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Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet β-cell-specific Kcnh6 knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels. Berberine is a compound with glucose-lowering effects in mice and humans. Here, the authors show that in mice berberine has beneficial glycemic effects by promoting insulin secretion, which requires the potassium channel KCNH6 in beta cells, and that berberine can promote insulin secretion in healthy men in a phase 1 clinical trial.

To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

Compassion fatigue significantly impacts nurses' work efficiency, care quality, and overall well-being. Consequently, the phenomenon of compassion fatigue among nurses has garnered considerable attention. Research from abroad indicates that demographic factors and the Big Five personality traits are closely related to the burnout dimension of compassion fatigue. This insight opens new avenues for studying compassion fatigue in nurses. This study aims to analyze the current state of compassion fatigue among nurses and its influencing factors. Furthermore, it seeks to explore the correlation between compassion fatigue and personality traits, providing valuable references for alleviating compassion fatigue among nurses. A survey using general information, the Chinese Compassion Fatigue Short Scale, and the brief version of the Chinese Neuroticism Extraversion Openness Five-Factor Inventory was conducted on 332 nurses from a major tertiary hospital. The total score for nurse compassion fatigue was 51.83(SD=22.02). Factors such as years of service, professional title, monthly income, and department were identified as influencing compassion fatigue. The total score for compassion fatigue exhibited a negative correlation with extraversion, openness, agreeableness, and conscientiousness, while it showed a positive correlation with neuroticism. The Big Five personality traits accounted for 47.9%, 45.2%, and 50.2% of the variance in secondary trauma, burnout, and the overall compassion fatigue score, respectively. Neuroticism and agreeableness are primary predictors of nurses' compassion fatigue. Nursing managers can implement targeted measures to alleviate compassion fatigue based on the identified influencing factors and the predictive role of the Big Five personality traits.

Malignant melanoma (MM) is a highly aggressive and deadly form of skin cancer, primarily caused by recurrence and metastasis. Therefore, it is crucial to investigate the regulatory mechanisms underlying melanoma recurrence and metastasis. Our study has identified a potential targeted regulatory relationship between LINC02202, miR‐526b‐3p and XBP1 in malignant melanoma. Through the regulation of the miR‐526b‐3p/XBP1 signalling pathway, LINC02202 may play a role in tumour progression and immune infiltration and inhibiting the expression of LINC02202 can increase the efficacy of immunotherapy for melanoma. Our findings shed light on the impact of LINC02202/XBP1 on the phenotype and function of malignant melanoma cells. Furthermore, this study provides a theoretical foundation for the development of novel immunotherapy strategies for malignant melanoma.

The long-term physical and mental sequelae of COVID-19 are a growing public health concern, yet there is considerable uncertainty about their prevalence, persistence and predictors. We conducted a comprehensive, up-to-date meta-analysis of survivors’ health consequences and sequelae for COVID-19. PubMed, Embase and the Cochrane Library were searched through Sep 30th, 2021. Observational studies that reported the prevalence of sequelae of COVID-19 were included. Two reviewers independently undertook the data extraction and quality assessment. Of the 36,625 records identified, a total of 151 studies were included involving 1,285,407 participants from thirty-two countries. At least one sequelae symptom occurred in 50.1% (95% CI 45.4-54.8) of COVID-19 survivors for up to 12 months after infection. The most common investigation findings included abnormalities on lung CT (56.9%, 95% CI 46.2–67.3) and abnormal pulmonary function tests (45.6%, 95% CI 36.3–55.0), followed by generalized symptoms, such as fatigue (28.7%, 95% CI 21.0–37.0), psychiatric symptoms (19.7%, 95% CI 16.1–23.6) mainly depression (18.3%, 95% CI 13.3–23.8) and PTSD (17.9%, 95% CI 11.6–25.3), and neurological symptoms (18.7%, 95% CI 16.2–21.4), such as cognitive deficits (19.7%, 95% CI 8.8–33.4) and memory impairment (17.5%, 95% CI 8.1–29.6). Subgroup analysis showed that participants with a higher risk of long-term sequelae were older, mostly male, living in a high-income country, with more severe status at acute infection. Individuals with severe infection suffered more from PTSD, sleep disturbance, cognitive deficits, concentration impairment, and gustatory dysfunction. Survivors with mild infection had high burden of anxiety and memory impairment after recovery. Our findings suggest that after recovery from acute COVID-19, half of survivors still have a high burden of either physical or mental sequelae up to at least 12 months. It is important to provide urgent and appropriate prevention and intervention management to preclude persistent or emerging long-term sequelae and to promote the physical and psychiatric wellbeing of COVID-19 survivors.

The role of focal amplifications and extrachromosomal DNA (ecDNA) is unknown in gastric cardia adenocarcinoma (GCA). Here, we identify frequent focal amplifications and ecDNAs in Chinese GCA patient samples, and find focal amplifications in the GCA cohort are associated with the chromothripsis process and may be induced by accumulated DNA damage due to local dietary habits. We observe diverse correlations between the presence of oncogene focal amplifications and prognosis, where ERBB2 focal amplifications positively correlate with prognosis and EGFR focal amplifications negatively correlate with prognosis. Large-scale ERBB2 immunohistochemistry results from 1668 GCA patients show survival probability of ERBB2 positive patients is lower than that of ERBB2 negative patients when their surviving time is under 2 years, however, the tendency is opposite when their surviving time is longer than 2 years. Our observations indicate that the ERBB2 focal amplifications may represent a good prognostic marker in GCA patients. The role of focal amplifications and extrachromosomal DNA (ecDNA) is unknown in gastric cardia adenocarcinoma (GCA). Here, the authors identify frequent focal amplifications and ecDNAs in Chinese GCA patient samples, as well as the potential associations of these alterations with prognosis and dietary habits.

Diabetes, a prevalent chronic condition, significantly increases the risk of mortality from COVID-19, yet the underlying mechanisms remain elusive. Emerging evidence implicates Cathepsin L (CTSL) in diabetic complications, including nephropathy and retinopathy. Our previous research identified CTSL as a pivotal protease promoting SARS-CoV-2 infection. Here, we demonstrate elevated blood CTSL levels in individuals with diabetes, facilitating SARS-CoV-2 infection. Chronic hyperglycemia correlates positively with CTSL concentration and activity in diabetic patients, while acute hyperglycemia augments CTSL activity in healthy individuals. In vitro studies reveal high glucose, but not insulin, promotes SARS-CoV-2 infection in wild-type cells, with CTSL knockout cells displaying reduced susceptibility. Utilizing lung tissue samples from diabetic and non-diabetic patients, alongside Lepr db/db mice and Lepr db/+ mice, we illustrate increased CTSL activity in both humans and mice under diabetic conditions. Mechanistically, high glucose levels promote CTSL maturation and translocation from the endoplasmic reticulum (ER) to the lysosome via the ER-Golgi-lysosome axis. Our findings underscore the pivotal role of hyperglycemia-induced CTSL maturation in diabetic comorbidities and complications. People with diabetes are at greater risk of developing severe COVID-19 and dying from the illness, which is caused by a virus known as SARS-CoV-2. The high blood sugar levels associated with diabetes appear to be a contributing factor to this heightened risk. However, diabetes is a complex condition encompassing a range of metabolic disorders, and it is therefore likely that other factors may contribute. Previous research identified a link between an enzyme called cathepsin L and more severe COVID-19 in people with diabetes. Elevated cathepsin L levels are known to contribute to diabetes complications, such as kidney damage and vision loss. It has also been shown that cathepsin L helps SARS-CoV-2 to enter and infect cells. This raised the question of whether elevated cathepsin L is responsible for the increased COVID-19 vulnerability in patients with diabetes. To investigate, He, Zhao et al. monitored disease severity and cathepsin L levels in patients with COVID-19. This confirmed that people with diabetes had more severe COVID-19 and that higher levels of cathepsin L are linked to more severe disease. Analysis also revealed that cathepsin L activity increases as blood glucose levels increase. In laboratory experiments, cells exposed to glucose or fluid from the blood of people with diabetes were more easily infected with SARS-CoV-2, with cells genetically modified to lack cathepsin L being more resistant to infection. Further experiments revealed this was due to glucose promoting maturation and migration of cathepsin L in the cells. The findings of He, Zhao et al. help to explain why people with diabetes are more likely to develop severe or fatal COVID-19. Therefore, controlling blood glucose levels in people with diabetes may help to prevent or reduce the severity of the disease. Additionally, therapies targeting cathepsin L could also potentially help to treat COVID-19, especially in patients with diabetes, although more research is needed to develop and test these treatments.

Background Helicobacter pylori infection is associated with several extragastric conditions including dyslipidemia and metabolic syndrome. This study aimed to investigate additional metabolic parameters associated with H. pylori infection in a Chinese population. Methods Using a case-control approach we studied 617 subjects with 13 C-urea breath test ( 13 C-UBT) values ≥10‰ who were defined as being positive for H. pylori (cases), while 617 sex and age- matched subjects with 13 C-UBT values ≤1‰ were defined as H. pylori negative (controls) in Beijing Tongren Hospital from March 2016 to May 2017. Biochemical parameters including serum bilirubin and lipids were tested. Results A total of 1982 subjects participated in this study. The H. pylori infected subjects had significantly lower serum direct bilirubin concentrations (2.34 ± 0.38 vs. 2.47 ± 0.90 μmol/L, P  = 0.008). H. pylori infection was independently associated with lower direct bilirubin levels (OR = 1.497, 95% CI =1.121–1.999, P  = 0.006) or total bilirubin levels (OR = 1.322, 95% CI =1.005–1.738, P  = 0.046) after adjustment for age, sex, body mass index (BMI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), high-density lipoprotein cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), total cholesterol (TC) and triglycerides(TG). In addition, the H. pylori infected subjects had higher LDL-C levels (2.98 ± 0.76 vs. 2.89 ± 0.75 mmol/L, P  = 0.033) and lower HDL-C levels (1.39 ± 0.37 vs. 1.44 ± 0.41 mmol/L, P  = 0.044). LDL-C was negatively correlated with direct bilirubin concentration (R = − 0.260, P  < 0.0001). Conclusions Bilirubin has been found to be a potent endogenous antioxidant and negatively associated with metabolic syndrome. Our results suggest that H. pylori infection is an independent risk factor for serum bilirubin reduction and less favorable lipid profiles.

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence of variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage of the S protein by host proteases is essential for viral infection. Here, we discovered that the S protein contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 and CS-2). Both sites are highly conserved among all known SARS-CoV-2 variants. Our structural studies revealed that CTSL cleavage promoted S to adopt receptor-binding domain (RBD) “up” activated conformations, facilitating receptor-binding and membrane fusion. We confirmed that CTSL cleavage is essential during infection of all emerged SARS-CoV-2 variants (including the recently emerged Omicron variant) by pseudovirus (PsV) infection experiment. Furthermore, we found CTSL-specific inhibitors not only blocked infection of PsV/live virus in cells but also reduced live virus infection of ex vivo lung tissues of both human donors and human ACE2-transgenic mice. Finally, we showed that two CTSL-specific inhibitors exhibited excellent In vivo effects to prevent live virus infection in human ACE2-transgenic mice. Our work demonstrated that inhibition of CTSL cleavage of SARS-CoV-2 S protein is a promising approach for the development of future mutation-resistant therapy.

This study aimed to assess levels of knowledge about human papillomavirus (HPV) and its vaccine among female undergraduates compare these levels between healthcare and non-healthcare majors, and examine their associations with vaccination willingness. A cross-sectional survey was conducted among 1,293 female undergraduate students from two universities in Chengdu. Knowledge was measured using a self-designed questionnaire, categorized into basic and advanced domains. Vaccination willingness was assessed via a 5-point Likert scale. Data were analyzed using descriptive statistics, t-tests, analysis of variance and hierarchical multiple regression to identify associations and compare the two student groups. A total of 1191 valid questionnaires were analyzed. Participants demonstrated moderate basic knowledge of HPV (mean score = 5.21 ± 1.91/8) and its vaccine (mean score = 2.99 ± 1.05/5), but low advanced knowledge of HPV (mean score = 1.02 ± 1.03/6) and its vaccine (mean score = 2.00 ± 1.53/6). Students in healthcare majors demonstrated significantly higher scores in HPV basic knowledge (p = 0.023),HPV vaccine basic knowledge (p = 0.012), and advanced HPV vaccine knowledge (p < 0.001) compared to their non-healthcare peers. Overall vaccination willingness was higher among healthcare majors (p = 0.011), students from urban areas (p < 0.001), and those with higher monthly living expenses (p < 0.001). Hierarchical multiple regression analysis revealed that higher scores in basic knowledge were significantly associated with greater vaccination willingness (p < 0.001, △R2 = 0.127). The study confirms a significant knowledge and intention gap between healthcare and non-healthcare students. Basic knowledge of HPV and its vaccine acts as an effective peripheral cue that boosts vaccination willingness, aligning with the Elaboration Likelihood Model (ELM). However, widespread deficits in advanced knowledge, even among healthcare students, impede central-route processing and durable attitude formation. Public health efforts should prioritize clear core messaging while simplifying and disseminating advanced knowledge to narrow knowledge gaps across student students with different academic backgrounds.