QingChang-XiaoPi decoction ameliorates intestinal inflammation of ulcerative colitis by regulating the pathogenicity of Th17 cells.

BACKGROUND: QingChang-XiaoPi Decoction (QCXPY), a Chinese herbal prescription, has been employed in the treatment of ulcerative colitis (UC) in China. However, its molecular mechanism of action in UC remains unclear. PURPOSE: To elucidate the therapeutic effects of QCXPY against UC and reveal its mechanism of action. STUDY DESIGN: We conducted a single-arm observation to evaluate the clinical efficacy of QCXPY in patients with mild-to-moderate UC. Inclusion and exclusion criteria were established to ensure the eligibility of participants, with a focus on excluding patients with specific conditions or complications that could confound the results. METHODS: The expression of inflammatory factors in patients' serum was detected using a Luminex assay. The main components of QCXPY were identified using UHPLC-Q-TOF-MS. Network pharmacology was employed to predict potential therapeutic targets and their mechanisms of action. The efficacy of QCXPY was evaluated using a dextran sulfate sodium (DSS)-induced mouse model. Disease activity index (DAI), histopathological score, cytokine detection by ELISA, T-helper 17 (Th17) cell proportion by flow cytometry, expression of the IL-23/IL-17 axis, and changes in the levels of its downstream effectors were detected by immunohistochemistry, immunofluorescence, and western blotting. RESULTS: QCXPY could alleviate the symptoms of diarrhea, abdominal pain, abdominal distension, and purulent stool in patients with mild-to-moderate UC. Moreover, it reduced the expression of IL-6, IL-17, and IL-23 in serum; alleviated DSS-induced experimental colitis in mice; reduced DAI, pathological scores, and the expressions of IL-6, IL-17, and IL-23 in colon tissue; and decreased the proportion of pathogenic Th17 cells and the expression of STAT3 and phospho-STAT3. CONCLUSION: This study confirmed for the first time that QCXPY could alleviate intestinal symptoms, reduce the levels of serum inflammatory factors, and improve the quality of life of patients with mild-to-moderate UC. Its mechanism of action may involve reducing the secretion of inflammatory cytokines, moderating the pathogenicity of Th17 cells, and inhibiting STAT3 phosphorylation, thereby alleviating intestinal inflammation in UC.

Follicular CD8+ T cells promote immunoglobulin production and demyelination in multiple sclerosis and a murine model.

Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35-55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.

Predictive efficacy of the preoperative neutrophil-lymphocyte ratio in lymph node metastasis of cN0 hormone receptor-positive breast cancer.

Breast cancer, as the most common cancer, has surpassed lung cancer worldwide. The neutrophil-to-lymphocyte ratio (NLR) has been linked to the onset of cancer and its prognosis in recent studies. However, quite a few studies have shown that there is a link between NLR and lymph node metastases in cN0 hormone receptor-positive (HR(+)) breast cancer. The purpose of this study was to evaluate the correlation between NLR and lymph node metastases in cN0 HR(+) breast cancer patients. From January 2012 to January 2022, 220 patients with cN0 HR(+) invasive breast cancers were enrolled in this study. The relationship between NLR and pathological data was statistically examined. The receiver operating characteristic (ROC) curve was used to determine the optimal cutoff of NLR, a chi-squared test was used for the univariate analysis, and logistic analysis was used for the multivariate analysis. The NLR had an optimal cutoff of 2.4 when the Jorden index was at a maximum. Patients with axillary lymph node metastases had a higher NLR (P < 0.05). A Univariate analysis showed that there were significant differences in cN0 HR(+) breast cancer with axillary lymph node metastasis among different clinical stages, histological grades, Ki-67 levels, tumor sizes, and NLR levels (P < 0.05). Clinical stage, tumor size, and NLR were found to be independent risk factors for lymph node metastases in multifactorial analysis. In cN0 HR(+) breast cancer, NLR is an independent risk factor for lymph node metastases. An NLR ≥ 2.4 indicates an increased probability of lymph node metastases. An elevated preoperative NLR has a high predictive value for axillary lymph node metastases.

Augmented microglial endoplasmic reticulum-mitochondria contacts mediate depression-like behavior in mice induced by chronic social defeat stress.

Extracellular ATP (eATP) signaling through the P2X7 receptor pathway is widely believed to trigger NLRP3 inflammasome assembly in microglia, potentially contributing to depression. However, the cellular stress responses of microglia to both eATP and stress itself remain largely unexplored. Mitochondria-associated membranes (MAMs) is a platform facilitating calcium transport between the endoplasmic reticulum (ER) and mitochondria, regulating ER stress responses and mitochondrial homeostasis. This study aims to investigate how MAMs influence microglial reaction and their involvement in the development of depression-like symptoms in response to chronic social defeat stress (CSDS). CSDS induced ER stress, MAMs' modifications, mitochondrial damage, and the formation of the IP3R3-GRP75-VDAC1 complex at the ER-mitochondria interface in hippocampal microglia, all concomitant with depression-like behaviors. Additionally, exposing microglia to eATP to mimic CSDS conditions resulted in analogous outcomes. Furthermore, knocking down GRP75 in BV2 cells impeded ER-mitochondria contact, calcium transfer, ER stress, mitochondrial damage, mitochondrial superoxide production, and NLRP3 inflammasome aggregation induced by eATP. In addition, reduced GRP75 expression in microglia of Cx3cr1CreER/+Hspa9f/+ mice lead to reduce depressive behaviors, decreased NLRP3 inflammasome aggregation, and fewer ER-mitochondria contacts in hippocampal microglia during CSDS. Here, we show the role of MAMs, particularly the formation of a tripartite complex involving IP3R3, GRP75, and VDAC1 within MAMs, in facilitating communication between the ER and mitochondria in microglia, thereby contributing to the development of depression-like phenotypes in male mice.

A multiplex one-step fluorescence quantitative differential diagnosis method for severe hand, foot and mouth disease caused by coxsackievirus A16.

Hand foot and mouth disease (HFMD) is a common childhood infectious disease which is caused by human enterovirus. The objective of this study was to develop a rapid, sensitive, and accurate method for detecting severe HFMD caused by coxsackievirus A16 (CV-A16). A closed-tube sensitive multiplex one-step reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) was applied to detect CV-A16 in the early stage of severe HFMD. This assay targeted the CV-A16 structure protein VP1 to distinguish CV-A16 from other coxsackieviruses The 5'UTR region of enteric viruses was used for detecting the enterovirus and ribonuclease P (RNaseP) was adopted as the internal reference gene. The multiplex MGB probe assay system was used to detect PCR amplicons with different fluorescence reporters in the same system. The limit of detection (LOD) of the RT-qPCR assay for the CV-A16 VP1 gene was 125.893 copies/µl, for the 5' UTR was 50.1187 copies/µl and for the RNaseP gene was 158.49 copies/µl. Furthermore, specificity analysis showed that the multiplex RT-PCR had no cross-reactivity with the influenza virus, herpangina virus and SARS-COV-2. In correlation analysis, the sensitivity of the multiplex RT-qPCR assay for CV-A16 detection was 100% (288/288) and the specificity of the multiplex RT-qPCR assay was 99.94% (3395/3397). The overall agreement between the multiplex RT-qPCR and the results of clinical diagnosis was 99.95% (3683/3685) and kappa value was 0.996 (p<0.001). The entire procedure, from specimen processing to result reporting, could be completed within 1.5hours. The one-step multiplex RT-qPCR assay for detecting CV-A16 developed in this study is a good laboratory diagnostic tool for rapid and reliable distinguished detection of CV-A16, especially for severe HFMD patients at an early stage in the disease with low virus load of CV-A16.

Chloride salt enhances plant resistance to biotic stresses.

Biotic stresses caused by bacterial and fungal pathogens damage crops; identifying treatments that enhance disease resistance provides important information for understanding plant defenses and sustainable agriculture. Salt stress affects crop yields worldwide; however, studies have focused on the toxic sodium ion, leaving the effects of the chloride ion unclear. In this study, we found that irrigation with a combination of chloride salts (MgCl2, CaCl2, and KCl) suppressed the cell death phenotype of the ceramide kinase mutant acd5. Chloride salt pre-irrigation also significantly limited the cell death caused by Pseudomonas syringae pv maculicola infection and inhibited the multiplication of this bacterial pathogen in a mechanism partially dependent on the salicylic acid pathway. Moreover, chloride salt pre-irrigation improved plant defenses against the fungal pathogen challenge, confining the lesion area caused by Botrytis cinerea infection. Furthermore, the growth of herbivorous larvae of Spodoptera exigua was retarded by feeding on chloride salt irrigated plants. Thus, our data suggest that treatment with Cl- increases broad spectrum resistance to biotic challenges.

Enhancing the performance of mode-pairing quantum key distribution by wavelength division multiplexing.

Mode-pairing quantum key distribution (MP-QKD) holds great promise for the practical implementation of QKD in the near future. It combines the security advantages of measurement device independence while still being capable of breaking the Pirandola-Laurenza-Ottaviani-Banchi bound without the need for highly demanding phase-locking and phase-tracking technologies for deployment. In this work, we explore optimization strategies for MP-QKD in a wavelength-division multiplexing scenario. The simulation results reveal that incorporation of multiple wavelengths not only leads to a direct increase in key rate but also enhances the pairing efficiency by employing our novel pairing strategies among different wavelengths. As a result, our work provides a new avenue for the future application and development of MP-QKD.

Role of mitochondria-associated membranes in the hippocampus in the pathogenesis of depression.

BACKGROUND: Pathological changes, such as microglia activation in the hippocampus frequently occur in individuals with animal models of depression; however, they may share a common cellular mechanism, such as endoplasmic reticulum (ER) stress and mitochondrial dysfunction. Mitochondria associated membranes (MAMs) are communication platforms between ER and mitochondria. This study aimed to investigate the role of intracellular stress responses, especially structural and functional changes of MAMs in depression. METHODS: We used chronic social defeat stress (CSDS) to mimic depression in C57 mice to investigate the pathophysiological changes in the hippocampus associated with depression and assess the antidepressant effect of electroacupuncture (EA). Molecular, histological, and electron microscopic techniques were utilized to study intracellular stress responses, including the ER stress pathway reaction, mitochondrial damage, and structural and functional changes in MAMs in the hippocampus after CSDS. Proteomics technology was employed to explore protein-level changes in MAMs caused by CSDS. RESULTS: CSDS caused mitochondrial dysfunction, ER stress, closer contact between ER and mitochondria, and enrichment of functional protein clusters at MAMs in hippocampus along with depressive-like behaviors. Also, EA showed beneficial effects on intracellular stress responses and depressive-like behaviors in CSDS mice. LIMITATION: The cellular specificity of MAMs related protein changes in CSDS mice was not explored. CONCLUSIONS: In the hippocampus, ER stress and mitochondrial damage occur, along with enriched mitochondria-ER interactions and MAM-related protein enrichment, which may contribute to depression's pathophysiology. EA may improve depression by regulating intracellular stress responses.

Structural characterization and human gut microbiota fermentation in vitro of a polysaccharide from Fucus vesiculosus.

In this study, an acidic polysaccharide (FVP-7 A) was isolated from Fucus vesiculosus by DEAE-Sepharose™ fast flow. The chemical composition, glycosidic bonds and in vitro fecal fermentation characteristics of FVP-7 A were studied. Results shown that FVP-7 A was a homogenous polysaccharide with average molecular weight of 30.94 kDa. Combined with FT-IR, monosaccharide composition, methylation and NMR analysis, the glycosidic bonds of FVP-7 A mainly composed of →4)-ß-D-Manp-(1→, →3)-α-L-Fucp-(1→, α-D-Manp-(1→, →3)-ß-D-Manp-(1 → and →4,6)-α-D-Manp-(1→. The zeta potential and atomic force microscopy images indicated that FVP-7 A could exist stably as a single chain-like structure in dilute solution. After gut fermentation, FVP-7 A was utilized and promoted multiple short-chain fatty acids production, especially acetic acid, butyric acid and valeric acid. For prebiotics, FVP-7 A significantly increased the relative abundance of short-chain fatty acids producing bacteria such as Bacteroides, Lachnospira, Faecalibacterium, Ruminococcus, Oscillospira and Dialister, and inhiited the growth of the harmful bacteria Shigella. These results indicated that FVP-7 A could be used as a potential dietary supplement to improve intestinal health.

[Determination of multiple residual solvents in ibandronate sodium using headspace-gas chromatography].

Ibandronate sodium, a third-generation diphosphate drug used worldwide to treat osteoporosis, has the advantages of convenient use, low toxicity, and significant therapeutic effects. However, the residual organic solvents in the synthesis process of sodium ibandronate not only have a negative impact on the efficacy of the drug, but also lead to a decrease in drug stability. Moreover, if the residual amounts of these solvents exceed safety standards, they may pose serious threats to human health. This study successfully established a convenient and efficient method based on headspace-gas chromatography (HS-GC) for the simultaneous determination of five residual solvents (methanol, acetone, benzene, toluene, 1-pentanol) in the raw materials of ibandronate sodium. The results indicated that satisfactory analytical performance can be achieved by using DB-624 capillary column (30 m×0.32 mm×1.8 µm) and a flame ionization detector in conjunction with headspace autosampling and a temperature program. The specific operating conditions included an initial temperature of 40 ℃, with a hold of 2 min, followed by a temperature ramp first to 200 ℃ at a rate of 5 ℃/min and then to 240 ℃ at a rate of 20 ℃/min, with a hold of 5 min. Nitrogen with a flow rate of 1 mL/min and split ratio of 14∶1 was used as the carrier gas. The headspace vial temperature was maintained at 80 ℃, and the sample equilibration time was 20 min. Under the established analytical conditions, good linear relationships were obtained between the mass concentrations of methanol (72-216 µg/mL), acetone (120-360 µg/mL), benzene (0.048-0.144 µg/mL), toluene (21.36-64.08 µg/mL), and 1-pentanol (120-360 µg/mL) and their corresponding peak areas, with correlation coefficients (r) greater than 0.990. The limits of detection for these solvents were 2.88, 0.011, 0.90, 0.24, and 0.024 ng/mL, respectively, with limits of quantification of 11.5, 0.043, 3.6, 0.96, and 0.096 ng/mL, respectively. Furthermore, the recoveries of these solvents ranged from 86.3% to 101.9%, with relative standard deviations (RSDs, n=3) of less than 2.49%. The proposed method is simple, accurate, reliable, and suitable for the rapid and simultaneous determination of five residual solvents in the raw materials of ibandronate sodium. This study has important practical significance in improving drug safety and ensuring public health.

Whole-plant silage maize to improve fiber digestive characteristics and intestinal microbiota of Hezuo pigs.

Introduction: Utilizing roughage resources is an effective approach to alleviate the shortage of corn-soybean feed and reducing the costs in the swine industry. Hezuo pig is one group of plateau type local Tibetan pig with strong tolerance to crude feeding. Nevertheless, current research on the roughage tolerance in Hezuo pigs and the microbiological mechanisms behind it is still minimally.This study explored the impact of various ratios of whole-plant silage (WPS) maize on the pH, cellulase activity, short-chain fatty acids (SCFAs), and intestinal microbiota in Hezuo pigs. Methods: Thirty-two Hezuo pigs were randomly divided into four groups (n = 8). The control group received a basal diet, while experimental groups I, II, and III were given diets with incremental additions of 5%, 10%, and 15% air-dried WPS maize, respectively, for 120 days. Results: The findings revealed that compared with the control group, in Group II, the pH of cecum and colon were notably decreased (p < 0.05), while acid detergent fiberdigestibility, the concentration of propionic and isobutyric acid in the cecum, and the concentration of isobutyric acid in the colon were significantly increased (p < 0.05). Also, carboxymethyl cellulase activity in the cecum in group II of Hezuo pigs was significantly higher than that in the other three groups (p < 0.05). Furthermore, the cecum microbiota showed a higher diversity in the group II of Hezuo pigs than that in the control group, as shown by the Simpson and Shannon indices. Specifically, 15 and 24 bacterial species showed a significant difference in relative abundance at the family and genus levels, respectively. Correlation analyses revealed significant associations between bacterial genera and SCFAs concentrations in the cecum. The abundance of Bacteroides and NK4A214_group was positively correlated with amounts of valeric and isovaleric acid but negatively with propionic acid (p < 0.05). The abundance of UCG-010 was positively linked with acetic acid and negatively correlated with butyric acid (p < 0.05). Actinobacillus abundance was positively associated with butyric acid levels (p < 0.05). Discussion: In conclusion, a 10% WPS maize diet improved crude fiber digestibility by lowering cecal and colonic chyme pH, enhancing intestinal cellulase activity, improving SCFA production, and increasing intestinal microbiota diversity.

Characterization of the gut butyrate-producing bacteria and lipid metabolism in African green monkey as a natural host of SIV infection.

OBJECTIVE: Natural hosts of simian immunodeficiency virus (SIV), such as the African green monkey (AGM), possess the ability to avoid acquired immune deficiency syndrome (AIDS) despite lifelong infection. The underlying mechanisms are not completely understood. This study aimed to characterize the gut microbiome and metabolite profiles of different nonhuman primates (NHPs) to provide potential insight into AIDS resistance. DESIGN AND METHODS: Fresh feces from Cynomolgus macaques (CMs), and Rhesus macaques (RMs), SIV- AGMs (AGM_N), and SIV+ AGMs (AGM_P) were collected and used for metagenomic sequencing and metabonomic analysis. RESULTS: Compared with CMs and RMs, significant decreases in the abundances of Streptococcus, Alistipes, Treponema, Bacteroides, and Methanobrevibacter (P < 0.01), and significant increases in the abundances of Clostridium, Eubacterium, Blautia, Roseburia, Faecalibacterium, and Dialister (P < 0.01) were detected in AGM_N. Compared with AGM_N, a trend toward increased abundances of Streptococcus and Roseburia were found in AGM_P. The levels of metabolites involved in lipid metabolism and butanoate metabolism significantly differed among AGM_P, AGM_N and CM (P < 0.05). CONCLUSIONS: Our data, for the first time, demonstrated distinguishing features in the abundances of butyrate-producing bacteria and lipid metabolism capacities between different NHP hosts of SIV infection. These findings may correlate with the different characteristics observed among these hosts in the maintenance of intestinal epithelial barrier integrity, regulation of inflammation, and provide insights into AIDS resistance in AGMs.

Ubiquitin-specific protease-7 promotes expression of airway mucin MUC5AC via the NF-κB signaling pathway.

Chronic obstructive pulmonary disease (COPD) and other respiratory diseases frequently present with airway mucus hypersecretion, which not only affects the patient's quality of life but also poses a constant threat to their life expectancy. Ubiquitin-specific protease 7 (USP7), a deubiquitinating enzyme, affects cell differentiation, tissue growth, and disease development. However, its role in airway mucus hypersecretion induced by COPD remains elusive. In this study, USP7 expression was significantly upregulated in airway epithelial samples from patients with COPD, and USP7 was also overexpressed in mouse lung and human airway epithelial cells in models of airway mucus hypersecretion. Inhibition of USP7 reduced the expression of nuclear factor kappa B (NF-κB), phosphorylated-NF-κB (p-NF-κB), and phosphonated inhibitor of nuclear factor kappa B (p-IκBα), and alleviated the airway mucus hypersecretion in vivo and in vitro. Further research revealed that USP7 stimulated airway mucus hypersecretion through the activation of NF-κB nuclear translocation. In addition, the expression of mucin 5AC (MUC5AC) was suppressed by the NF-κB inhibitor erdosteine. These findings suggest that USP7 stimulates the NF-κB signaling pathway, which promotes airway mucus hypersecretion. This study identifies one of the mechanisms regulating airway mucus secretion and provides a new potential target for its prevention and treatment.

Effects of Berberine on Lipid Metabolism, Antioxidant Status, and Immune Response in Liver of Tilapia (Oreochromis niloticus) under a High-Fat Diet Feeding.

Berberine, a natural alkaloid found abundantly in various medicinal plants, exhibits antioxidative, anti-inflammatory, and lipid metabolism-regulatory properties. Nonetheless, its protective effects and the molecular mechanisms underlying liver injury in fish have not been fully elucidated. The aims of this study were to investigate the antioxidative, anti-inflammatory, and lipid metabolism-regulating effects of berberine against high-fat diet (HFD)-induced liver damage and to clarify the underlying molecular mechanisms. Tilapia were fed diets containing two doses of berberine (50 and 100 mg/kg diet) alongside high fat for 60 days. The results showed that berberine treatments (50 and/or 100 mg/kg) significantly reduced elevated aminotransferases, triglycerides (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-c) in the plasma. In the liver, berberine treatments significantly increased the expression of peroxisome proliferator-activated receptor α (pparα) and carnitine palmitoyltransferase 1 (cpt-1) genes, leading to a reduction in lipid accumulation. Meanwhile, berberine treatment suppressed lipid peroxidation formation and enhanced antioxidant capacity. Berberine upregulated the mRNA levels of erythroid 2-related factor 2 (nrf2) and its downstream genes including heme oxygenase 1 (ho-1) and glutathione-S-transferase (gstα). Additionally, berberine attenuated the inflammation by inhibiting the expression of toll-like receptor 2 (tlr2), myeloid differential protein-88 (myd88), relb, and inflammatory cytokines such as interleukin-1ß (il-1ß), tumor necrosis factor-α (tnf-α), and il-8. In summary, this study suggested that berberine offers protection against HFD-induced liver damage in tilapia via regulating lipid metabolism, antioxidant status, and immune response. This protective effect may be attributed to the modulation of the Nrf2, TLR2/MyD88/NF-κB, and PPARα signaling pathways.

Cellular mechanism underlying leptin-induced anion secretion of rat epididymal epithelial cells.

BACKGROUND: A large number of studies have shown that leptin plays an important role in the regulation of fertility via the hypothalamus-pituitary-gonad axis. However, its peripheral function in epididymis was still elusive. OBJECTIVE: The purpose of this study was to determine the pro-secretion effect of leptin on the rat epididymal epithelium. MATERIALS AND METHODS: In the present study, real-time quantitative polymerase chain reaction, western blot, and immunohistochemical analysis were employed to detect the expression pattern of leptin receptors in rat epididymis. The pro-secretion effect of leptin on epididymal epithelial cells was measured by short-circuit current, and the prostaglandin E2 and cyclic adenosine monophosphate level was evaluated by enzyme-linked immunosorbent assay. RESULTS: We verified that the leptin receptor was located on the epididymal epithelium, with a relatively high expression level in corpus and cauda epididymis. Ussing chamber experiments showed that leptin stimulated a significant rise of the short-circuit current in rat epididymal epithelial cells, which could be abolished by the specific leptin receptor antagonist peptide Allo-aca, or by removing the ambient Cl- and HCO3 -. Furthermore, the leptin-stimulated short-circuit current response could be abrogated by blocking the apical cystic fibrosis transmembrane regulator or the basolateral Na+-K+-2Cl- cotransporter. Our pharmacological experiments manifested that interfering with the prostaglandin H synthase-2-prostaglandin E2-EP2/EP4-adenylate cyclase pathways could significantly blunt the cystic fibrosis transmembrane regulator-mediated anion secretion induced by leptin. The enzyme-linked immunosorbent assay demonstrated that leptin could induce a substantial increase in prostaglandin E2 release and cyclic adenosine monophosphate synthesis of primary cultured rat cauda epididymal epithelial cells. Our data also suggested that JAK2, ERK, and PI3K-dependent phosphorylation may be involved in the activation of prostaglandin H synthase-2 and the subsequent prostaglandin E2 production. CONCLUSIONS: The present study demonstrated the pro-secretion function of leptin in rat epididymal epithelium via the activation of cystic fibrosis transmembrane regulator and Na+-K+-2Cl- cotransporter, which was dependent on the paracrine/autocrine prostaglandin E2 stimulated EP2/EP4-adenylate cyclase pathways, and thus contributed to the formation of an appropriate microenvironment essential for sperm maturation.

Prediction of specific structural damage to the knee joint using qualitative isokinetic analysis.

BACKGROUND: An isokinetic moment curve (IMC) pattern-damaged structure prediction model may be of considerable value in assisting the diagnosis of knee injuries in clinical scenarios. This study aimed to explore the association between irregular IMC patterns and specific structural damages in the knee, including anterior cruciate ligament (ACL) rupture, meniscus (MS) injury, and patellofemoral joint (PFJ) lesions, and to develop an IMC pattern-damaged structure prediction model. METHODS: A total of 94 subjects were enrolled in this study and underwent isokinetic testing of the knee joint (5 consecutive flexion-extension movements within the range of motion of 90°-10°, 60°/s). Qualitative analysis of the IMCs for all subjects was completed by two blinded examiners. A multinomial logistic regression analysis was used to investigate whether a specific abnormal curve pattern was associated with specific knee structural injuries and to test the predictive effectiveness of IMC patterns for specific structural damage in the knee. RESULTS: The results of the multinomial logistic regression revealed a significant association between the irregular IMC patterns of the knee extensors and specific structural damages ("Valley" - ACL, PFJ, and ACL + MS, "Drop" - ACL, and ACL + MS, "Shaking" - ACL, MS, PFJ, and ACL + MS). The accuracy and Macro-averaged F1 score of the predicting model were 56.1% and 0.426, respectively. CONCLUSION: The associations between irregular IMC patterns and specific knee structural injuries were identified. However, the accuracy and Macro-averaged F1 score of the established predictive model indicated its relatively low predictive efficacy. For the development of a more accurate predictive model, it may be essential to incorporate angle-specific and/or speed-specific analyses of qualitative and quantitative data in isokinetic testing. Furthermore, the utilization of artificial intelligence image recognition technology may prove beneficial for analyzing large datasets in the future.

ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence.

Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/ß-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.

Integrated rice-yellow catfish farming resulting in variations in the agricultural environment, rice growth performance, and soil bacterial communities.

Different rice production patterns exert varying comprehensive impacts on the agricultural environment. Integrated rice-fish farming, an advanced and rapidly developing agricultural production pattern, aims to improve resource utilization efficiency and enhance food productivity. To unravel the responses and internal interactions of the agricultural ecological environment to integrated rice-fish farming, we assessed and compared environmental factor, rice growth performance, and soil microbiome in both integrated rice-yellow catfish farming (IRYF) and rice monoculture (RM) systems. Our results revealed significant increases in the total nitrogen and ammonia concentrations in the paddy water and soil induced by the IRYF. Rice growth performance in the IRYF group surpassed that in the RM group. IRYF obviously impacted almost all dominant bacterial phyla, genera, and functional groups (top ten most abundant), enhancing the ability of bacteria to degrade and utilize organic matter. Additionally, IRYF led to noticeable reductions in the Shannon, Simpson, Chao 1, and Pielou_J indices. IRYF strengthened the interconnections between various taxonomic units in bacterial co-occurrence network, resulting in increased complexity, stability, and disturbance resistance in the soil bacterial community. IRYF notably facilitated the transition from a community assembly dominated by stochastic processes to one dominated by deterministic processes for the soil bacterial community. The deterministic process driving this transition was variable selection. All the environmental factors, except for soil nitrate, demonstrated relatively high contributions to alterations in soil bacterial communities, with environmental variables significantly positively correlated with the soil bacterial community in the IRYF group. Alterations in functionality, composition, and diversity of the soil bacterial community were clearly associated with most environmental variables and rice growth performance indices. Our research contributed to understanding the comprehensive impacts of integrated rice-fish farming on agricultural ecosystems and provide theoretical support for achieving the sustainable agricultural production and optimizing the rice production patterns.

Parathyroid hormone related-protein (PTHrP) in tissues with poor prognosis in prostate cancer patients.

BACKGROUND: Parathyroid hormone-related peptide (PTHrP) is known to have a pivotal role in the progression of various solid tumors, among which prostate cancer stands out. However, the extent of PTHrP expression and its clinical implications in prostate cancer patients remain shrouded in obscurity. The primary objective of this research endeavor was to shed light on the relevance of PTHrP in the context of prostate cancer patients and to uncover the potential underlying mechanisms. METHODS: The expression of PTHrP, E-cadherin, and vimentin in tumor tissues of 88 prostate cancer patients was evaluated by immunohistochemical technique. Subsequently, the associations between PTHrP and clinicopathological parameters and prognosis of patients with prostate cancer were analyzed. RESULTS: Immunohistochemical analysis showed that the expression rates of PTHrP, E-cadherin, and vimentin in prostate cancer tissues were 95.5%, 88.6%, and 84.1%, respectively. Patients with a high level of PTHrP had a decreased expression of E-cadherin (P = .013) and an increased expression of vimentin (P = .010) compared with patients with a low level of PTHrP. Besides, the high expression of PTHrP was significantly correlated with a higher level of initial prostate-specific antigen (P = .026), positive lymph node metastasis (P = .010), osseous metastasis (P = .004), and Gleason score (P = .026). Moreover, patients with a high level of PTHrP had shorter progression-free survival (P = .002) than patients with a low level of PTHrP. CONCLUSION: The present study indicates that PTHrP is associated with risk factors of poor outcomes in prostate cancer, while epithelial-mesenchymal transition may be involved in this process.

Determination of the chromosomal position effects for plug-and-play application in the Myxococcus xanthus chassis cells.

The chromosomal position effect can significantly affect the transgene expression, which may provide an efficient strategy for the inauguration of alien genes in new hosts, but has been less explored rationally. The bacterium Myxococcus xanthus harbors a large circular high-GC genome, and the position effect in this chassis may result in a thousand-fold expression variation of alien natural products. In this study, we conducted transposon insertion at TA sites on the M. xanthus genome, and used enrichment and dilution indexes to respectively appraise high and low expression potentials of alien genes at insertion sites. The enrichment sites are characteristically distributed along the genome, and the dilution sites are overlapped well with the horizontal transfer genes. We experimentally demonstrated the enrichment sites as high expression integration sites (HEISs), and the dilution sites unsuitable for gene integration expression. This work highlights that HEISs are the plug-and-play sites for efficient expression of integrated genes.