Promotion Effect of Catalpol on Angiogenesis and Potential Mechanisms: A Research Based on Network Pharmacology.

Catalpol, a natural iridoid glycoside, has potential therapeutic benefits, including anti-inflammatory and neuroprotective effects. Investigating catalpol's role in angiogenesis is critical for understanding its potential therapeutic applications, particularly in diseases where modulating angiogenesis is beneficial. This study investigates catalpol's influence on angiogenesis and its mechanisms, combining network pharmacology and in vitro experiments. The target genes corresponding to the catalpol were analyzed by SwissTargetPrediction. Then angiogenesis-related targets were acquired from databases like GeneCards. Subsequently, the Database for Annotation, Visualization and Integrated Discovery was employed for Gene Ontology and pathway analysis, while Cytoscape visualized protein interactions. The effect of catalpol on viability and angiogenesis of HUVECs was further examined using Cell Counting Kit-8 and angiogenesis assays. RT-qPCR and western blot were applied to check the expression of angiogenesis-related proteins. Totally, 312 target genes of catalpol and 823 angiogenesis-related targets were obtained with 56 common targets leading to PPI network analysis, highlighting hub genes (AKT1, EGFR, STAT3, MAPK3, and CASP3). These hub genes were mainly enriched in lipid and atherosclerosis pathway and EGFR-related pathway. The in vitro experimental results showed that catalpol achieved a concentration-dependent increase in HUVECs viability. Catalpol also promoted the migration and angiogenesis of HUVECs and up-regulated the expression of EGFR. EGFR knockdown inhibited the effect of catalpol on HUVECs. Catalpol promotes angiogenesis in HUVECs by upregulating EGFR and angiogenesis-related proteins, indicating its potential therapeutic application in vascular-related diseases.

Association between body mass index and semen quality: a systematic review and meta-analysis.

The continuous decline of human semen quality during the past decades has drawn much concern globally. Previous studies have suggested a link between abnormal BMI and semen quality decline, but the results remain inconsistent. This systematic review and meta-analysis aimed to evaluate the association between body mass index (BMI) and semen quality. We searched PubMed, Embase, and Web of Science for eligible studies from inception to April 17, 2022. We considered men with BMI < 25.0 kg/m2 as the reference and calculated the pooled weighted mean difference of men with overweight (BMI 25.0-29.9 kg/m2), obesity (BMI ≥ 30.0 kg/m2), class I obesity (BMI 30.0-34.9 kg/m2), and class II/III obesity (BMI ≥ 35.0 kg/m2). A total of 5070 articles were identified, of which 50 studies were included (71,337 subjects). Compared with men with BMI < 25.0 kg/m2, men with obesity had an average reduction of 0.24 ml in semen volume, 19.56 × 106 in total sperm number, 2.21% in total motility, 5.95% in progressive motility, and 1.08% in normal forms, respectively, while men with overweight had an average reduction of 0.08 ml in semen volume and 2.91% in progressive motility, respectively. The reduction of semen quality was more pronounced among men with obesity than that among men with overweight. Moreover, significant reductions in semen quality were identified in men with different classes of obesity, which were more pronounced in men with class II/III obesity than that in men with class I obesity. Across men from the general population, infertile or subfertile men, and suspiciously subfertile men, we identified significant semen quality reductions in men with obesity/overweight. In conclusion, obesity and overweight were significantly associated with semen quality reductions, suggesting that maintaining normal weight may help prevent semen quality decline.

Immunodeviation towards T cell-mediated immune response in the testes of LPS-induced mouse epididymo-orchitis.

The testicular consequences of acute epididymo-orchitis remain largely unelucidated in long-term damage, which might be a neglected factor for male infertility. In this study, the differential phenotype of testicular immune cell subpopulations in lipopolysaccharide (LPS)-induced mouse epididymo-orchitis were analyzed by flow cytometry on day 1, day 7, and day 28. The number of macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs) steadily decreased in the testes with inoculation. Total F4/80-CD11c+ dendritic cells (DCs) maintained a relatively stable level, whereas conventional type 1 dendritic cells (cDC1) increased gradually from day 1 to day 28. There was a lower number of CD4+ and CD8+ T cells at day 1 and day 7, and they had similar results with a ceiling level at day 28. The testes displayed a higher level of CD3+ T cells but a lower frequency of macrophages, cDC2, and neutrophils at 28 days post-inoculation compared with the epididymis. In summary, our data indicates acute epididymo-orchitis could lead to long-term damage in the testes, which is characterized by CD3+ T cell (including CD4+ and CD8+ T cells)-mediated immune responses.

Construction of high-quality genomes and gene catalogue for culturable microbes of sugarcane (Saccharum spp.).

Microbes living inside or around sugarcane (Saccharum spp.) are crucial for their resistance to abiotic and biotic stress, growth, and development. Sequences of microbial genomes and genes are helpful to understand the function of these microbes. However, there is currently a lack of such knowledge in sugarcane. Here, we combined Nanopore and Illumina sequencing technologies to successfully construct the first high-quality metagenome-assembled genomes (MAGs) and gene catalogues of sugarcane culturable microbes (GCSCMs), which contained 175 species-level genome bins (SGBs), and 7,771,501 non-redundant genes. The SGBs included 79 novel culturable bacteria genomes, and 3 bacterial genomes with nitrogen-fixing gene clusters. Four single scaffold near-complete circular MAGs (cMAGs) with 0% contamination were obtained from Nanopore sequencing data. In conclusion, we have filled a research gap in the genomes and gene catalogues of culturable microbes of sugarcane, providing a vital data resource for further understanding the genetic basis and functions of these microbes. In addition, our methodology and results can provide guidance and reference for other plant microbial genome and gene catalogue studies.

PI3Kδ and mTOR dual inhibitors: Design, synthesis and anticancer evaluation of 3-substituted aminomethylquinoline analogues.

Phosphatidylinositide-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) have recently been identified as potential cancer targets. In our work, a new family of quinoline analogues was designed, developed, and evaluated as dual inhibitors of PI3Kδ/mTOR. The preliminary biological activity analysis led to the discovery of the lead compounds 5h and 5e. Compounds 5h and 5e exhibited excellent anti-tumor potency with IC50 of 0.26 µM and 0.34 µM against Ramos cells, respectively. Importantly, based on the enzymatic activity assay results, compounds 5h and 5e were identified as dual inhibitors of PI3Kδ and mTOR, with IC50 values of 0.042 µM and 0.056 µM for PI3Kδ and 0.059 µM and 0.073 µM for mTOR, respectively. Furthermore, these compounds showed superior selectivity for blocking PI3Kδ compared to other PI3K isoforms (α, ß, and γ), supporting the concept of developing inhibitors that specifically target PI3Kδ/mTOR. The most effective compound 5h was chosen for additional biological testing. At a low dose of 0.5 µM, a western blot investigation confirmed the anticancer effects by inhibiting the PAM cascade, which in turn reduced downstream biomarkers pAkt (Ser473), pAkt (Thr308), and pRPS6 (Ser235/236). Furthermore, it increased apoptosis at the early (10.03 times) and late (17.95 times) stages in the Annexin-V assay as compared to the standard. In addition, the expression of p53, caspase-3, caspase-9, and the Bax/BCl-2 ratio were all significantly increased by compound 5h in the ELISA assay. Based on these results, it appears that 5h may activate the intrinsic apoptosis pathway, which in turn triggers cell death. Furthermore, the anticancer effects could be attributed to the inhibition of PI3Kδ/mTOR, as shown by docking interactions. Lastly, it demonstrated improved in vitro metabolic stability and passed the in silico ADMET/drug-likeness test. This profile recommends 5h for future in vivo PK-PD and efficacy investigations in animal cancer models.

Based on the prognosis model of immunogenes, the prognosis model was constructed to predict the invasion of immune genes and immune cells related to primary liver cancer and its experimental validation.

Background: Primary liver cancer (PLC) is a prevalent malignancy of the digestive system characterized by insidious symptom onset and a generally poor prognosis. Recent studies have highlighted a significant correlation between the initiation and prognosis of liver cancer and the immune function of PLC patients. Purpose: Revealing the expression of PLC-related immune genes and the characteristics of immune cell infiltration provides assistance for the analysis of clinical pathological parameters and prognosis of PLC patients. Methods: PLC-related differentially expressed genes (DEGs) with a median absolute deviation (MAD > 0.5) were identified from TCGA and GEO databases. These DEGs were intersected with immune-related genes (IRGs) from the ImmPort database to obtain PLC-related IRGs. The method of constructing a prognostic model through immune-related gene pairs (IRGPs) is used to obtain IRGPs and conduct the selection of central immune genes. The central immune genes obtained from the selection of IRGPs are validated in PLC. Subsequently, the relative proportions of 22 types of immune cells in different immune risk groups are evaluated, and the differential characteristics of PLC-related immune cells are verified through animal experiments. Results: Through database screening and the construction of an IRGP prognosis model, 84 pairs of IRGPs (P < 0.001) were ultimately obtained. Analysis of these 84 IRGPs revealed 11 central immune genes related to PLC, showing differential expression in liver cancer tissues compared to normal liver tissues. Results from the CiberSort platform indicate differential expression of immune cells such as naive B cells, macrophages, and neutrophils in different immune risk groups. Animal experiments demonstrated altered immune cell proportions in H22 tumor-bearing mice, validating findings from peripheral blood and spleen homogenate analyses. Conclusion: Our study successfully predicted and validated PLC-related IRGs and immune cells, suggesting their potential as prognostic indicators and therapeutic targets for PLC.

PCMRESP: A Method for Polarizable Force Field Parameter Development and Transferability of the Polarizable Gaussian Multipole Models Across Multiple Solvents.

The transferability of force field parameters is a crucial aspect of high-quality force fields. Previous investigations have affirmed the transferability of electrostatic parameters derived from polarizable Gaussian multipole models (pGMs) when applied to water oligomer clusters, polypeptides across various conformations, and different sequences. In this study, we introduce PCMRESP, a novel method for electrostatic parametrization in solution, intended for the development of polarizable force fields. We utilized this method to assess the transferability of three models: a fixed charge model and two variants of pGM models. Our analysis involved testing these models on 377 small molecules and 100 tetra-peptides in five representative dielectric environments: gas, diethyl ether, dichloroethane, acetone, and water. Our findings reveal that the inclusion of atomic polarization significantly enhances transferability and the incorporation of permanent atomic dipoles, in the form of covalent bond dipoles, leads to further improvements. Moreover, our tests on dual-solvent strategies demonstrate consistent transferability for all three models, underscoring the robustness of the dual-solvent approach. In contrast, an evaluation of the traditional HF/6-31G* method indicates poor transferability for the pGM-ind and pGM-perm models, suggesting the limitations of this conventional approach.

Assessment of Amino Acid Electrostatic Parametrizations of the Polarizable Gaussian Multipole Model.

Accurate parametrization of amino acids is pivotal for the development of reliable force fields for molecular modeling of biomolecules such as proteins. This study aims to assess amino acid electrostatic parametrizations with the polarizable Gaussian Multipole (pGM) model by evaluating the performance of the pGM-perm (with atomic permanent dipoles) and pGM-ind (without atomic permanent dipoles) variants compared to the traditional RESP model. The 100-conf-combterm fitting strategy on tetrapeptides was adopted, in which (1) all peptide bond atoms (-CO-NH-) share identical set of parameters and (2) the total charges of the two terminal N-acetyl (ACE) and N-methylamide (NME) groups were set to neutral. The accuracy and transferability of electrostatic parameters across peptides with varying lengths and real-world examples were examined. The results demonstrate the enhanced performance of the pGM-perm model in accurately representing the electrostatic properties of amino acids. This insight underscores the potential of the pGM-perm model and the 100-conf-combterm strategy for the future development of the pGM force field.

From Waterloo to the Great Wall: A retrospective, multicenter study on the clinical practice and cultural attitudes in the management of premature ejaculation, in China.

Premature ejaculation (PE), despite its wide prevalence, is largely underdiagnosed and undertreated. Being a multifactorial dysfunction with strong cultural characteristics, PE requires skillful attitudes in the psychosexological support, necessary to manage the patient's and the couple's expectations, as well as in the medical treatment. Dapoxetine is a short-acting selective serotonin reuptake inhibitor approved for use in lifelong and acquired PE in a number of countries. Opinions, not always generated by the evidence-based medicine, impacted the attitudes of Western andrologists, as a nocebo effect which produced a drug's Waterloo, characterized by low prescription rates much more built on the patients' and doctors' expectations than on costs, side effects, and efficacy. In the present study, we retrospectively reviewed real-life data from eight Andrology and Sexual Medicine Public Centers in China to assess the prevalence of PE among attending patients, its association with erectile dysfunction, its subtype, and the proposed treatments. In 2019, among 156,486 patients coming to the centers, 32,667 visits having PE as the chief complaint were performed (20.9%). Almost all patients received treatment prescriptions (32,641 patients, 99.92%); 23,273 patients came back for a follow-up visit in the subsequent 12 months (71.2% of those who initially received treatment). Dapoxetine, either alone or in combination with another therapy, was the most prevalent treatment, prescribed to 22,767 patients (69.7% of treated patients), followed by traditional Chinese medicine (TCM) (39.4%). At follow-up, 8174 patients were unsatisfied with treatment, and a new treatment was proposed (35.12%). Dapoxetine was the best treatment, with an overall 27.1% switching rate when used either alone or in combination: Although the switching rate for Dapoxetine alone was 44.2%, the association of the same drug with psychotherapy resulted in much lower rates (19.5%) and reached a minimum of 12% when also combined with TCM demonstrating how cultural aspects and medical attitudes may dramatically impact on the therapy of a multifaceted, complex, and culture-grounded sexual symptom such as PE. In conclusion, taking switching rates as surrogate markers of treatment failure, this real-life study-the largest in the field-shows that in a more patient-oriented (as in Chinese medical culture), and less symptom-oriented (as in Western medical attitudes), Dapoxetine is a successful treatment for PE patients, with higher reliability when used alone or as part of combined and integrated therapies.

Integrating network pharmacology and experimental verification to explore the mucosal protective effect of Chimonanthus nitens Oliv. Leaf Granule on ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Chimonanthus nitens Oliv. Leaf Granule (COG) is a commonly used clinical preparation of traditional Chinese medicine for the treatment of cold, but there are folk reports that it can treat diarrhea and other gastrointestinal diseases. Therefore, the mechanism of COG in the treatment of ulcerative colitis with diarrhea as the main symptom needs to be studied. AIM OF THE STUDY: Combined network pharmacology and experimental validation to explore the mechanism of COG in the treatment of ulcerative colitis. MATERIALS AND METHODS: First, the main components of COG were characterized by liquid chromatography-mass spectrometry (LC-MS); subsequently, a network pharmacology approach was used to screen the effective chemical components and action targets of COG to construct a target network of COG for the treatment of ulcerative colitis (UC). The protein-protein interaction network (PPI) and literature reports were combined to identify the potential targets of COG for the treatment of UC. Finally, the predicted results of network pharmacology were validated by animal and cellular experiments. RESULTS: 19 components of COG were characterized by LC-MS, among which 10 bioactive components could act on 377 potential targets of UC. Key therapeutic targets were collected, including SRC, HSP90AA1, PIK3RI, MAPK1 and ESR1. KEGG results are enriched in pathways related to oxidative stress. Molecular docking analysis showed good binding activity of main components and target genes. Animal experiments showed that COG significantly relieved the colitis symptoms in mice, regulated the Treg/Th17 balance, and promoted the secretion of IL-10 and IL-4, along with the inhibition of IL-1ß and TNF-α. Additionally, COG reduced the apoptosis of colon epithelial cells, and significantly improved the levels of SOD, MAO, GSH-px, and inhibited MDA, iNOS, eNOS in colon. Also, it increased the expression of tight junction proteins such as ZO-1, Claudin1, Occludin and E-cadherin. In vitro experiments, COG inhibited the oxidative stress and inflammatory injury of HCT116 cells induced by LPS. CONCLUSIONS: Combining network pharmacology and in vitro and in vivo experiments, COG was verified to have a good protective effect in UC, which may be related to enhancing antioxidation in colon tissues.

Association between central obesity and semen quality: A cross-sectional study in 4513 Chinese sperm donation volunteers.

BACKGROUND: General obesity classified by body mass index has been linked to a reduction in semen quality; however, evidence on the adverse effect of central obesity on semen quality remains limited. OBJECTIVES: To investigate the association between central obesity and semen quality. MATERIALS AND METHODS: We conducted a cross-sectional study of 4513 sperm donation volunteers in Guangdong Provincial Human Sperm Bank during 2018-2021. Three central obesity indicators, including waist circumference, waist-to-hip ratio, and waist-to-height ratio, were measured using a multi-frequency bioelectrical impedance analysis for each subject. Semen analysis was conducted according to the World Health Organization laboratory manual for the examination and processing of human semen 5th edition. Linear regression models and unconditional logistic regression models were used to quantify the association between central obesity and semen parameters. RESULTS: With adjustment for age, race, education level, marital status, fertility status, occupation, year of semen collection, abstinence period, ambient temperature, and relative humidity, central obesity defined as waist circumference ≥90 cm, waist-to-hip ratio ≥0.9, or waist-to-height ratio ≥0.5 was significantly associated with a 0.27 (95% confidence interval: 0.15, 0.38) mL, 14.47 (3.60, 25.34) × 106 , 7.06 (0.46, 13.76) × 106 , and 6.80 (0.42, 13.18) × 106 reduction in semen volume, total sperm number, total motile sperm number, and total progressive motile sperm number, respectively, and a 53% (10%, 112%) increase in odds of below the World Health Organization 2010 reference value for semen volume. These associations did not significantly vary across age. Similar results were observed for central obesity defined using each of the three indicators, except that subjects with a waist circumference ≥90 cm had a slightly higher total motility (estimated change: 1.30%; 95% confidence interval: 0.27%, 2.34%) and progressive motility (estimated change: 1.27%; 95% confidence interval: 0.23%, 2.31%). DISCUSSION AND CONCLUSION: We found that central obesity was significantly associated with a reduction in semen volume, total sperm number, total motile sperm number, and total progressive motile sperm number. Future studies are warranted to confirm our results in other regions and populations.

[Expression of RACK1 and EGP40 in oral squamous cell carcinoma and its correlation with clinicopathological features and prognosis].

PURPOSE： To investigate the expression of tissue-active protein kinase C receptor 1 (RACK1) and epithelin glycoprotein 40 (EGP40) in oral squamous cell carcinoma (OSCC) and their relationship with clinicopathological features and prognosis. METHODS: A total of 103 patients with OSCC who were admitted to Shangrao People's Hospital from January 2016 to February 2019 were prospectively selected as the research subjects. All patients underwent radical resection of OSCC and were followed up for 3 years. Immunohistochemistry was used to detect the positive expression levels of RACK1 and EGP40 in cancer tissues and adjacent tissues. The positive expression of RACK1 and EGP40 in cancer tissues and adjacent tissues were compared. The relationship between the positive expression level of RACK1 and EGP40 in cancer tissues of OSCC patients and clinicopathological parameters was analyzed. Factors affecting postoperative recurrence and metastasis in OSCC patients were analyzed. The relationship between the expression of RACK1 and EGP40 in cancer tissues and postoperative disease-free survival of OSCC patients was analyzed. SPSS 18.0 software package was used for statistical analysis of the data. RESULTS: The positive expression rate of RACK1 and EGP40 in cancer tissues was significantly higher than those in adjacent tissues (P＜0.05). The positive expression rate of RACK1 and EGP40 in cancer tissues of OSCC patients with poorly differentiated, stage III, cervical lymph node metastasis, and infiltrating vessels was significantly higher than that in patients with moderate and high differentiation, stage II, no cervical lymph node metastasis, and no infiltrating vessels(P＜0.05). The positive expression rate of RACK1 in cancer tissue of OSCC patients in T3 stage was significantly higher than that in T2 stage(P＜0.05). Cox multivariate regression analysis showed pathological grade (RR=6.290, 95%CI: 2.588-15.287), cervical lymph node metastasis(RR=5.995, 95%CI: 2.467-14.571), RACK1 positive rate (RR=4.495, 95%CI: 1.850-10.925) and EGP40 positive rate (RR=4.559, 95%CI: 1.876-11.079) were factors affecting the recurrence and metastasis of OSCC patients after surgery(P＜0.05). The disease-free survival curve of patients with negative expression of RACK1 was significantly better than that of patients with positive expression (P＜0.05). The disease-free survival curve of patients with negative expression of EGP40 was significantly better than that of patients with positive expression (P＜0.05). CONCLUSIONS: The expression of RACK1 and EGP40 in cancer tissues of OSCC patients is related to clinicopathological parameters and prognosis. Patients with positive expression of RACK1 and EGP40 have a high risk of recurrence and metastasis after surgery.

Pien Tze Huang alleviates Concanavalin A-induced autoimmune hepatitis by regulating intestinal microbiota and memory regulatory T cells.

BACKGROUND: Traditional Chinese medicine has used the drug Pien Tze Huang (PTH), a classic prescription, to treat autoimmune hepatitis (AIH). However, the precise mode of action is still unknown. AIM: To investigate the mechanism of PTH in an AIH mouse model by determining the changes in gut microbiota structure and memory regulatory T (mTreg) cells functional levels. METHODS: Following induction of the AIH mouse model induced by Concanavalin A (Con A), prophylactic administration of PTH was given for 10 d. The levels of mTreg cells were measured by flow cytometry, and intestinal microbiota was analyzed by 16S rRNA analysis, while western blotting was used to identify activation of the toll-like receptor (TLR)2, TLR4/nuclear factor-κB (NF-κB), and CXCL16/CXCR6 signaling pathways. RESULTS: In the liver of mice with AIH, PTH relieved the pathological damage and reduced the numbers of T helper type 17 cells and interferon-γ, tumor necrosis factor-alpha, interleukin (IL)-1ß, IL-2, IL-6, and IL-21 expression. Simultaneously, PTH stimulated the abundance of helpful bacteria, promoted activation of the TLR2 signal, which may enhance Treg/mTreg cells quantity to produce IL-10, and suppressed activation of the TLR4/NF-κB and CXCL16/CXCR6 signaling pathways. CONCLUSION: PTH regulates intestinal microbiota balance and restores mTreg cells to alleviate experimental AIH, which is closely related to the TLR/CXCL16/CXCR6/NF-κB signaling pathway.

Alterations of small non-coding RNA in the spermatozoa of mice with paternal experimental autoimmune epididymo-orchitis are associated with metabolic dysfunction in offspring.

BACKGROUND: Infection and inflammation of the genital tract are major potentially treatable factors contributing to male infertility. The profile of small non-coding RNA (sncRNAs) in spermatozoa can be altered by environmental exposures and inflammatory conditions. OBJECTIVES: Experimental autoimmune epididymo-orchitis (EAEO) is a well-established model of autoimmune-induced chronic testicular and epididymal inflammation. This model investigates the effect of chronic inflammation on sperm sncRNA profiles and offspring phenotypes. MATERIALS AND METHODS: Regarding the EAEO model, mice were immunized with testis homogenates thrice. Subsequently, flow cytometry and histological analyses were conducted on EAEO mice. Next-generation sequencing was used to profile small RNA of spermatozoa from the caput, corpus, and cauda epididymis. We performed a comprehensive integrative analysis of sperm sncRNAs and chronic epididymitis and identified their molecular signatures. The metabolic functions of the first-generation (F1) offspring were evaluated using a glucose tolerance test (GTT). RESULTS: Body weight and metabolic function were significantly altered in F1 offspring from EAEO sperm donors. The analysis of cauda sperm sncRNA profiles revealed that the proportions of miRNAs and tsRNAs increased and decreased, respectively, after autoimmunization. Three differentially expressed miRNAs and seven differentially expressed tsRNAs were significantly correlated with F1 metabolic dysfunction. The expression patterns of miRNAs and tsRNAs in mice partially overlapped with those observed in the spermatozoa from human patients with chronic epididymitis. DISCUSSION AND CONCLUSIONS: We revealed that autoimmune epididymo-orchitis alters sncRNA profiles in mouse spermatozoa. Offspring from mice with autoimmune orchitis develop metabolic disorders. A comprehensive analysis of human and mouse inflammation data revealed an association between alterations in the miRNA and tsRNA profiles of epididymal spermatozoa and offspring phenotypes.

Adrenomedullin has a pivotal role in trophoblast differentiation: A promising nanotechnology-based therapeutic target for early-onset preeclampsia.

Early-onset preeclampsia (EOPE) is a severe pregnancy complication associated with defective trophoblast differentiation and functions at implantation, but manifestation of its phenotypes is in late pregnancy. There is no reliable method for early prediction and treatment of EOPE. Adrenomedullin (ADM) is an abundant placental peptide in early pregnancy. Integrated single-cell sequencing and spatial transcriptomics confirm a high ADM expression in the human villous cytotrophoblast and syncytiotrophoblast. The levels of ADM in chorionic villi and serum were lower in first-trimester pregnant women who later developed EOPE than those with normotensive pregnancy. ADM stimulates differentiation of trophoblast stem cells and trophoblast organoids in vitro. In pregnant mice, placenta-specific ADM suppression led to EOPE-like phenotypes. The EOPE-like phenotypes in a mouse PE model were reduced by a placenta-specific nanoparticle-based forced expression of ADM. Our study reveals the roles of trophoblastic ADM in placental development, EOPE pathogenesis, and its potential clinical uses.

Age-dependent changes in the gut microbiota and serum metabolome correlate with renal function and human aging.

Human aging is invariably accompanied by a decline in renal function, a process potentially exacerbated by uremic toxins originating from gut microbes. Based on a registered household Chinese Guangxi longevity cohort (n = 151), we conducted comprehensive profiling of the gut microbiota and serum metabolome of individuals from 22 to 111 years of age and validated the findings in two independent East Asian aging cohorts (Japan aging cohort n = 330, Yunnan aging cohort n = 80), identifying unique age-dependent differences in the microbiota and serum metabolome. We discovered that the influence of the gut microbiota on serum metabolites intensifies with advancing age. Furthermore, mediation analyses unveiled putative causal relationships between the gut microbiota (Escherichia coli, Odoribacter splanchnicus, and Desulfovibrio piger) and serum metabolite markers related to impaired renal function (p-cresol, N-phenylacetylglutamine, 2-oxindole, and 4-aminohippuric acid) and aging. The fecal microbiota transplantation experiment demonstrated that the feces of elderly individuals could influence markers related to impaired renal function in the serum. Our findings reveal novel links between age-dependent alterations in the gut microbiota and serum metabolite markers of impaired renal function, providing novel insights into the effects of microbiota-metabolite interplay on renal function and healthy aging.

Curcumin alleviated dextran sulfate sodium-induced colitis by recovering memory Th/Tfh subset balance.

BACKGROUND: Restoration of immune homeostasis by targeting the balance between memory T helper (mTh) cells and memory follicular T helper (mTfh) cells is a potential therapeutic strategy against ulcerative colitis (UC). Because of its anti-inflammatory and immunomodulatory properties, curcumin (Cur) is a promising drug for UC treatment. However, fewer studies have demonstrated whether Cur can modulate the mTh/mTfh subset balance in mice with colitis. AIM: To explore the potential mechanism underlying Cur-mediated alleviation of colitis induced by dextran sulfate sodium (DSS) in mice by regulating the mTh and mTfh immune homeostasis. METHODS: Balb/c mice were administered 3% and 2% DSS to establish the UC model and treated with Cur (200 mg/kg/d) by gavage on days 11-17. On the 18th d, all mice were anesthetized and euthanized, and the colonic length, colonic weight, and colonic weight index were evaluated. Histomorphological changes in the mouse colon were observed through hematoxylin-eosin staining. Levels of Th/mTh and Tfh/mTfh cell subsets in the spleen were detected through flow cytometry. Western blotting was performed to detect SOCS-1, SOCS-3, STAT3, p-STAT3, JAK1, p-JAK1, and NF-κB p65 protein expression levels in colon tissues. RESULTS: Cur effectively mitigates DSS-induced colitis, facilitates the restoration of mouse weight and colonic length, and diminishes the colonic weight and colonic weight index. Simultaneously, it hinders ulcer development and inflammatory cell infiltration in the colonic mucous membrane. While the percentage of Th1, mTh1, Th7, mTh7, Th17, mTh17, Tfh1, mTfh1, Tfh7, mTfh7, Tfh17, and mTfh17 cells decreased after Cur treatment of the mice for 7 d, and the frequency of mTh10, Th10, mTfh10, and Tfh10 cells in the mouse spleen increased. Further studies revealed that Cur administration prominently decreased the SOCS-1, SOCS-3, STAT3, p-STAT3, JAK1, p-JAK1, and NF-κB p65 protein expression levels in the colon tissue. CONCLUSION: Cur regulated the mTh/mTfh cell homeostasis to reduce DSS-induced colonic pathological damage, potentially by suppressing the JAK1/STAT3/SOCS signaling pathway.

Association of folic acid dosage with circulating unmetabolized folic acid in Chinese adults with H-type hypertension: a multicenter, double-blind, randomized controlled trial.

Background: There is growing concern regarding elevated levels of circulating unmetabolized folic acid (UMFA) due to excessive intake of folic acid (FA). However, no randomized clinical trial has been conducted to examine the FA-UMFA dose-response relationship. Objective: This study aimed to investigate the FA-UMFA dose-response relationship in Chinese adults with hypertension and elevated homocysteine (H-type hypertension), a population with clear clinical indication for FA treatment. Methods: The data for this study were derived from a randomized, double-blind, multicenter clinical trial of 8 FA dosages on efficacy of homocysteine (Hcy) lowering. The parent trial had three 3 stages: screening period (2-10 days), run-in period (0-2 weeks, baseline visit), and double-blind treatment period (8 weeks) with follow-up visits at the end of the 2nd, 4th, 6th, and 8th weeks of treatment. Participants were randomly assigned to 8 treatment groups corresponding to FA dosages of 0, 0.4, 0.6, 0.8, 1.2, 1.6, 2.0 mg to 2.4 mg. Results: This study included 1,567 Chinese adults aged ≥45 years with H-type hypertension. There was a positive but non-linear association between FA supplementation and UMFA levels in the dosage range of 0 mg to 2.4 mg. In the regression analysis, the coefficients for the linear and quadratic terms of FA dosage were both statistically significant (P < 0.001). Notably, the slope for UMFA was greater for FA dosages >0.8 mg (ß = 11.21, 95% CI: 8.97, 13.45) compared to FA dosages ≤0.8 mg (ß = 2.94, 95% CI: 2.59, 3.29). Furthermore, FA dosages higher than 0.8 mg did not confer additional benefits in terms of increasing 5-methyl tetrahydrofolic acid (5-MTHF, active form of folate) or reducing homocysteine (Hcy). Conclusion: In Chinese adults with H-type hypertension, this study showed a positive, non-linear, dosage-response relationship between FA supplementation ranging from 0 to 2.4 mg and circulating UMFA levels. It revealed that 0.8 mg FA is an optimal dosage in terms of balancing efficacy (increasing 5-MTHF and lowering Hcy) while minimizing undesirable elevation of UMFA. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03472508?term=NCT03472508&draw=2&rank=1, identifier NCT03472508.

Modification on Flower Defects and Electronic Properties of Epitaxial Graphene by Erbium.

Manipulating the topological defects and electronic properties of graphene has been a subject of great interest. In this work, we have investigated the influence of Er predeposition on flower defects and electronic band structures of epitaxial graphene on SiC. It is shown that Er atoms grown on the SiC substrate actually work as an activator to induce flower defect formation with a density of 1.52 × 1012 cm-2 during the graphitization process when the Er coverage is 1.6 ML, about 5 times as much as that of pristine graphene. First-principles calculations demonstrate that Er greatly decreases the formation energy of the flower defect. We have discussed Er promoting effects on flower defect formation as well as its formation mechanism. Scanning tunneling microscopy (STM) and Raman and X-ray photoelectron spectroscopy (XPS) have been utilized to reveal the Er doping effect and its modification to electronic structures of graphene. N-doping enhancement and band gap opening can be observed by using angle-resolved photoemission spectroscopy (ARPES). With Er coverage increasing from 0 to 1.6 ML, the Dirac point energy decreases from -0.34 to -0.37 eV and the band gap gradually increases from 320 to 360 meV. The opening of the band gap is attributed to the synergistic effect of substitution doping of Er atoms and high-density flower defects.

The relationship between trimethylamine-N-oxide and the risk of acute ischemic stroke: A dose‒response meta-analysis.

BACKGROUND: Although trimethylamine-N-oxide (TMAO) shows a notable correlation with cardiovascular disease, its association with acute ischemic stroke (AIS) remains uncertain and necessitates further investigation. OBJECTIVE: A meta-analysis was conducted to assess the relationship between trimethylamine-N-oxide and acute ischemic stroke. METHODS: We conducted a comprehensive search in PubMed, Embase, Cochrane, CNKI, VIP, Wanfang, and CBM, spanning from their inception to 23 September 2023. The search was consistently updated and supplemented by bibliographies of retrieved articles and previous reviews. A total of 20 eligible studies, including 17 case‒controls and 3 cohort studies, were selected, involving 9141 participants (5283 case group, 3858 control group). For the dose‒response analysis, three case-control studies were eligible. We extracted and pooled TMAO mean and standard deviation from observational studies for control and ischemic stroke groups. The effect sizes were combined using the random-effects model. Where possible, dose‒response analysis was performed. RESULT: Overall, the pooled standardized mean difference (SMD) demonstrated significantly higher concentrations of serum/plasma TMAO in AIS compared to the control group (SMD = 1.27; 95% CI: 0.9, 1.61, P<0.001). Additionally, the dose‒response meta-analysis revealed a 12.1% relative increase in the risk of acute ischemic stroke per 1 µmol/L rise in TMAO concentration (RR = 1.12; 95% CI 1.07-1.17; P<0.05; I2 = 1.6%, P = 0.4484). CONCLUSION: These findings indicate a potential increased risk of AIS associated with elevated TMAO levels.