Association between different composite dietary antioxidant indexes and constipation in American male adults: a cross-sectional study.

Background: Oxidative stress is acknowledged as a pivotal factor in the intricate pathophysiological processes and pathogenesis of constipation. Modifying dietary patterns can elevate in vivo antioxidant biomarker levels, consequently mitigating oxidative stress. The Composite Dietary Antioxidant Index (CDAI) provides a dependable scoring mechanism for quantifying the potential antioxidant capacity of diets. The association between CDAI levels and the risk of constipation remains uncertain. Purpose: To investigate the potential correlation between CDAI and constipation, aiming to improve constipation management through dietary guidance. Methods: A total of 11,165 adults aged ≥20 years, drawn from the 2005-2010 National Health and Nutrition Examination Survey, were enrolled in this cross-sectional study. We evaluated the correlation between CDAI levels and the risk of constipation through three weighted logistic regression models. Restricted cubic spline (RCS) analysis was employed to assess nonlinear trends, and stratified analyses were conducted. Results: After adjusting for all confounding variables, the findings revealed an association between CDAI and constipation [OR = 0.937; 95% CI (0.892, 0.984), p = 0.012]. Moreover, individuals in the highest quartile of CDAI demonstrated a 40.1% lower likelihood of experiencing constipation compared to those in the lowest quartile [OR = 0.599; 95% CI (0.382, 0.939), p = 0.027]. The RCS analysis indicated a linear relationship between CDAI and constipation (P-non-linear =0.1016). Subgroup analysis by gender revealed a negative correlation in the male population [OR = 0.871; 95% CI (0.801, 0.947), p = 0.002], with men in the highest CDAI quartile exhibiting a 59.8% lower likelihood of experiencing constipation compared to those in the lowest quartile [OR = 0.402; 95% CI (0.206, 0.787), p = 0.010]. Furthermore, alterations in selenium [OR = 0.997; 95% CI (0.995, 1.000), p = 0.039] per milligram were independently linked to constipation. In a gender subgroup analysis of a single antioxidant, changes per milligram of vitamin E [OR = 0.904; 95% CI (0.838 to 0.975), p = 0.011] among males were independently associated with constipation. Conclusion: The fully adjusted model showed a correlation between CDAI and constipation and a significant correlation in quartiles. Meanwhile, subgroup analysis by gender showed that CDAI was negatively associated with constipation in the male population. Moreover, the findings of this study imply that investigations into antioxidant diets should be contextualized within dietary patterns.

The causal relationship between gut microbiota and nine infectious diseases: a two-sample Mendelian randomization analysis.

Background: Evidence from observational studies and clinical trials has associated gut microbiota with infectious diseases. However, the causal relationship between gut microbiota and infectious diseases remains unclear. Methods: We identified gut microbiota based on phylum, class, order, family, and genus classifications, and obtained infectious disease datasets from the IEU OpenGWAS database. The two-sample Mendelian Randomization (MR) analysis was then performed to determine whether the gut microbiota were causally associated with different infectious diseases. In addition, we performed reverse MR analysis to test for causality. Results: Herein, we characterized causal relationships between genetic predispositions in the gut microbiota and nine infectious diseases. Eight strong associations were found between genetic predisposition in the gut microbiota and infectious diseases. Specifically, the abundance of class Coriobacteriia, order Coriobacteriales, and family Coriobacteriaceae was found to be positively associated with the risk of lower respiratory tract infections (LRTIs). On the other hand, family Acidaminococcaceae, genus Clostridiumsensustricto1, and class Bacilli were positively associated with the risk of endocarditis, cellulitis, and osteomyelitis, respectively. We also discovered that the abundance of class Lentisphaeria and order Victivallales lowered the risk of sepsis. Conclusion: Through MR analysis, we found that gut microbiota were causally associated with infectious diseases. This finding offers new insights into the microbe-mediated infection mechanisms for further clinical research.

Associations between the oxidative balance score and constipation: a cross-sectional study of the NHANES, 2005-2010.

OBJECTIVE: The oxidative balance score (OBS) reflects the overall burden of oxidative stress in an individual, with a higher OBS indicating greater antioxidant exposure. This study aimed to explore the association between constipation and OBS. METHODS: Variables were extracted from participants who completed a constipation questionnaire as part of the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2010. The OBS was developed based on dietary and lifestyle factors, encompassing 16 nutrients and 4 lifestyle variables. Weighted logistic regression and restricted cubic spline (RCS) analyses were employed to evaluate the association between OBS and constipation. RESULTS: After adjusting for all covariates, weighted multivariate logistic regression analysis revealed a 4% reduction in the incidence of constipation for each additional unit of OBS (OR: 0.96, 95% CI: 0.95-0.97, p < 0.001). In the OBS subgroup, the risk of constipation significantly decreased compared to that in the lowest quartile (Q2: 0.72, P = 0.024; Q3: 0.59, P < 0.001; Q4: 0.54, P < 0.001). CONCLUSIONS: The present study demonstrated a significant association between constipation and the oxidative balance score (OBS), particularly dietary OBS, and that an increase in OBS may reduce the risk of developing constipation, in which oxidative stress may play an important role. This finding suggested that dietary modification could be an important approach for preventing constipation.

Construction and validation of nomogram prognostic model for predicting survival in hepatoblastoma patients: a population-based study.

For patients with hepatoblastoma (HB), current staging system is not accurate in predicting survival outcomes. The aim of this study was to develop two accurate survival prediction models to guide clinical decision making. A retrospective analysis of 424 HB patients was performed from 2004 to 2015 using the Surveillance, Epidemiology and End Results (SEER) database. Univariate and multivariate Cox regression analysis was used to screen for variables. The identified variables were used to build survival prediction model. The performance of the nomogram models was assessed based on the concordance index (C-index), calibration plot, and receiver operating characteristic (ROC) curve. The Cox regression analysis identified six variables affecting overall survival (OS) in HB patients, including race, tumor size, lymph node involvement, distant metastases, surgery and chemotherapy. And the Cox regression analysis identified five variables including race, lymph node involvement, distant metastases, surgery, and chemotherapy that affect cancer-specific survival (CCS) in HB patients. In the training cohort, the C-index of the nomogram in predicting the OS was 0.791 [95% confidence intervals (95% CI) 0.717-0.865], CSS was 0.805(95% CI 0.728-0.882). In the validation cohort, the C-index of the nomogram in predicting the OS was 0.712 (95% CI 0.511-0.913), the CSS was 0.751 (95% CI 0.566-0.936). In the training cohort, the area under the receiver operator characteristics curve (AUC) values of the nomogram in prediction of the 1-, 3-, and 5-year OS were 0.842 (95% CI 0.739-0.944), 0.759 (95% CI 0.670-0.849), and 0.770 (95% CI 0.686-0.852), respectively. In the validation cohort, the AUC values for prediction of the 1-, 3-, and 5-year OS were 0.920 (95% CI 0.806-1.034), 0.863 (95% CI 0.750-0.976), and 0.844 (95% CI 0.721-0.967), respectively. Two nomogram models were developed and validated in this study which provided accurate prediction of the OS and CSS in HB patients. The constructed models can be used for predicting survival outcomes and guide treatment for HB patients.

The Role of Gut Microbiota in Male Erectile Dysfunction of Rats.

PURPOSE: Erectile dysfunction (ED) is a common male sexual dysfunction. Gut microbiota plays an important role in various diseases. To investigate the effects and mechanisms of intestinal flora dysregulation induced by high-fat diet (HFD) on erectile function. MATERIALS AND METHODS: Male Sprague-Dawley rats aged 8 weeks were randomly divided into the normal diet (ND) and HFD groups. After 24 weeks, a measurement of erectile function was performed. We performed 16S rRNA sequencing of stool samples. Then, we established fecal microbiota transplantation (FMT) rat models by transplanting fecal microbiota from rats of ND group and HFD group to two new groups of rats respectively. After 24 weeks, erectile function of the rats was evaluated and 16S rRNA sequencing was performed, and serum samples were collected for the untargeted metabolomics detection. RESULTS: The erectile function of rats and the species diversity of intestinal microbiota in the HFD group was significantly lower, and the characteristics of the intestinal microbiota community structure were also significantly different between the two groups. The erectile function of rats in the HFD-FMT group was significantly lower than that of rats in the ND-FMT group. The characteristics of the intestinal microbiota community structure were significantly different. In the HFD-FMT group, 27 metabolites were significantly different and they were mainly involved in the several inflammation-related pathways. CONCLUSIONS: Intestinal microbiota disorders induced by HFD can damage the intestinal barrier of rats, change the serum metabolic profile, induce low-grade inflammation and apoptosis in the corpus cavernosum of the penis, and lead to ED.

Log odds of positive lymph nodes (LODDS)-based novel nomogram for survival estimation in patients with invasive micropapillary carcinoma of the breast.

BACKGROUND: Invasive micropapillary carcinoma (IMPC) of the breast is known for its high propensity for lymph node (LN) invasion. Inadequate LN dissection may compromise the precision of prognostic assessments. This study introduces a log odds of positive lymph nodes (LODDS) method to address this issue and develops a novel LODDS-based nomogram to provide accurate prognostic information. METHODS: The study analyzed data from 1,901 patients with breast IMPC from the Surveillance, Epidemiology, and End Results database. It assessed the relationships between LODDS and the number of excised LN (eLN), positive LN (pLN), and the pLN ratio (pLNR), identifying an optimal threshold value using a restricted cubic spline method. Predictive factors were identified by the Cox least absolute shrinkage and selection operator (Cox-LASSO) regression and validated through multivariate Cox regression to construct a nomogram. The model's accuracy, discrimination, and utility were assessed. The study also explored the consequences of excluding LODDS from the nomogram and compared its effectiveness with the tumor-node-metastasis (TNM) staging system. RESULTS: LODDS improved N status classification by identifying heterogeneity in patients with pLN ratios of 0% (pLN =0) or 100% (pLN =eLN) and setting -1.08 as the ideal cutoff. Five independent prognostic factors for breast cancer-specific survival (BCSS) were identified: tumor size, N status, LODDS, progesterone receptor status, and histological grade. The LODDS-based nomogram achieved a strong concordance index of 0.802 (95% CI: 0.741-0.863), surpassing both the version without LODDS and the conventional TNM staging in all tests. CONCLUSIONS: For breast IMPC, LODDS served as an independent prognostic factor, its effectiveness unaffected by the anatomical LN count, enhancing the accuracy of N staging. The LODDS-based nomogram showed promise in offering more personalized prognostic information.

FDA-Approved Tedizolid Phosphate Prevents Cisplatin-Induced Hearing Loss Without Decreasing Its Anti-tumor Effect.

PURPOSE: Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing loss. Currently, there appears one drug approved in clinic only used for reducing ototoxicity associated with cisplatin in pediatric patients, which needs to further explore other candidate drugs. METHODS: Here, by screening 1967 FDA-approved drugs to protect cochlear hair cell line (HEI-OC1) from cisplatin damage, we found that Tedizolid Phosphate (Ted), a drug indicated for the treatment of acute infections, had the best protective effect. Further, we evaluated the protective effect of Ted against ototoxicity in mouse cochlear explants, zebrafish, and adult mice. The mechanism of action of Ted was further explored using RNA sequencing analysis and verified. Meanwhile, we also observed the effect of Ted on the anti-tumor effect of cisplatin. RESULTS: Ted had a strong protective effect on hair cell (HC) loss induced by cisplatin in zebrafish and mouse cochlear explants. In addition, when administered systemically, it protected mice from cisplatin-induced hearing loss. Moreover, antitumor studies showed that Ted had no effect on the antitumor activity of cisplatin both in vitro and in vivo. RNA sequencing analysis showed that the otoprotective effect of Ted was mainly achieved by inhibiting phosphorylation of ERK. Consistently, ERK activator aggravated the damage of cisplatin to HCs. CONCLUSION: Collectively, these results showed that FDA-approved Ted protected HCs from cisplatin-induced HC loss by inhibiting ERK phosphorylation, indicating its potential as a candidate for preventing cisplatin ototoxicity in clinical settings.

Association of dietary inflammatory index with constipation: Evidence from the National Health and Nutrition Examination Survey.

The association of dietary inflammatory index (DII) with constipation has not been well studied in general population. Therefore, the aim of this cross-sectional study was to investigate whether DII is associated with constipation in a large representative sample of the US population. Data were obtained from the 2005-2010 National Health and Nutrition Examination Survey (NHANES). A total of 12,308 participants aged ≥20 years were included in the analysis. DII was calculated based on a single 24-h dietary recall, and constipation was defined as having fewer than three bowel movements per week by the questionnaire on bowel health. Logistic regression analysis demonstrated a significant positive association between DII score and constipation, with each unit increase in DII score associated with a 20% increase in constipation risk (95% CI: 1.13-1.28). Subgroup analysis revealed high odds ratios (ORs) among individuals classified as "Other Race" (OR: 1.42, 95% CI: 1.12-1.80) and "Non-Hispanic White" (OR: 1.31, 95% CI: 1.12-1.54). In addition, RCS analysis indicated a nonlinear relationship between DII and constipation among individuals with a BMI less than 25 (OR: 1.17, 95% CI: 1.07-1.28), while the overall trend remained positive correlation (OR: 1.20, 95% CI: 1.10-1.31). Briefly, our study suggests that there may be a link between DII and constipation, which has implications for the development of dietary interventions aimed at preventing and managing constipation. However, this association was complex and variable depending on individual factors such as BMI and racial background and needed to establish longitudinal studies to confirm the underlying mechanisms between DII and constipation.

Comparing overall survival between pediatric and adult retinoblastoma with the construction of nomogram for adult retinoblastoma: A SEER population-based analysis.

BACKGROUND: Retinoblastoma (RB) is a rare primary malignant tumor primarily affecting children. Our study aims to compare the overall survival (OS) between pediatric and adult RB patients and establish a predictive model for adult RB patients' OS to assist clinical decision-making. METHODS: This study retrospectively analyzed data from 1938 RB patients in the Surveillance, Epidemiology, and End Results (SEER) database, covering the period from 2000 to 2015. Propensity score matching (PSM) ensured balanced characteristics between pediatric and adult groups. A Cox proportional hazards regression model was used to assess prognostic factors, and selected variables were utilized to construct a predictive survival model. The Nomogram model's performance was evaluated through the C-index, time-dependent ROC curves, calibration curves, and decision curve analysis (DCA). RESULTS: Following PSM, adult RB patients had lower OS compared to pediatric RB patients. Independent prognostic factors for adult RB OS included age, gender, disease stage, radiation therapy, income, and diagnosis confirmation. In the training cohort, the Nomogram achieved a C-index for OS of 0.686 and accurately predicted 2-year, 3-year, and 5-year OS with AUC values of 0.672, 0.680, and 0.660, respectively. The C-index, time-dependent ROC curves, calibration curves, and DCA in both training and validation cohorts confirmed the Nomogram's excellent performance. CONCLUSION: In this study, adult RB patients have worse OS than pediatric RB patients. Consequently, we constructed a Nomogram to predict the risk for adult RB patients. The Nomogram demonstrated good accuracy and reliability, making it suitable for widespread application in clinical practice to assist healthcare professionals in assessing patients' prognoses.

Structure characterization of polysaccharides from Cistanche deserticola and their neuroprotective effects against oxidative stress in slow transit constipation mice.

Oxidative stress-induced enteric neuropathy is an important factor in slow transit constipation (STC). Cistanche deserticola crude polysaccharides (CDCP) are natural antioxidants with various biological activities. We prepared CDCP through water-extract and alcohol-precipitation methods. The structural characteristics of CDCP were analyzed by infrared spectroscopy and methylation analysis. The results showed that CDCP was primarily composed of (1 â†’ 4)-linked glucans with minor amounts of pectic polysaccharides. Different doses of CDCP (100, 200, and 400 mg/kg) were administered to loperamide-induced STC mice to explore the therapeutic effects of CDCP. Compared with the untreated group, CDCP treatment significantly improved constipation symptoms, relevant gut-regulating peptides levels, colonic pathological damage, and colonic myenteric nerons injury. CDCP enhanced the antioxidant capacity by decreasing Malondialdehyde (MDA) content, increasing Superoxide Dismutase (SOD) activity and Reduced Glutathione (GSH) content. CDCP significantly reduced oxidative stress-induced injury by preserving mitochondrial function in the colonic myenteric plexus. Furthermore, the neuroprotective effects of CDCP might be associated with the Nrf2/Keap1 pathway. Thus, our findings first revealed the potential of CDCP to protect the colonic myenteric plexus against oxidative stress-induced damage in STC, establishing CDCP as promising candidates for natural medicine in the clinical management of STC.

Surgery versus radiotherapy for limited-stage small cell esophageal carcinoma: a multicenter, retrospective, cohort study in China (ChiSCEC).

BACKGROUND: There is no standard management for small cell esophageal carcinoma (SCEC). The purpose of this multicenter, retrospective study (ChiSCER) was to investigate the treatment, outcomes, and risk factors impacting survival endpoints in patients with limited-stage SCEC (LS-SCEC). MATERIALS AND METHODS: Consecutive patients with LS-SCEC from 14 institutions between 2000 and 2020 in China were enrolled. Survival curves were constructed using the Kaplan-Meier method and compared using a log-rank test. Univariate and multivariate Cox regression models and propensity score matching (PSM) analysis were adopted in the prognostic analysis. Results were reported as hazard ratio (HR), 95% confidence interval (CI), and P value. Statistical significance was set as P value <0.05 in a two-tailed test. RESULTS: Among 458 LS-SCEC patients, the median age was 63 [interquartile range (IQR), 57-68] years, and 318 (69%) were males. Eighty-four (18%), 167 (36%), and 207 (45%) patients received chemotherapy (CT) alone, CT plus definitive radiotherapy (CT+RT), and CT plus radical surgery (CT+S), respectively. With a median follow-up time of 58.7 (95% CI 48.9-68.6) months, the median overall survival (OS) and 3-year OS rate for all patients 24.3 (95% CI 21.6-27) months and 37.3% (95% CI 32.8-42.5%), respectively. Multivariate analysis indicated that treatment modes, Karnofsky performance status (KPS), TNM stage, and CT cycle were independent prognostic factors for OS ( P <0.05). Compared with CT alone, patients treated with CT+RT (HR 0.57, 95% CI 0.41-0.8, P =0.001) or CT+S (HR 0.59, 95% CI 0.42-0.82, P =0.002) had an improved OS, with no significant survival differences between CT+S and CT+RT groups after multivariate and PSM analyses ( P >0.05). Subgroup analysis indicated that compared with CT+RT, patients with tumor location at lower 1/3 (HR 0.59, 95% CI 0.37-0.93, P =0.03) or tumor length >5 cm (HR 0.52, 95% CI 0.3-0.9, P =0.02) could obtain significant OS benefit from CT+S. Patients with tumor location at middle 1/3 (HR 1.55, 95% CI 1.03-2.36, P =0.04) or tumor length ≤5 cm (HR 1.49, 95% CI 1.02-2.17, P =0.04) favored CT+RT. Distant metastasis accounted for 73.7% of all treatment failures after multidisciplinary treatments. CONCLUSION: Surgery and RT were equally effective local therapies for patients with LS-SCEC. The personalized decision of local therapy should be made after comprehensive considerations on tumor location, length, comorbidities, and organ preservation.

Immunomodulatory activity and protective effect of a capsular polysaccharide in Caenorhabditis elegans, isolated from Lactobacillus fermentum GBJ.

A capsular polysaccharide, namely CPS-2, was isolated from Lactobacillus fermentum GBJ, purified using DEAE-52 anion exchange chromatography, and structurally characterized. We found that CPS-2 is homogenous, has an average molecular weight of 377 KDa, and is mainly composed of galactose and glucose at a molar ratio of 1.54:1.00. Its backbone comprises α-D-Galp-(1 â†’ 3), α-D-Galp-(1 â†’ 3,6), ß-D-Glcp-(1 â†’ 2), ß-D-Galp-(1 â†’ 6), and α-D-Galp-(1 â†’ 4) residues with a side chain of ß-D-Glcp-(1→). CPS-2 exerts an immunomodulatory effect by improving the proliferation and phagocytosis of macrophage RAW264.7 and promoting the secretion of NO and cytokines. The maximum secretion levels of IL-1ß, IL-6, IL-10, and TNF-α were 1.96-, 0.11-, 0.22-, and 0.46-fold higher than those of the control, respectively. Furthermore, CPS-2 could significantly enhance the antioxidant system, extend lifespan, and improve stress tolerance of Caenorhabditis elegans at both exposure doses of 31.25 and 62.5 µg/mL. The average lifespan of nematodes reached a maximum in the 62.5 µg/mL-treated group after 10.39 days, 6.56 h, and 23.56 h in normal, oxidative stress, and heat shock environment, with extension percentages of 16.61 %, 43.23 %, and 15.77 %, respectively; therefore, CPS-2 displays an anti-aging effect. The significant bioactivity of CPS-2 promotes its application as a promising immunomodulatory and anti-aging ingredient in the food or pharmaceutical field.

Integrated metabolite profiling and transcriptome analysis unraveling mechanism of RC catabolism in Paenarthrobacter ilicis CR5301.

Steviol glycosides are ideal sweeteners that are widely used in food, medicine, and cosmetics. Rebaudioside C (RC) is considered to be the third most abundant steviol glycoside, which has a bitter aftertaste that limits its application. Hydrolysis of RC to generate other bioactive steviol glycosides is an effective way to promote its additional utilization. In our previous study, a bacterium Paenarthrobacter ilicis CR5301 was isolated and identified for hydrolyzing RC with high efficiency. Herein, the expression profiles of P. ilicis CR5301 in the deletion and presence of RC were investigated by RNA-seq. The RC metabolites were identified by high-performance liquid chromatography and ultra-performance liquid chromatography-triple-time of flight mass spectrometry. Novel results were discovered in four aspects of research. First, the identification of metabolites revealed that four metabolites, namely, dulcoside A, dulcoside B, dulcoside A1, and steviol, were produced during RC metabolism. Second, RNA-seq analyses unraveled that 105 genes of P. ilicis CR5301 were significantly differentially expressed, and 7 pathways were significantly enriched. Third, independent RT-qPCR verified the accuracy and reliability of the RNA-seq results. Finally, a complete catabolic model of RC in P. ilicis CR5301 was proposed, and key genes were indicated in the RC catabolic metabolism by combining them with literature and sequence alignments. This study comprehensively unraveled the genes and pathways of RC catabolism in P. ilicis CR5301 at the transcriptional and metabolic levels. It provided new insights and evidence for understanding the mechanism of RC catabolism in bacteria. Key candidate genes may potentially contribute to the RC hydrolysis and preparation of other functional steviol glycosides in the future.

Effect of megarectum on postoperative defecation of female patients with congenital rectovestibular fistula or rectoperineal fistula.

Background: To assess the effect of megarectum on postoperative defecation of female patients with congenital rectovestibular fistula or rectoperineal fistula. Methods: From March 2013 to February 2021, 74 female patients with congenital rectovestibular fistula or rectoperineal fistula were treated. The age of patients ranged from 3 months to 1 year. Barium enema and spinal cord MRI were performed in all children. 4 patients were removed from the study because of spinal cord and sacral agenesis. Finally, 70 patients underwent one-stage anterior sagittal anorectoplasty (ASARP). Anal endoscopy and anorectal pressure measurement were performed 1 year after surgery. All patients were divided into two groups depending on the presence of megarectum (+) and (-) and observed for constipation and anal sphincter function. Results: 16 patients (4 months to 1 year) were complicated with megarectum, and 5 patients (3 months to 9 months) were without megarectum. The incision infection was seen in 3 patients. All patients were followed up for 1 year to 5 years. Fecal soiling was seen in 2 patients and constipation in 14 patients. Among 16 patients with megarectum, soiling was seen in 1 patient and the constipation in 12 patients. Among 54 patients without megarectum, soiling was seen in 1 patient and constipation in 2 patients. There was a significant difference in the incidence of postoperative constipation between the two groups (megarectum (+) 75% vs. megarectum (-) 3.7% (P < 0.05)). However, there was no significant difference in the score of anal sphincters between the two groups (P < 0.05). And there was no significant difference in anal resting pressure (P = 0.49) and length of anal high pressure area (P = 0.76). 7 patients with constipation and megarectum acquired normal anal function after the dilated rectum was resected. Conclusion: Megarectum increases the possibility of difficult postoperative defecation in the patients with congenital rectovestibular fistula or rectoperineal fistula. However, constipation was not associated with ASARP postoperative effects on sphincter function. Resection of megarectum is helpful to the improvement of constipation.

RhoGDIα regulates spermatogenesis through Rac1/cofilin/F-actin signaling.

Spermatogenesis is an extremely complex process, and any obstruction can cause male infertility. RhoGDIα has been identified as a risk of male sterility. In this study, we generate RhoGDIα knockout mice, and find that the males have severely low fertility. The testes from RhoGDIα-/- mice are smaller than that in WT mice. The numbers of spermatogonia and spermatocytes are decreased in RhoGDIα-/- testis. Spermatogenesis is compromised, and spermatocyte meiosis is arrested at zygotene stage in RhoGDIα-/- mice. Acrosome dysplasia is also observed in sperms of the mutant mice. At the molecular level, RhoGDIα deficiency activate the LIMK/cofilin signaling pathway, inhibiting F-actin depolymerization, impairing testis and inducing low fertility in mouse. In addition, the treatment of RhoGDIα-/- mice with Rac1 inhibitor NSC23766 alleviate testis injury and improve sperm quality by inhibiting the LIMK/cofilin/F-actin pathway during spermatogenesis. Together, these findings reveal a previously unrecognized RhoGDIα/Rac1/F-actin-dependent mechanism involved in spermatogenesis and male fertility.

A Fluorinated Supramolecular Self-Assembled Peptide as Nanovaccine Adjuvant for Enhanced Cancer Vaccine Therapy.

Adjuvants play an important role in enhancing vaccine-induced immune protection. Adequate cellular uptake, robust lysosomal escape, and subsequent antigen cross-presentation are critical steps for vaccine adjuvants to effectively elicit cellular immunity. Here, a fluorinated supramolecular strategy to generate a series of peptide adjuvants by using arginine (R) and fluorinated diphenylalanine peptide (DP) is adopted. It is found that the self-assembly ability and antigen-binding affinity of these adjuvants increase with the number of fluorine (F) and can be regulated by R. By comparison, 4RDP(F5) shows the strongest binding affinity with model antigen ovalbumin (OVA) and the best performance in dendritic cells maturation and antigen's lysosomal escape, which contributes to the subsequent antigen cross-presentation. As a consequence, 4RDP(F5)-OVA nanovaccine generates a strong cellular immunity in a prophylactic OVA-expressing EG7-OVA lymphoma model, leading to long-term immune memory for resisting tumor challenge. What's more, 4RDP(F5)-OVA nanovaccine in combination with anti-programmed cell death ligand-1 (anti-PD-L1) checkpoint blockade could effectively elicit anti-tumor immune responses and inhibit tumor growth in a therapeutic EG7-OVA lymphoma model. Overall, this study demonstrates the simplicity and effectiveness of fluorinated supramolecular strategies for constructing adjuvants and might provide an attractive vaccine adjuvant candidate for cancer immunotherapy.

Relief effects of Laoshan cherry extracts as a dietary supplement against the symptoms of acute gouty arthritis in rats induced by urate crystals.

We evaluated the effects of Laoshan cherry as a food or dietary supplement on relieving the symptoms of acute gouty arthritis in rats induced by urate crystals. Rats in groups of 10 were given Laoshan cherry functional extracts at doses of 5, 10, and 20 mg/kg by oral gavage for 21 days and then injected with a sodium nitrate suspension in the rear ankle area as an induced acute gouty arthritis model. The ankle swelling and inflammations in the model (no treatment) group increased significantly compared with blank group; the ankle inflammations reduced in experimental groups receiving three different doses of the cherry extract and the joint swelling reduced in the high-dose group by 43% compared with the model group. Serum uric acid and xanthine oxidase activities were also elevated in the model group and these parameters were reduced by a maximum of 8% and 33%, respectively, in the rats receiving the cherry extracts. The serum levels of the inflammatory cytokine IL-1ß in the high-dose group decreased by 12% compared with the model group. These results demonstrated that the cherries possess a functional substance that has a significant alleviating effect on the symptoms of gouty arthritis in rats induced by sodium urate injection.

Efficient conversion of rebaudioside C to steviol by Paenarthrobacter ilicis CR5301.

To improve the conversion efficiency of rebaudioside C, this study screened the Paenarthrobacter ilicis CR5301 from soil samples and identified it by 16S rRNA. The conversion experiment proved that P. ilicis CR5301 was capable of converting rebaudioside C. The effects of initial pH, temperature, inoculation amount, and substrate concentration on rebaudioside C conversion rate were investigated. The results showed that the conversion rate of rebaudioside C reached up to 100% when CR5301 was incubated in a conversion medium with an initial pH of 7.0 for 8 h at 28°C and 270 rpm. The conversion time was reduced by at least 16 h compared with previous studies. The conversion product was analyzed and identified as steviol by high performance liquid chromatography, ultra performance liquid chromatography-triple-time of flight mass spectrometer, and Fourier transform infrared spectroscopy methods. In addition, stevioside, rebaudioside A, dulcoside A, and some unknown components in steviol glycosides byproduct were all efficiently converted to steviol. These findings provide an efficient approach to the conversion of rebaudioside C and byproduct to steviol to simplify the subsequent industrial process and improve the reuse value of steviol glycosides.

Conditional deletion of Hspa5 leads to spermatogenesis failure and male infertility in mice.

Heat shock proteins (HSPs) have important roles in different developmental stages of spermatogenesis. The heat shock 70 kDa protein 5 (HSPA5) is an important component of the unfolded protein response that promotes cell survival under endoplasmic reticulum (ER) stress conditions. In this study, we explored the function of HSPA5 in spermatogenesis, by generating a germ cell-specific deletion mutant of the Hspa5 gene (conditional knockout of the Hspa5 gene, Hspa5-cKO) using CRISPR/Cas9 technology and the Cre/Loxp system. Hspa5 knockout resulted in severe germ cell loss and vacuolar degeneration of seminiferous tubules, leading to complete arrest of spermatogenesis, testicular atrophy, and male infertility in adult mice. Furthermore, defects occurred in the spermatogenic epithelium of Hspa5-cKO mice as early as Cre recombinase expression. Germ cell ablation of Hspa5 impaired spermatogonia proliferation and differentiation from post-natal day 7 (P7) to P10, which led to a dramatic reduction of differentiated spermatogonia, compromised meiosis, and led to impairment of testis development and the disruption of the first wave of spermatogenesis. Consistent with these results, single-cell RNA sequencing (scRNA-seq) analysis showed that germ cells, especially differentiated spermatogonia, were dramatically reduced in Hspa5-cKO testes compared with controls at P10, further confirming that HSPA5 is crucial for germ cell development. These results suggest that HSPA5 is indispensable for normal spermatogenesis and male reproduction in mice.

Association between gut microbiota and glioblastoma: a Mendelian randomization study.

Background: Glioblastoma (GBM) is the most prevalent malignant brain tumor, significantly impacting the physical and mental wellbeing of patients. Several studies have demonstrated a close association between gut microbiota and the development of GBM. In this investigation, Mendelian randomization (MR) was employed to rigorously evaluate the potential causal relationship between gut microbiota and GBM. Methods: We utilized summary statistics derived from genome-wide association studies (GWAS) encompassing 211 gut microbiota and GBM. The causal association between gut microbiota and GBM was scrutinized using Inverse Variance Weighted (IVW), MR-Egger, and Weighted Median (WM) methods. Cochrane's Q statistic was employed to conduct a heterogeneity test. MR-Pleiotropic Residuals and Outliers (MR-PRESSO) were applied to identify and eliminate SNPs with horizontal pleiotropic outliers. Additionally, Reverse MR was employed to assess the causal relationship between GBM and pertinent gut microbiota. Results: The MR study estimates suggest that the nine gut microbiota remain stable, considering heterogeneity and sensitivity methods. Among these, the family.Peptostreptococcaceae and genus.Eubacterium brachy group were associated with an increased risk of GBM, whereas family.Ruminococcaceae, genus.Anaerostipes, genus.Faecalibacterium, genus.LachnospiraceaeUCG004, genus.Phascolarctobacterium, genus.Prevotella7, and genus.Streptococcus were associated with a reduced risk of GBM. Following Benjamini and Hochberg (BH) correction, family.Ruminococcaceae (OR = 0.04, 95% CI: 0.01-0.19, FDR = 0.003) was identified as playing a protective role against GBM. Conclusion: This groundbreaking study is the first to demonstrate that family.Ruminococcaceae is significantly associated with a reduced risk of GBM. The modulation of family_Ruminococcaceae for the treatment of GBM holds considerable potential clinical significance.