of the two combined infection.

AIM To observe the protective effects of Qigu Capsule-medicated serum on C2C12 myotube cell atrophy induced by dexamethasone.METHODS The Qigu Capsule-medicated serum was prepared.C2C12 cells cultured in vitro were divided into the normal control group,the dexamethasone group,the 10%blank serum group and the 10%Qigu Capsule-medicated serum group for 48 h,corresponding drug treatment,followed by 24 h culture with 10 μmol/L dexamethasone except the control group,and had cell viability detection by CCK-8 method.With their myotube cells intervened accordingly by the aforementioned regime following 6-7 days differentiation with 2%horse serum induction,the C2C12 cells had their myotube cells diameter measured;and the expressions of proteins related to MyHC,MuRF-1,Atrogin-1 and PI3K/Akt signaling pathway detected by Western blot.The impact of PI3K inhibitor LY294002 on the diameter of myotube cells and the expression of MuRF-1,Atorgin-1 and PI3K/Akt signaling pathway related proteins were detected as well.RESULTS Compared with the normal control group,the dexamethasone group and the blank serum group were observed with decreased viability of C2C12 cells(P<0.01),decreased diameter of myotube cells(P<0.01),increased protein expressions of MuRF-1 and Atrogin-1(P<0.01),and decreased expression of MyHC protein and phosphorylation levels of PI3K,Akt,mTOR and FoxO3a(P<0.01).Compared with the dexamethasone group,the Qigu Capsule-medicated serum group showed increased viability of C2C12 cells(P<0.01);increased diameter of myotube cells(P<0.01);decreased protein expressions of MuRF-1 and Atrogin-1(P<0.01);and increased expression of MyHC protein and phosphorylation levels of PI3K,Akt,mTOR and FoxO3a(P<0.05,P<0.01).The intervention of LY294002 upon the Qigu Capsule-medicated serum group offset the anti-muscular tube atrophy effect(P<0.01),increased the protein expressions of MuRF-1 and Atorgin-1(P<0.01),and decreased the phosphorylation levels of PI3K,Akt,mTOR and FoxO3a(P<0.05,P<0.01).CONCLUSION The Qigu Capsule-medicated serum can alleviate the atrophy of C2C12 myotubes induced by dexamethasone,and its mechanism may be related to the activation of PI3K/Akt signaling pathway.

BACKGROUND: Shenyankangfu Tablet (SYKFT) is a Chinese patent medicine that has been used widely to decrease proteinuria and the progression of chronic kidney disease. OBJECTIVE: This trial compared the efficacy and safety of SYKFT, for the control of proteinuria in primary glomerulonephritis patients, against the standard drug, losartan potassium. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This was a multicenter, double-blind, randomized, controlled clinical trial. Primary glomerulonephritis patients, aged 18-70 years, with blood pressure ≤ 140/90 mmHg, estimated glomerular filtration rate (eGFR) ≥ 45 mL/min per 1.73 m MAIN OUTCOME MEASURES: The primary outcome was change in the 24-hour proteinuria level, after 48 weeks of treatment. RESULTS: A total of 735 participants were enrolled. The percent decline of urine protein quantification in the SYKFT group after 48 weeks was 8.78% ± 2.56% (P = 0.006) more than that in the losartan 50 mg group, which was 0.51% ± 2.54% (P = 1.000) less than that in the losartan 100 mg group. Compared with the losartan potassium 50 mg group, the SYKFT plus losartan potassium 50 mg group had a 13.39% ± 2.49% (P < 0.001) greater reduction in urine protein level. Compared with the losartan potassium 100 mg group, the SYKFT plus losartan potassium 100 mg group had a 9.77% ± 2.52% (P = 0.001) greater reduction in urine protein. With a superiority threshold of 15%, neither was statistically significant. eGFR, serum creatinine and serum albumin from the baseline did not change statistically significant. The average change in TCM syndrome score between the patients who took SYKFT (-3.00 [-6.00, -2.00]) and who did not take SYKFT (-2.00 [-5.00, 0]) was statistically significant (P = 0.003). No obvious adverse reactions were observed in any group. CONCLUSION: SYKFT decreased the proteinuria and improved the TCM syndrome scores of primary glomerulonephritis patients, with no change in the rate of decrease in the eGFR. SYKFT plus losartan potassium therapy decreased proteinuria more than losartan potassium therapy alone. TRIAL REGISTRATION NUMBER NCT02063100 on ClinicalTrials.gov.

Objective To establish a mouse model of exogenous iron overload combined with tuberculosis(TB). Methods C57BL/6N mice were divided into negative control, low-, medium-, and high-dose iron groups and received intraperitoneal injection of iron dextran at 0, 3.75, 7.50, and 15.00 mg/dose(3 times/week for 4 weeks), respectively.After 4 weeks, the organ morphology and body weight of the mice were evaluated.The content of serum iron, ferritin, transferrin, and transferrin receptor was determined by ELISA.Heart, liver, spleen, lung, kidney, and small intestine were analyzed for tissue iron content and iron deposition pathology.
Animals ; Humans ; Iron ; Iron Overload ; Iron-Dextran Complex ; Mice ; Mice, Inbred C57BL ; Tuberculosis

Objective To explore the associations between cesarean section with different types and intensity of physical activity in the second trimester pregnant women． Methods Six hundred and seventy－two participants from the Chinese pregnant women cohort study ( CPWCS) were analyzed． The pregnancy physical activity questionnaire ( PPAQ) was used to collect the status of physical activities in pregnant women． The participants were followed up and the data of delivery way was collected． Logistic regression model was conducted to analyze the associations． Ｒesults A total of 273 pregnant women ( 40. 63%) were delivered by cesarean section． After adjusting age，pre-pregnancy BMI and history of childbirth，results of Logistic regression model showed that pregnant women with higher levels of exercise had a lower risk of cesarean section than those who did not participate in exercise ( OＲ= 0. 564，95% CI: 0. 338－0. 941) . In terms of physical activity intensity，pregnant women who participated in the higher level of moderate to vigorous physical activity had a lower risk of cesarean section than those who partici- pated in the lower level ( OＲ= 0．642，95% CI: 0．437－0．972) ． Conclusions Exercise and moderate to vigorous physical activity are protective factors for cesarean section． Health education should be further strengthened to encourage pregnant women to carry out appropriate physical activity during pregnancy．

Objective To explore the influence of reproduction history on depression during pregnancy． Methods Data on 3 792 pregnant women from the Chinese pregnant women cohort study with complete information on reproduction history and depression were used in the present study． The Edinburgh postnatal depression scale was used to assess depression status among pregnant women． A chi-square test was used for univariate analysis，and a Log－binomial regression was used for multivariate analysis． The adjusted relative risks ( ＲＲs) with 95% confidence intervals ( 95% CIs) were calculated，and were presented in a forest plot． Ｒesults The results of Log－binomial regression showed that a history of delivery could increase the risk of depression during the second trimester ( ＲＲ: 1. 04，95% CI: 1. 01 － 1. 08，P= 0. 042) and the third trimester ( ＲＲ: 1. 05，95% CI: 1. 01－1. 10，P= 0. 020) ． There was a 6% increase of risk on depression in women with a history of cesarean delivery compared with women without that during the third trimester ( ＲＲ: 1. 06，95% CI: 1. 01－1. 11，P = 0. 041) ． Conclusions There is asignificant influence of reproduction history on gestational depression． Maternal and child health personnel should focus on these pregnant women，and conduct targeted health education and mental nursing． In addition，medical personnel should also pay attention to the emotional changes of these women and provide them with several adjustment strategies．

Objective To explore the association between unhealthy diets and depression in early pregnancy. Methods 7 976 women in early pregnancy were recruited and analyzed in this study from the Chinese Pregnant Women Cohort Study (CPWCS) from July 25th, 2017 to July 24th, 2018. Differences of baseline characteristics between the two groups were conducted by a chi-square test. The qualitative food frequency questionnaire and the edinburgh postnatal depression scale were used to assess depression status and food intake frequency during the first trimester respectively. Log-binomial regression was used to analyze the relationship between unhealthy diets and depression in early pregnancy. Prevalence ratio (PR) and its 95% confidence interval (95% CI) were calculated. Results Eating regularly (PR=0.45, 95% CI:0.38-0.54，P<0.001) and eating breakfast frequently (PR=0.80, 95% CI:0.72-0.90, P<0.001) were related to the low incidence of depression while frequent consumption of fried food (PR=1.25, 95% CI:1.03-1.53, P=0.027), Western-style fast food (PR=1.36, 95% CI:1.06-1.74, P=0.015) and puffed food (PR=1.37, 95% CI:1.11-1.70, P=0.003) as well as drinking sugar-sweetened beverage (PR=1.37, 95% CI:1.17-1.61, P<0.001),wine (PR=1.60, 95% CI:1.26-2.01, P<0.001) and liqueur (PR=1.26, 95% CI:1.00-1.59, P=0.047) were linked with the high incidence of depression. Conclusions There might be an association between unhealthy diets and depression in early pregnancy. Pregnant women should take the initiative to better understand what are healthy diets and reduce the frequency of unhealthy diets consumption to decrease the incidence of depression during pregnancy.