Gray matter morphometric biomarkers for distinguishing manganese-exposed welders from healthy adults revealed by source-based morphometry.

BACKGROUND: Chronic overexposure to manganese (Mn) may result in neurotoxicity, which is characterized by motor and cognitive dysfunctions. This study aimed to utilize multivariate source-based morphometry (SBM) to explore the biomarkers for distinguishing Mn-exposed welders from healthy controls (HCs). METHODS: High-quality 3D T1-weighted MRI scans were obtained from 45 Mn-exposed full-time welders and 33 age-matched HCs in this study. After extracting gray matter structural covariation networks by SBM, multiple classic interaction linear models were applied to investigate distinct patterns in welders compared to HCs, and Z-transformed loading coefficients were compared between the two groups. A receiver operating characteristic (ROC) curve was used to identify potential biomarkers for distinguishing Mn-exposed welders from HCs. Additionally, we assessed the relationships between clinical features and gray matter volumes in the welders group. RESULTS: A total of 78 subjects (45 welders, mean age 46.23±4.93 years; 33 HCs, mean age 45.55±3.40 years) were evaluated. SBM identified five components that differed between the groups. These components displayed lower loading weights in the basal ganglia, thalamus, default mode network (including the lingual gyrus and precuneus), and temporal lobe network (including the temporal pole and parahippocampus), as well as higher loading weights in the sensorimotor network (including the supplementary motor cortex). ROC analysis identified the highest classification power in the thalamic network. CONCLUSIONS: Altered brain structures might be implicated in Mn overexposure-related disturbances in motivative modulation, cognitive control and information integration. These results encourage further studies that focus on the interaction mechanisms, including the basal ganglia network, thalamic network and default mode network. Our study identified potential neurobiological markers in Mn-exposed welders and illustrated the utility of a multivariate method of gray matter analysis.

Risk factors for preeclampsia in patients with chronic kidney disease primarily focused on stage 1 CKD. Are referred and registered patients alike?

Limited research exists on identifying risk factors for preeclampsia (PE) in the chronic kidney disease (CKD) population, especially across different patient sources. This study aimed to address this gap by analyzing clinical data from CKD pregnant women admitted to Peking University Third Hospital from January 2012 to December 2022. Logistic regression analysis identified independent risk factors for PE in the CKD population and assessed variations among patients from different sources. Additionally, a predictive model for PE was established using data from the registered group. The study included 524 CKD patients. Hypertension, proteinuria, fibrinogen >4 g/L, serum albumin ≤30 g/L, and uric acid >260 µmol/L were independent risk factors for PE in the overall CKD population. Subgroup analysis revealed that hypertension, serum albumin ≤30 g/L, and uric acid >260 µmol/L were independent risk factors in the referred group, while hypertension, uric acid >260 µmol/L, and fibrinogen >4 g/L were independent risk factors in the registered group. The prediction model based on registered group risk factors showed good predictive efficiency, with the area under the curve of 0.774 in the training set and 0.714 in the validation set. In conclusion, this study revealed that hypertension and elevated uric acid are independent risk factors for PE in CKD patients regardless of patient source, while serum albumin and fibrinogen levels are associated with PE risk in specific patient subgroups. Our predictive model enables clinicians to quickly identify the risk of PE in CKD patients, and early intervention treatment to improve pregnancy outcomes.

The Combination of Bacillus natto JLCC513 and Ginseng Soluble Dietary Fiber Attenuates Ulcerative Colitis by Modulating the LPS/TLR4/NF-κB Pathway and Gut Microbiota.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that is currently difficult to treat effectively. Both Bacillus natto (BN) and ginseng-soluble dietary fiber (GSDF) are anti-inflammatory and helps sustain the intestinal barrier. In this study, the protective effects and mechanism of the combination of B. natto JLCC513 and ginseng-soluble dietary fiber (BG) in DSS-induced UC mice were investigated. Intervention with BG worked better than taking BN or GSDF separately, as evidenced by improved disease activity index, colon length, and colon injury and significantly reduced the levels of oxidative and inflammatory factors (LPS, ILs, and TNF-α) in UC mice. Further mechanistic study revealed that BG protected the intestinal barrier integrity by maintaining the tight junction proteins (Occludin and Claudin1) and inhibited the LPS/TLR4/NF-κB pathway in UC mice. In addition, BG increased the abundance of beneficial bacteria such as Bacteroides and Turicibacter and reduced the abundance of harmful bacteria such as Allobaculum in the gut microbiota of UC mice. BG also significantly upregulated genes related to linoleic acid metabolism in the gut microbiota. These BG-induced changes in the gut microbiota of mice with UC were significantly correlated with changes in pathological indices. In conclusion, this study demonstrated that BG exerts protective effect against UC by regulating the LPS/TLR4/NF-κB pathway and the structure and metabolic function of gut microbiota. Thus, BG can be potentially used in intestinal health foods to treat UC.

Cu-BTC Derived Mesoporous CuS Nanomaterial as Nanozyme for Colorimetric Detection of Glutathione.

In this paper, Cu-BTC derived mesoporous CuS nanomaterial (m-CuS) was synthesized via a two-step process involving carbonization and sulfidation of Cu-BTC for colorimetric glutathione detection. The Cu-BTC was constructed by 1,3,5-benzenetri-carboxylic acid (H3BTC) and Cu2+ ions. The obtained m-CuS showed a large specific surface area (55.751 m2/g), pore volume (0.153 cm3/g), and pore diameter (15.380 nm). In addition, the synthesized m-CuS exhibited high peroxidase-like activity and could catalyze oxidation of the colorless substrate 3,3',5,5'-tetramethylbenzidine to a blue product. Peroxidase-like activity mechanism studies using terephthalic acid as a fluorescent probe proved that m-CuS assists H2O2 decomposition to reactive oxygen species, which are responsible for TMB oxidation. However, the catalytic activity of m-CuS for the oxidation of TMB by H2O2 could be potently inhibited in the presence of glutathione. Based on this phenomenon, the colorimetric detection of glutathione was demonstrated with good selectivity and high sensitivity. The linear range was 1-20 µM and 20-300 µM with a detection limit of 0.1 µM. The m-CuS showing good stability and robust peroxidase catalytic activity was applied for the detection of glutathione in human urine samples.

The safety and efficacy of Compound Kushen Injection with chemoradiotherapy for the outcomes of lung and gastrointestinal cancers: A PRIMSA-compliant meta-analysis.

BACKGROUND: Compound Kushen injection (CKI) is a mixture of natural compounds extracted from Radix Sophorae and Smilax glabra Roxb. CKI, as an antitumor preparation, plays a vital role in the clinical treatment of lung and gastrointestinal cancers. METHODS: Electronic databases such as the China National Knowledge Infrastructure, Wanfang data, PubMed, EMBASE, and Web of Science were searched for studies. The included studies were evaluated according to the Cochrane Handbook for Systematic Reviews, and meta-analyses were performed using RevMan 5.3 software. RESULTS: Twenty-four randomized controlled trials were selected for meta-analysis. The outcomes showed that CKI adjuvant therapy significantly improved complete remission (CR) and partial response (PR) compared to patients without CKI treatment in gastrointestinal cancers (CR: odds ratio [OR] = 1.76, 95% confidence interval [CI]: [1.29, 2.41], P = .0004; PR: OR = 1.64, 95% CI: [1.29, 2.07], P =.0001), and lung cancer (CR: OR = 2.18, 95% CI: [1.36, 3.51], P = .001); PR: OR = 1.81, 95% CI: [1.31, 2.50], P = .0003). CKI adjuvant therapy had a statistically significant advantage in optimizing life and health status (quality of life [QOL] for gastrointestinal cancers: MD = 1.76, 95% CI: [6.41, 13.80], P = .001, and Karnofsky performance status [KPS] for gastrointestinal cancers: MD = 4.64, 95% CI: [2.72, 6.57], P = .001; KPS for lung cancer: MD = 6.24, 95% CI [1.78, 10.71], P = .006). CKI reduced the pain in lung cancer patients (MD = -1.76, 95% CI: [-1.94, -1.58], P < .00001), increased immunity level (MD = 2.51, 95% CI: [2.17, 2.85], P < .00001), and alleviated the adverse reactions for lung and gastrointestinal cancers (MD = 0.38, 95% CI: (0.32, 0.46); P < .00001). CONCLUSION: The combination of CKI and chemoradiotherapy for treating lung and gastrointestinal cancer has positive effects on short-term and long-term outcomes and has advantages over chemoradiotherapy alone regarding safety and efficacy.

The potential role of CMC1 as an immunometabolic checkpoint in T cell immunity.

T cell immunity is critical for human defensive immune response. Exploring the key molecules during the process provides new targets for T cell-based immunotherapies. CMC1 is a mitochondrial electron transport chain (ETC) complex IV chaperon protein. By establishing in-vitro cell culture system and Cmc1 gene knock out mice, we evaluated the role of CMC1 in T cell activation and differentiation. The B16-OVA tumor model was used to test the possibility of targeting CMC1 for improving T cell anti-tumor immunity. We identified CMC1 as a positive regulator in CD8+T cells activation and terminal differentiation. Meanwhile, we found that CMC1 increasingly expressed in exhausted T (Tex) cells. Genetic lost of Cmc1 inhibits the development of CD8+T cell exhaustion in mice. Instead, deletion of Cmc1 in T cells prompts cells to differentiate into metabolically and functionally quiescent cells with increased memory-like features and tolerance to cell death upon repetitive or prolonged T cell receptor (TCR) stimulation. Further, the in-vitro mechanistic study revealed that environmental lactate enhances CMC1 expression by inducing USP7, mediated stabilization and de-ubiquitination of CMC1 protein, in which a mechanism we propose here that the lactate-enriched tumor microenvironment (TME) drives CD8+TILs dysfunction through CMC1 regulatory effects on T cells. Taken together, our study unraveled the novel role of CMC1 as a T cell regulator and its possibility to be utilized for anti-tumor immunotherapy.

Coupling vibration analysis of heat exchanger tube bundles under different stiffness conditions.

A two-dimensional tube bundles fluid-structure coupling model was developed using the CFD approach, with a rigid body motion equation and the Newmark integral method. The numerical simulations were performed to determine the vibration coupling properties between various tube bundles of stiffness. Take the corner square tube bundles with a pitch ratio of 1.28 as the research object. The influence of adjacent tubes with different stiffness on the vibration of the central target tube was analyzed. The research results show that the vibration characteristic of tube bundles is affected by the flow field dominant frequency and the inherent frequency of tube bundles. The vibration of adjacent tube bundles significantly impacts the amplitude and frequency of the central target tube. The equal stiffness and large stiffness tubes upstream or downstream inhibit the vibration displacement of the target tube to some extent. The low-stiffness tubes upstream or downstream significantly enhanced the amplitude of the target tube. The findings can be used to provide a basis for reasonable design and vibration suppression of shell-and-tube heat exchangers.

Manipulating the Microenvironment of Single Atoms by Switching Support Crystallinity for Industrial Hydrogen Evolution.

Modulating the microenvironment of single-atom catalysts (SACs) is critical to optimizing catalytic activity. Herein, we innovatively propose a strategy to improve the local reaction environment of Ru single atoms by precisely switching the crystallinity of the support from high crystalline and low crystalline, which significantly improves the hydrogen evolution reaction (HER) activity. The Ru single-atom catalyst anchored on low-crystalline nickel hydroxide (Ru-LC-Ni(OH)2 ) reconstructs the distribution balance of the interfacial ions due to the activation effect of metal dangling bonds on the support. Single-site Ru with a low oxidation state induces the aggregation of hydronium ions (H3 O+ ), leading to the formation of a local acidic microenvironment in alkaline media, breaking the pH-dependent HER activity. As a comparison, the Ru single-atom catalyst anchored on high-crystalline nickel hydroxide (Ru-HC-Ni(OH)2 ) exhibits a sluggish Volmer step and a conventional local reaction environment. As expected, Ru-LC-Ni(OH)2 requires low overpotentials of 9 and 136 mV at 10 and 1000 mA cm-2 in alkaline conditions and operates stably at 500 mA cm-2 for 500 h in an alkaline seawater anion exchange membrane (AEM) electrolyzer. This study provides a new perspective for constructing highly active single-atom electrocatalysts.

Stiffened tumor microenvironment enhances perineural invasion in breast cancer via integrin signaling.

BACKGROUND: Accumulating studies have shown that tumors are regulated by nerves, and there is abundant nerve infiltration in the tumor microenvironment. Many solid tumors including breast cancer (BRCA) have different degrees of perineural invasion (PNI), which is closely related to the tumor occurrence and progression. However, the regulatory mechanism of PNI in BRCA remains largely unexplored. METHODS: PNI-related molecular events are analyzed by the RNAseq data of BRCA samples deposited in The Cancer Genome Atlas (TCGA) database. Extracellular matrix (ECM) components within the tumor microenvironment are analyzed by immunohistochemical staining of α-SMA, Sirius red staining, and Masson trichrome staining. Soft and stiff matrix gels, living cell imaging, and dorsal root ganglion (DRG) coculture assay are used to monitor cancer cell invasiveness towards nerves. Western blotting, qRT-PCR, enzyme-linked immunosorbent assay combined with neutralizing antibody and small molecular inhibitors are employed to decode molecular mechanisms. RESULTS: Comparative analysis that the ECM was significantly associated with PNI status in the TCGA cohort. BRCA samples with higher α-SMA activity, fibrillar collagen, and collagen content had higher frequency of PNI. Compared with soft matrix, BRCA cells cultured in stiff matrix not only displayed higher cell invasiveness to DRG neurons but also had significant neurotrophic effects. Mechanistically, integrin ß1 was identified as a functional receptor to the influence of stiff matrix on BRCA cells. Moreover, stiffened matrix-induced activation of integrin ß1 transduces FAK-YAP signal cascade, which enhances cancer invasiveness and the neurotrophic effects. In clinical setting, PNI-positive BRCA samples had higher expression of ITGB1, phosphorylated FAK, YAP, and NGF compared with PNI-negative BRCA samples. CONCLUSIONS: Our findings suggest that stiff matrix induces expression of pro-metastatic and neurotrophic genes through integrin ß1-FAK-YAP signals, which finally facilitates PNI in BRCA. Thus, our study provides a new mechanism for PNI in BRCA and highlights nerve-based tumor treatment strategies.

Synthesis and fabrication of segregative and durable MnO2@chitosan composite aerogel beads for uranium(VI) removal from wastewater.

To address the imperative need for efficient removal of uranium-containing wastewater and mitigate radioactive contamination risks associated with nuclear energy, the development of materials with high removal efficiency and facile separation is crucial. This study designed and synthesised MnO2@chitosan (CTS) composite aerogel beads by in-situ growing δ-MnO2 on porous CTS aerogel beads. This approach not only mitigates the agglomeration of MnO2 nanospheres but also significantly enhances the porous structure and surface area of MnO2@CTS. These cost-effective and eco-friendly millimeter-scale spherical aerogels exhibited convenient separation properties after adsorption. These characteristics help mitigate the risk of equipment seam blockage and secondary pollution that are often associated with powdered adsorbents. Additionally, MnO2@CTS exhibited remarkable mechanical strength (stress approximately 0.55 MPa at 60 % strain), enabling rapid separation and easy regeneration while maintaining high adsorption performance even after five cycles. Significantly, MnO2@CTS exhibited a maximum adsorption capacity of 410.7 mg/g at pH 6 and 298 K, surpassing reported values for most CTS/MnO2-based adsorbents. The chemisorption process of U(VI) on MnO2@CTS followed the pseudo-second-order kinetic and Dubinin-Radushkevish models. X-ray photoelectron spectroscopy analysis further confirmed the reduction of U(VI) to U(V/IV). These findings highlight the substantial potential of MnO2@CTS aerogel beads for U(VI) removal from aqueous solutions, positioning them as a promising solution for addressing U(VI) contamination in wastewater.

Association of IL-17 and IL-27 polymorphisms with susceptibility to recurrent pregnancy loss and pre-eclampsia: A systematic review and meta-analysis.

OBJECTIVE: Recurrent pregnancy loss (RPL) and pre-eclampsia (PE) are immune-related pregnancy complications that have been linked to CD4+ T cells and their cytokines, which can be influenced by genetic polymorphisms. This meta-analysis aimed to investigate the relationship between interleukin (IL)-17 and -27 polymorphisms and the susceptibility to RPL and PE. METHODS: All eligible case-control studies published up to February 2023 were identified by searching PubMed, EMBASE, Cochrane, Web of Science, and Google Scholar. The risk of recurrent pregnancy loss and PE associated with the IL-17 rs2275913, IL-17 rs763780, IL-27 rs153109, and IL-27 rs17855750 polymorphisms were estimated for each study. RESULTS: The meta-analysis incorporated a total of 13 studies. The overall analysis indicated that IL-17 rs2275913, IL-17 rs763780, IL-27 rs153109, and IL-27 rs17855750 polymorphisms were not significantly associated with immune-related pregnancy complications, including RPL and PE. However, when the analysis was stratified by disease type, the IL-17 rs2275913 polymorphism was found to be associated with an increased risk of RPL (recessive model AA/GA + GG: OR = 1.68, 95% confidence interval [CI]: 1.13-2.49, p = .01). CONCLUSIONS: The IL-17 rs763780, IL-27 rs153109, and IL-27 rs17855750 polymorphisms were not significantly associated with RPL and PE, whereas the IL-17 rs2275913 polymorphism was associated with the susceptibility to recurrent miscarriage.

Wogonin inhibits hepatoma cell proliferation by targeting miR-27b-5p/YWHAZ axis.

Wogonin (5,7-dihydroxy-8-methoxyflavone), a natural flavonoid compound in herbal plants, can suppress growth in hepatocellular carcinoma (HCC). However, the microRNA (miRNA) expression profiles that are influenced by wogonin have not been thoroughly described. To explore the novel miRNAs and the biological mechanism underlying the effect of wogonin on HCC cells. The effect of wogonin on Huh7 cell growth was assessed both in vitro and in vivo. The expression profiles of miRNAs were obtained by small RNA sequencing. Luciferase reporter experiment and bioinformatics analysis were conducted to determine whether tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ) can bind to miR-27b-5p. Effects of the ectopic expression of YWHAZ and miR-27b-5p on Huh7 cells proliferation and apoptosis were evaluated. Furthermore, the cell cycle, apoptosis and multiple signaling pathway-related molecules were detected by Western blot analysis. Wogonin substantially inhibited the growth of Huh7 cells both in vitro and in vivo. Seventy miRNAs exhibited greater than twofold changes in wogonin-treated cells. Upregulation of miR-27b-5p inhibited Huh7 cell proliferation, and the anticancer effect of wogonin was reversed after miR-27b-5p knockdown. miR-27b-5p directly targeted YWHAZ in HCC cells. The proliferation-inhibiting effect of miR-27b-5p was revoked by YWHAZ overexpression. Meanwhile, inhibition of HCC growth was achieved by downregulating YWHAZ. Wogonin exerted antitumor activity through multiple signaling molecules, such as focal adhesion kinase, protein kinase B, mammalian target of rapamycin and molecules related to apoptosis and cell cycle by upregulating miR-27b-5p and downregulating YWHAZ. Our findings suggest that miR-27b-5p/YWHAZ axis contributes to the inhibitory effect of wogonin in HCC by targeting related genes and multiple signaling pathways.

T-cell senescence induced by peripheral phospholipids.

We present an integrated analysis of the clinical measurements, immune cells, and plasma lipidomics of 2000 individuals representing different age stages. In the study, we explore the interplay of systemic lipids metabolism and circulating immune cells through in-depth analysis of immune cell phenotype and function in peripheral dynamic lipids environment. The population makeup of circulation lymphocytes and lipid metabolites changes dynamically with age. We identified a major shift between young group and middle age group, at which point elevated, immune response is accompanied by the elevation of specific classes of peripheral phospholipids. We tested the effects in mouse model and found that 10-month-dietary added phospholipids induced T-cell senescence. However, the chronic malignant disease, the crosstalk between systemic metabolism and immunity, is completely changed. In cancer patients, the unusual plasma cholesteryl esters emerged, and free fatty acids decreased. The study reveals how immune cell classes and peripheral metabolism coordinate during age acceleration and suggests immune senescence is not isolated, and thus, system effect is the critical point for cell- and function-specific immune-metabolic targeting. • The study identifies a major shift of immune phenotype between young group and middle age group, and the immune response is accompanied by the elevation of specific classes of peripheral phospholipids; • The study suggests potential implications for translational studies such as using metabolic drug to regulate immune activity.

Proteolytic activation of angiomotin by DDI2 promotes angiogenesis.

The scaffolding protein angiomotin (AMOT) is indispensable for vertebrate embryonic angiogenesis. Here, we report that AMOT undergoes cleavage in the presence of lysophosphatidic acid (LPA), a lipid growth factor also involved in angiogenesis. AMOT cleavage is mediated by aspartic protease DNA damage-inducible 1 homolog 2 (DDI2), and the process is tightly regulated by a signaling axis including neurofibromin 2 (NF2), tankyrase 1/2 (TNKS1/2), and RING finger protein 146 (RNF146), which induce AMOT membrane localization, poly ADP ribosylation, and ubiquitination, respectively. In both zebrafish and mice, the genetic inactivation of AMOT cleavage regulators leads to defective angiogenesis, and the phenotype is rescued by the overexpression of AMOT-CT, a C-terminal AMOT cleavage product. In either physiological or pathological angiogenesis, AMOT-CT is required for vascular expansion, whereas uncleavable AMOT represses this process. Thus, our work uncovers a signaling pathway that regulates angiogenesis by modulating a cleavage-dependent activation of AMOT.

Schisandrin B induces HepG2 cells pyroptosis by activating NK cells mediated anti-tumor immunity.

Pyroptosis, an inflammatory programmed cell death, has been suggested as a novel molecular mechanism for the treatment of hepatocellular carcinoma (HCC) with chemotherapeutic agents. Recent studies showed that natural killer (NK) cells could inhibit apoptosis and regulate the progression of pyroptosis in tumor cells. Schisandrin B (Sch B), a lignan isolated from Schisandrae chinensis (Turcz.) Baill. (Schisandraceae) Fructus, has various pharmacological activities including anti-cancer effects. The purpose of this study was to investigate the effect of NK cells on Sch B's regulation of pyroptosis in HCC cells and the molecular mechanisms implicated. The results showed that Sch B alone could decrease cell viability and induce apoptosis in HepG2 cells. However, Sch B induced apoptosis in HepG2 cells was transformed into pyroptosis in the presence of NK cells. The mechanisms underlying NK cell's effect on pyroptosis in Sch B-treated HepG2 cells was related to its activation of caspase 3-Gasdermin E (GSDME). Further studies revealed that NK cell induced caspase 3 activation was derived from its activation of perforin-granzyme B pathway. This study explored the effect of Sch B and NK cells on pyroptosis in HepG2 cells and revealed that perforin-granzyme B-caspase 3-GSDME pathway is involved in the process of pyroptosis. These results proposed an immunomodulatory mechanism of Sch B on HepG2 cells pyroptosis and suggested Sch B as a promising immunotherapy combination partner for the treatment of HCC.

Peripheral immune mapping and multi-omics analysis in Pd-1 inhibitor-induced myocarditis.

More immune-related adverse events (irAEs) have emerged along with increased immune checkpoint inhibitor (ICI) treatment. ICI-induced myocarditis is a rare type of irAE with early onset, rapid progression, and high mortality. Its specific pathophysiological mechanism is not fully understood. In total, 46 patients with tumors and 16 patients with ICI-induced myocarditis were included. We performed single-cell RNA sequencing on CD3 + T cells, flow cytometry, proteomics, and lipidomics to improve our understanding of the disease. First, we demonstrate the clinical features of patients with PD-1 inhibitor-induced myocarditis. We then identified 18 subsets of T cells using single-cell RNA sequencing and performed comparative analysis and further verification. The composition of T cells in the peripheral blood of patients has changed remarkably. Compared with non-irAE patients, effector T cells were increased in irAE patients, while naive T cells, γδ T cells, and mucosal-associated invariant T cell cluster cells were decreased. Besides, reduced γδ T cells characterized with effector functions, increased natural killer T cells with high levels of FCER1G in patients may suggest an association with disease development. Meanwhile, the peripheral inflammatory response was exacerbated in patients, accompanied by upregulation of exocytosis as well as increased levels of multiple lipids. We provide a comprehensive overview of the composition, gene profiles, and pathway signatures of CD3+ T cells driven by PD-1 inhibitor-induced myocarditis, as well as illustrate clinical features and multi-omic characteristics, providing a unique perspective on disease progression and therapy in clinical practice.

Schisandrin B promotes senescence of activated hepatic stellate cell via NCOA4-mediated ferritinophagy.

CONTEXT: Schisandrin B (Sch B), an active ingredient from Schisandrae chinensis (Turcz.) Baill. (Schisandraceae) Fructus, possesses diverse pharmacological activities including antitumor, anti-inflammation, and hepatoprotection. OBJECTIVE: To explore the effect of Sch B on activated HSCs senescence in hepatic fibrosis and the mechanisms implicated. MATERIALS AND METHODS: ICR mice with CCl4-induced hepatic fibrosis were supplemented with Sch B (40 mg/kg) for 30 d and LX2 cells were treated with Sch B (5, 10 and 20 µM) for 24 h. Cellular senescence was assessed by senescence-related indicators senescence-associated ß-galactosidase (SA-ß-gal) activity and the expression of p16, p21, p53, γ-H2AX, H3K9me3, TERT, TRF1, and TRF2. Ferric ammonium citrate (FAC) and NCOA4 siRNA were used to evaluate the mechanisms underlying Sch B's regulation of cellular senescence. RESULTS: Sch B (40 mg/kg) reduced serum levels of AST and ALT (53.2% and 63.6%), alleviated hepatic collagen deposition, and promoted activated HSCs senescence in mice. Treatment with Sch B (20 µM) decreased cell viability to 80.38 ± 4.87% and elevated SA-ß-gal activity, with the levels of p16, p21 and p53 increased by 4.5-, 2.9-, and 3.5-fold and the levels of TERT, TRF1 and TRF2 decreased by 2.4-, 2.7-, and 2.6-fold in LX2 cells. FAC (400 µM) enhanced Sch B's effect mentioned above. NCOA4 siRNA weakened the effects of Sch B on iron deposition and HSCs senescence. CONCLUSIONS: Sch B could ameliorate hepatic fibrosis through the promotion of activated HSCs senescence, which might be attributed to its induction of NCOA4-mediated ferritinophagy and subsequent iron overload.

Prenatal BPA exposure disrupts male reproductive functions by interfering with DNA methylation and GDNF expression in the testes of male offspring rats.

BPA is a ubiquitous environmental endocrine-disrupting chemical, and maternal exposure to BPA is associated with impaired male reproductive functions; however, the mechanisms remain to be elucidated. Glial cell line-derived neurotrophic factor (GDNF) plays an important role in maintaining normal spermatogenesis and fertility. However, the effect of prenatal BPA exposure on GDNF expression and its mechanism in the testis has not been reported. In this study, pregnant Sprague-Dawley rats were respectively exposed to 0, 0.05, 0.5, 5, and 50 mg/kg/day BPA via oral gavage from gestational day (GD) 5 to GD 19, with 6 pregnant rats in each group. ELISA, histochemistry, real-time PCR, western blot, and methylation-specific PCR (MSP) were used to detect the sex hormone levels, testicular histopathology, mRNA and protein expression of DNA methyltransferases (DNMTs) and GDNF, and the promoter methylation of Gdnf in the testes of male offspring at postnatal day (PND) 21 and PND 56. Prenatal BPA exposure increased body weight; decreased sperm counts and serum levels of testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH); and induced testicular histological damage, which indicated the damage of male reproductive function. Prenatal BPA exposure also upregulated Dnmt1 in 5 mg/kg group and Dnmt3b in 0.5 mg/kg group, but down-regulated Dnmt1 in 50 mg/kg group at PND 21. At PND 56, Dnmt1 was significantly increased in 0.05 mg/kg group but decreased in 0.5, 5, and 50 mg/kg groups, Dnmt3a was decreased, and Dnmt3b was markedly increased in 0.05 and 0.5 mg/kg groups but decreased in 5 and 50 mg/kg groups. The mRNA and protein expression levels of Gdnf were decreased markedly in 0.5 and 50 mg/kg groups at PND 21. And the methylation level of Gdnf promoter was significantly increased in 0.5 mg/kg group, but decreased in 5 and 50 mg/kg groups at PND 21. In conclusion, our study indicates that prenatal BPA exposure disrupts male reproductive functions, interferes with the expression of DNMTs, and decreases Gdnf expression in the testes of male offspring. Gdnf expression may be regulated by DNA methylation; however, the detailed mechanism needs to be further investigated.