The Secondary Metabolites from Genus Kitasatospora: A Promising Source for Drug Discovery.

Microbial secondary metabolites are well-known resource for drug discovery. Kitasatospora is one of the rare genera of Actinomycetes and important antibiotics producer that are not fully explored. Recently an explosively increasing number of reports have proved that the genus is capable of producing various bioactive secondary metabolites. Here, we comprehensively summarized secondary metabolites from Kitasatospora strains including their chemical structures, biological effects, mechanisms of actions together with the related genomic and biosynthetic analyses. The review covered more than 100 metabolites with their significant pharmacological properties which included a class of peptide aldehyde natural products that had been optimized to a promising lead compound. This work provides detailed information of Kitasatospora-derived natural products and presents their potential for therapeutically relevant utilization, which would inspire the drug discovery from this genus in future.

Affinity ultrafiltration based metabolomic profiling directed discovery novel butyrylcholinesterase inhibitors from Uncaria sessilifructus.

The butyrylcholinesterase (BChE) is an attractive target for treating Alzheimer's disease. In this study, we report the discovery of five new monoterpene indole alkaloids (MIAs) along with three known analogues from Uncaria sessilifructus Roxb. as BChE inhibitors using affinity ultrafiltration based metabolomic profiling directed isolation strategy. Their structures were well identified through comprehensive spectroscopic and chiroptical analyses. Compounds 1-2 featured unique glycosidic linkages with 1,3-dioxane structure. All the compounds exhibited BChE inhibitory bioactivity without any cytotoxic effects. Enzymatic kinetic and molecular docking analyses of compounds 1 and 6 demonstrated their inhibiting mechanisms and binding patterns to BChE. These findings provide a valuable workflow for efficiently screening ligands that bind to proteins, and scientific recognition in the discovery of BChE inhibitors for treating neurodegenerative disorders.

Epidemiological characteristics and influencing factors of tuberculosis aggregation in schools in Wuhan, China during 2017-2022.

Background: Wuhan is located in the hinterland of China, in the east of Hubei Province, at the intersection of the Yangtze River and Hanshui River. It is a national historical and cultural city, an important industrial, scientific, and educational base, and a key transportation hub. There are many schools in Wuhan, with nearly a thousand of all kinds. The number of students is ~2.2 million, accounting for nearly one-fifth of the resident population; college or university students account for ~60% of the total student population. The geographical location of these colleges is relatively concentrated, and the population density is relatively high, making it prone to tuberculosis cluster epidemic. Objective: This study analyzed the epidemiological characteristics and influencing factors of tuberculosis aggregation in schools in Wuhan, China, during 2017-2022 to provide the basis for the scientific development of tuberculosis prevention and control strategies and measures in schools. Methods: This study adopted the methods of descriptive epidemiology to analyze the epidemic characteristics of tuberculosis aggregation in schools in Wuhan from January 2017 to December 2022, collecting the relevant data on tuberculosis prevention and control in all kinds of schools in the city using Questionnaire Star, an application of the China network questionnaire survey, and analyze the influencing factors of tuberculosis aggregation by using multifactor logistic regression analysis. Results: From 2017 to 2022, 54 outbreaks of pulmonary tuberculosis aggregation in schools were reported in Wuhan, which involved 37 different schools, including 32 colleges or universities and five senior high schools; 176 cases were reported, among which 73 were positive for pathogens and 18 were rifampicin or izoniazid resistant. The median duration of a single cluster epidemic was 46 (26,368) days. Universities were more prone to cluster outbreaks than middle schools (χ2 = 105.160, P = 0.001), and the incidence rate among male students was higher than that of female students in cluster epidemics (χ2 = 12.970, P = 0.001). The multivariate logistic regression analysis results showed that boarding in school (OR = 7.60) is the risk factor for a tuberculosis cluster epidemic in schools. The small number of students (OR = 0.50), the location of the school in the city (OR = 0.60), carry out physical examinations for freshmen (OR = 0.44), carry out illness absence and cause tracking (OR = 0.05), dormitories and classrooms are regularly ventilated with open windows (OR = 0.16), strict implement the management of sick student's suspension from school (OR = 0.36), and seeking timely medical consultation (OR = 0.32) were the protective factors for a tuberculosis cluster epidemic in schools. Conclusion: We successfully identified the epidemiological characteristics and influencing factors of tuberculosis aggregation in schools in Wuhan. The results revealed the influence and status of various factors and indicated ways for schools to improve their TB prevention and control measures in their daily activities. These measures can effectively help curb the cluster epidemic of tuberculosis in schools.

Psychological resilience and related factors among primary care workers in Wuhan, China: A cross-sectional study.

Purpose: Primary medical workers constitute a high-risk group for mental health problems, and psychological resilience might protect them from the negative psychological impacts of their work. Therefore, this study aimed to investigate the current situation of psychological resilience among primary care workers in Wuhan, China, as well as related factors. Methods: In this cross-sectional study, a total of 417 primary care workers (30.0 % men; 38.5 ± 8.5 years old) were randomly selected to complete a questionnaire. The brief version of the National Mental Health Literacy Questionnaire and the Psychological Resilience Scale were used to assess participants' mental health literacy and psychological resilience, respectively. Multiple linear regression was performed to identify factors associated with the psychological resilience of primary care workers. Results: More than four-fifths of the primary care workers included in this study exhibited appropriate levels of mental health knowledge. In terms of mental health skills, participants' attainment rates, ranging from high to low, were 60.9 % for distracting attention, 45.3 % for interpersonal support and 43.9 % for cognitive reappraisal. The average psychological resilience score obtained by primary care workers was 27.81 ± 5.71, and the factors associated with increased psychological resilience included being male, being older, and possessing higher mental health skills, including skills pertaining to interpersonal support and distracting attention. Conclusion: The psychological resilience of primary care workers in Wuhan is at a moderate level and thus requires further improvement. Although these medical staff exhibit appropriate levels of mental health knowledge, their mental health skills are relatively poor, despite the fact that interpersonal support and distracting attention are significantly associated with psychological resilience. Hence, interventions targeting mental health skills are recommended to promote psychological resilience among primary care workers.

Quinomycins with an unusual N-methyl-3-methylsulfinyl-alanine residue from a Streptomyces sp.

Four new echinomycin congeners, quinomycins M-P (1-4) were isolated from the cultures of the soil-derived Streptomyces sp. CPCC205575. The planar structures were determined by comprehensive analyses of NMR and HRESIMS/MS data. The absolute configurations were elucidated by the advanced Marfey's method combined with biosynthetic gene analysis. Compounds 1-4 represent the first examples of quinomycin-type natural products with the sulfur atom at the N,S-dimethylcysteine residue oxidized as a sulfoxide group forming the unusual N-methyl-3-methylsulfinyl-alanine residue. Bioassay results revealed that the oxidation of the sulfur atom at the Cys or Cys' residues led to dramatic decrease of cytotoxicity and antimicrobial activity.

Acremosides A-G, Sugar Alcohol-Conjugated Acyclic Sesquiterpenes from a Sponge-Derived Acremonium Species.

Seven new sugar alcohol-conjugated acyclic sesquiterpenes, acremosides A-G (1-7), were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 cultivated with heat-killed Pseudomonas aeruginosa. The structures were determined by comprehensive analyses of 1D and 2D NMR spectroscopic data. The relative configurations were established by J-based configuration analysis and acetonide derivatization. The absolute configurations were elucidated by the Mosher ester method and ECD calculations. The structures of acremosides E-G (5-7) featured the linear sesquiterpene skeleton with a tetrahydrofuran moiety attached to a sugar alcohol. Acremosides A (1) and C-E (3-5) showed significant inhibitory activities against hepatitis C virus (EC50 values of 4.8-8.8 µM) with no cytotoxicity (CC50 of >200 µM).

Stigma toward mental disorders and associated factors among community mental health workers in Wuhan, China.

BACKGROUND: Stigma toward mental disorders (STMD) is a significant barrier to mental health service delivery. To improve the provision of mental health services for community-dwelling residents in China, this study investigated STMD and its associated factors in community mental health workers (CMHWs) in Wuhan, China. METHODS: In this cross-sectional study, a total of 3869 CMHWs (22.9% men and 37.1 ± 8.4 years old) were randomly selected through multistage sampling and invited to participate in this survey. The perceived devaluation-discrimination scale (PDD) and the National Mental Health Literacy Questionnaire (NMHLQ) were used to assess STMD and mental health knowledge, respectively. The presence of STMD was indicated by a mean item score of 3.0 or higher on the PDD. Multiple logistic regression was used to identify factors associated with STMD. RESULTS: Of the CMHWs, 41.9% had poor mental health knowledge (NMHLQ score < 80), and 18.5% exhibited STMD. In multiple regression analysis, factors significantly associated with STMD were social workers (vs. primary care physicians, OR = 1.44, p < .001), poor self-rated capacity to handle common mental health problems (vs. good, OR = 1.57, p < .001), and poor mental health knowledge (vs. NMHLQ score ≥ 80, OR = 1.46, p < .001). CONCLUSION: STMD is common among Chinese CMHWs. To reduce STMD among CMHWs, training programs in mental health care skills and mental health education may be necessary.

Corrigendum: Digitizing tuberculosis treatment monitoring in Wuhan city, China, 2020-2021: Impact on medication adherence.

[This corrects the article DOI: 10.3389/fpubh.2023.1033532.].

Digitizing tuberculosis treatment monitoring in Wuhan city, China, 2020-2021: Impact on medication adherence.

Introduction: Digital technologies can improve adherence to tuberculosis (TB) treatment. We studied the impact of digitizing TB treatment monitoring on adherence among TB patients in Wuhan, China, during 2020-2021. Methods: We compared an electronic system introduced to monitor TB medication adherence (e-Patient Service System; e-PSS) with the p paper-based standard of care (TB Control Information System; TCIS) in terms of prescribed TB treatment doses taken by patients and patient outcome after six months of follow up. We designed a cross sectional study using retrospective data for all drug susceptible pulmonary TB patients recorded on both systems. The main indicators were: compliant first follow up visit (within 3 days of start of treatment); medication adherence (80% or more of monthly doses taken); and end of treatment success ratio. Results: A total of 1,576 TB patients were recorded in TCIS in July September, 2020 and 1,145 TB cases were included in e-PSS in January March, 2021. The distribution of patient demographic and clinical features was similar between the two groups. A larger proportion from the e-PSS group visited the community doctor in the first three days compared with the TCIS group (48.91 versus 29. 76 % respectively). Medication adherence was also higher in the e-PSS group during the 6 months of treatment than in the TCIS group (84. 28 versus 80.3 3 % respectively). Treatment success was 92.52% in the e-PSS group and 92.07% in the TCIS group. Multivariate logistic regress ion analysis demonstrated that adjusted odds ratios for compliant first follow up visit, medication adherence and favorable treatment outcome in the e-PSS versus TCIS groups were 2.94 (95% 2.47 3.50), 1.33 (95% 1.08 1.63), and 1. 12 (95% CL: 0.79 1.57) respectively. Discussion: This study revealed improvements in TB care following an intervention to monitor treatment digitally in patients in Wuhan, China.

Exploring seasonal diurnal surface temperature variation in cities based on ECOSTRESS data: A local climate zone perspective.

High urban temperatures affect city livability and may be harmful for inhabitants. Analyzing spatial and temporal differences in surface temperature and the thermal impact of urban morphological heterogeneity can promote strategies to improve the insulation of the urban thermal environment. Therefore, we analyzed the diurnal variation of land surface temperature (LST) and seasonal differences in the Fifth Ring Road area of Beijing from the perspective of the Local Climate Zone (LCZ) using latest ECOSTRESS data. We used ECOSTRESS LST data with a resolution of 70 m to accurately interpret the effects of urban morphology on the local climate. The study area was dominated by the LCZ9 type (sparse low-rise buildings) and natural LCZ types, such as LCZA/B (woodland), LCZD (grassland), and LCZG (water body), mainly including park landscapes. There were significant differences in LST observed in different seasons as well as day and night. During daytime, LST was ranked as follows: summer > spring > autumn > winter. During night-time, it was ranked as follows: summer > autumn > spring > winter. All data indicated that the highest and lowest LST was observed in summer and winter, respectively. LST was consistent with LCZ in terms of spatial distribution. Overall, the LST of each LCZ during daytime was higher than that of night-time during different seasons (except winter), and the average LST of each LCZ during the diurnal period in summer was higher than that of other seasons. The LST of each LCZ during daytime in winter was lower than that of the corresponding night-time, which indicates that it is colder in the daytime during winter. The results presented herein can facilitate improved analysis of spatial and temporal differences in surface temperature in urban areas, leading to the development of strategies aimed at improving livability and public health in cities.

Nitrogen fertilization coupled with iron foliar application improves the photosynthetic characteristics, photosynthetic nitrogen use efficiency, and the related enzymes of maize crops under different planting patterns.

Photosynthetic rate (Pn) and photosynthetic nitrogen use efficiency (PNUE) are the two important factors affecting the photosynthesis and nutrient utilization of plant leaves. However, the effect of N fertilization combined with foliar application of Fe on the Pn and PNUE of the maize crops under different planting patterns (i.e., monocropping and intercropping) is elusive. Therefore, this experiment was conducted to determine the effect of N fertilization combined with foliar application of Fe on the photosynthetic characteristics, PNUE, and the associated enzymes of the maize crops under different planting patterns. The results of this study showed that under intercropping, maize treated with N fertilizer combined with foliar application of Fe had not only significantly (p < 0.05) improved physio-agronomic indices but also higher chlorophyll content, better photosynthetic characteristics, and related leaf traits. In addition, the same crops under such treatments had increased photosynthetic enzyme activity (i.e., rubisco activity) and nitrogen metabolism enzymes activities, such as nitrate reductase (NR activity), nitrite reductase (NiR activity), and glutamate synthase (GOGAT activity). Consequently, intercropping enhanced the PNUE and soluble sugar content of the maize crops, thus increasing its yield compared with monocropping. Thus, these findings suggest that intercropping under optimal N fertilizer application combined with Fe foliation can improve the chlorophyll content and photosynthetic characteristics of maize crops by regulating the associated enzymatic activities. Consequently, this results in enhanced PNUE, which eventually leads to better growth and higher yield in the intercropping system. Thus, practicing intercropping under optimal nutrient management (i.e., N and Fe) could be crucial for better growth and yield, and efficient nitrogen use efficiency of maize crops.

Optimizing component formula suppresses lung cancer by blocking DTL-mediated PDCD4 ubiquitination to regulate the MAPK/JNK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge and Panax ginseng C. A. Meyer have special curative effect on cancer treatment. The optimizing component formula (OCF) extracted from those two herbs was in line with the anti-lung cancer treatment principle of activating blood and supplementing 'Qi'. However, the study on the mechanism of component formula has always been an insurmountable challenge. Nowadays, the application of network pharmacology and artificial intelligence (AI) in the field of TCM provides new ideas for the study of new targets and mechanisms of TCM, which promotes the modernization of TCM. AIM OF THE STUDY: This study aims to further explore the anti-lung cancer mechanism of OCF by using an integrated strategy of network pharmacology and AI technology. MATERIALS AND METHODS: Bioinformatic analysis was used to analyze the expression levels, prognosis and survival of DTL and PDCD4 in cancer patients. The binding strength of OCF and DTL was simulated by molecular docking, and the affinity between them was detected by Bio-layer interferometry. Network pharmacology was used to predict the active components, potential targets and pathways of OCF. The association between key targets and their corresponding components and DTL was analyzed by Ingenuity Pathway Analysis (IPA). MTT assay, colony formation assay, wound-healing assay and transwell assay were used to verify the inhibitory effects of OCF on lung cancer cells in vitro. qRT-PCR and Western blot assay were used to detect the effects of OCF on mRNA and protein expression of DTL, PDCD4 and key genes in MAPK/JNK pathways. RESULTS: Bioinformatics analysis showed that DTL was significantly up-regulated in lung cancer, which was associated with high malignancy rate, high metastasis rate and poor prognosis of primary tumor. PDCD4 was down-regulated in lung cancer, and associated with high metastasis rate and poor prognosis. The good affinity between OCF and DTL was predicted and verified by molecular docking and Bio-layer interferometry. Based on the network pharmacological databases, 40 active components and 220 corresponding targets of OCF were screened out. KEGG analysis showed that OCF component targets were mainly enriched in MAPK signaling pathway. IPA results showed the interrelationship between DTL, PDCD4, MAPK pathway genes and their corresponding OCF components. In addition, in vitro experiments demonstrated anti-lung cancer activity of OCF, as validated, via impairing cell viability and cell proliferation, as well as inhibiting migration and invasion abilities in lung cancer cells. qRT-PCR showed that OCF down-regulated the mRNA expression of DTL, MAP4K1, JNK, c-Jun and c-Myc, and up-regulated the mRNA expression of PDCD4 and P53 genes in A549 lung cancer cells. Western blot suggested that OCF suppressed the protein level of DTL and blocked the ubiquitination of PDCD4 in A549 lung cancer cells, and down-regulated the protein levels of MAP4K1, p-JNK and p-c-Jun while up-regulated the proteins expression level of P53. CONCLUSIONS: OCF might elicit an anti-lung cancer effect by blocking DTL-mediated PDCD4 ubiquitination and suppression of the MAPK/JNK pathway. Meanwhile, our work revealed that network pharmacology and AI technology strategy are cogent means of studying the active components and mechanism of TCM.

Zelkovamycins F and G, Cyclopeptides with Cα-Methyl-threonine Residues, from an Endophytic Kitasatospora sp.

Zelkovamycins F and G (1 and 2), two new natural cyclic octapeptides possessing the unprecedented nonproteinogenic amino acid residues l-α-methyl-threonine and l-α-methyl-allo-threonine, respectively, along with four new analogues, zelkovamycins H-K (3-6), were identified from the endophytic Kitasatospora sp. CPCC 204717. Their structures were elucidated by detailed analysis of NMR and HRESIMS/MS spectroscopic data. The configurations of amino acid residues were determined by Marfey's analysis combined with NMR calculations. Compounds 1, 2, and 4 showed potent antibacterial activity against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis. The structure-activity relationship study revealed that the 2-methyl-3-oxobutyrine and sarcosine residues played important roles in their antibacterial activities. Zelkovamycin (7) and zelkovamycin E (8) exhibited significant antiviral activity against the hepatitis C virus.

Gamma-glutamyl Transpeptidase to Platelet Ratio Predicts Liver Injury in Hepatitis B e Antigen-negative Chronic Hepatitis B Patients With Normal Alanine Aminotransferase.

Background and Aims: Chronic hepatitis B virus (HBV) infection is a serious health problem worldwide. Evaluating liver injury in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) with detectable HBV DNA and normal alanine aminotransferase (ALT) is crucial to guide their clinical management. We aimed to investigate the stages of liver inflammation and fibrosis as well as the predictive accuracy of gamma-glutamyl transpeptidase-to-platelet ratio (GPR) in these patients. Methods: A total of 184 treatment-naïve HBeAg-negative CHB patients with detectable HBV DNA and normal ALT were enrolled. The Scheuer scoring system was used to classify liver inflammation and fibrosis. Results: The distribution of patients with different liver inflammation grades were as follows: G0, 0 (0%); G1, 97 (52.7%); G2, 68 (37.0%); G3, 12 (6.5%); and G4, 7 (3.8%). The distribution of patients with different liver fibrosis stages were as follows: S0, 22 (12.0%); S1, 72 (39.1%); S2, 42 (22.8%); S3, 19 (10.3%); and S4, 29 (15.8%). The areas under the receiver operating characteristic (AUROC) curves of GPR in predicting significant inflammation, severe inflammation, and advanced inflammation were 0.723, 0.895, and 0.952, respectively. The accuracy of GPR was significantly superior to that of ALT in predicting liver inflammation. The AUROCs of GPR in predicting significant fibrosis, severe fibrosis, and cirrhosis were 0.691, 0.780, and 0.803, respectively. The predictive accuracy of GPR was significantly higher than that of aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4) in identifying advanced fibrosis and cirrhosis, and it was superior to FIB-4 but comparable to APRI in identifying significant fibrosis. Conclusions: Nearly half of the HBeAg-negative CHB patients with detectable HBV DNA and normal ALT levels had significant liver inflammation or fibrosis. GPR can serve as an accurate predictor of liver inflammation and fibrosis in these patients.

Acremopeptaibols A-F, 16-Residue Peptaibols from the Sponge-Derived Acremonium sp. IMB18-086 Cultivated with Heat-Killed Pseudomonas aeruginosa.

Six new 16-residue peptaibols, acremopeptaibols A-F (1-6), along with five known compounds, were isolated from the cultures of the sponge-associated fungus Acremonium sp. IMB18-086 grown in the presence of the autoclaved bacterium Pseudomonas aeruginosa on solid rice medium. The peptaibol sequences were established based on comprehensive analysis of 1D and 2D NMR spectroscopic data in conjunction with HRESIMS/MS experiments. The configurations of the amino acid residues were determined by advanced Marfey's analysis. Compounds 1-6 feature the lack of the highly conserved Thr6 and Hyp10 residues in comparison with other members of the SF3 subfamily peptaibols. A plausible biosynthetic pathway of compounds 1-6 was proposed on the basis of genomic analysis. Compounds 1, 5, 7, and 10 exhibited significant antimicrobial activity against Staphylococcus aureus, methicillin-resistant S. aureus, Bacillus subtilis, and Candida albicans. Compounds 7-10 showed potent cytotoxicities against the A549 and/or HepG2 cancer cell lines.

Rational generation of lasso peptides based on biosynthetic gene mutations and site-selective chemical modifications.

Lasso peptides are a unique family of natural products whose structures feature a specific threaded fold, which confers these peptides the resistance to thermal and proteolytic degradation. This stability gives lasso peptides excellent pharmacokinetic properties, which together with their diverse reported bioactivities have garnered extensive attention because of their drug development potential. Notably, the threaded fold has proven quite inaccessible by chemical synthesis, which has hindered efficient generation of structurally diverse lasso peptides. We herein report the discovery of a new lasso peptide stlassin (1) by gene activation based on a Streptomyces heterologous expression system. Site-directed mutagenesis on the precursor peptide-encoding gene is carried out systematically, generating 17 stlassin derivatives (2-17 and 21) with residue-replacements at specific positions of 1. The solution NMR structures of 1, 3, 4, 14 and 16 are determined, supporting structural comparisons that ultimately enabled the rational production of disulfide bond-containing derivatives 18 and 19, whose structures do not belong to any of the four classes currently used to classify lasso peptides. Several site-selective chemical modifications are first applied on 16 and 21, efficiently generating new derivatives (20, 22-27) whose structures bear various decorations beyond the peptidyl monotonicity. The high production yields of these stlassin derivatives facilitate biological assays, which show that 1, 4, 16, 20, 21 and 24 possess antagonistic activities against the binding of lipopolysaccharides to toll-like receptor 4 (TLR4). These results demonstrate proof-of-concept for the combined mutational/chemical generation of lasso peptide libraries to support drug lead development.

Genetic variants of cell cycle pathway genes are associated with head and neck squamous cell carcinoma in the Chinese population.

Genetic alterations in the cell cycle pathway are common in head and neck squamous cell carcinoma (HNSCC). We identified four novel HNSCC susceptibility loci (CDKN1C rs452338, CDK4 rs2072052, E2F2 rs3820028 and E2F2 rs2075993) through a two-stage matched case-control study. There was a combined effect among the four single nucleotide polymorphisms (SNPs), as the number of risk genotypes increased, the risk of HNSCC displayed an increasing trend (Ptrend < 0.001). And there were multiplicative interactions between rs452338 and rs2072052, rs2072052 and rs3820028, rs2072052 and rs2075993. Functional bioinformatics analysis and dual-luciferase reporter assay revealed that E2F2 rs2075993 T>C reduced the stability of E2F2 3'-UTR secondary structure and affected the binding of E2F2 to miR-940, which was up-regulated in HNSCC tumor tissues (P = 2.9e-8) and was correlated with poor overall survival of HNSCC (HR = 1.39, 95% CI = 1.02-1.90). In vitro assays, we discovered that the expression of miR-940 was regulated by METTL3, and miR-940 promoted the proliferation, migration and invasion, and inhibited the senescence and autophagy of tumor cells. In terms of mechanism, compared with rs2075993 allele T, we found that the protective variant rs2075993 allele C interfered with the translational inhibition of E2F2 by miR-940, resulting in increased expression of E2F2 protein, which further reduced the proliferation, migration, invasion, and increased the senescence of tumor cells.

B Cell-mediated Humoral Immunity in Chronic Hepatitis B Infection.

B cell-mediated humoral immunity plays a vital role in viral infections, including chronic hepatitis B virus (HBV) infection, which remains a critical global public health issue. Despite hepatitis B surface antigen-specific antibodies are essential to eliminate viral infections, the reduced immune functional capacity of B cells was identified, which was also correlated with chronic hepatitis B (CHB) progression. In addition to B cells, T follicular helper (Tfh) cells, which assist B cells to produce antibodies, might also be involved in the process of anti-HBV-specific antibody production. Here, we provide a comprehensive review of the role of various subsets of B cells and Tfh cells during CHB progression and discuss current novel treatment strategies aimed at restoring humoral immunity. Understanding the mechanism of dysregulated B cells and Tfh cells will facilitate the ultimate functional cure of CHB patients.

Discovery of Neuritogenic Securinega Alkaloids from Flueggea suffruticosa by a Building Blocks-Based Molecular Network Strategy.

A combined strategy of building blocks recognition and molecular network construction, termed the building blocks-based molecular network (BBMN), was first presented to facilitate the efficient discovery of novel natural products. By mapping the BBMN of the total alkaloid fraction of Flueggea suffruticosa, three Securinega alkaloids (SEAs) with unusual chemical architectures, suffranidines A-C (1-3), were discovered and isolated. Compound 1 characterizes an unprecedented 8/5/6/5/6/6/6/6-fused octacyclic scaffold with a unique cage-shaped 3-azatricyclo[6.4.0.03,11 ]dodecane core. Compounds 2 and 3 are highly modified SEA dimers that incorporate additional C6 motifs. A hypothetical biosynthetic pathway for 1-3 was proposed. In addition, 1 significantly induced neuronal differentiation and neurite extension by upregulating eukaryotic elongation factor 2 (eEF2)-mediated protein synthesis.

A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a type of solid tumor derived from the bile duct epithelium that features universal gemcitabine resistance. Here, we utilized a gene-encoded ROS biosensor probe (HyPer3 probe) to sort subpopulations with different redox statuses from CCA cells. The isolated HyPer-low subpopulation CCA cells, which exhibited relatively lower cellular ROS levels, exhibited higher chemoresistance to gemcitabine than HyPer-high subpopulation CCA cells in vitro and in vivo. Mechanistically, increased expression of MTHFD1 was found in HyPer-low cells. Knocking down MTHFD1 in HyPer-low cells enhanced cellular ROS and restored sensitivity to gemcitabine. Furthermore, the MTHFD1 inhibitor antifolate compound methotrexate (MTX) increased cellular ROS, and combining gemcitabine with MTX effectively suppressed cholangiocarcinoma cell growth. In summary, the MTHFD1 level mediated the heterogeneous cellular redox status in CCA, which resulted in chemoresistance to gemcitabine. Our data suggest a novel strategy for CCA chemotherapy.