Altered vaginal cervical microbiota diversity contributes to HPV-induced cervical cancer via inflammation regulation.

Background: Cancer has surpassed infectious diseases and heart ailments, taking the top spot in the disease hierarchy. Cervical cancer is a significant concern for women due to high incidence and mortality rates, linked to the human papillomavirus (HPV). HPV infection leads to precancerous lesions progressing to cervical cancer. The cervix's external os, near the vagina, hosts various microorganisms. Evidence points to the link between vaginal microbiota and HPV-induced cervical cancer. Cervical cancer onset aligns with an imbalanced Th1/Th2 immune response, but the role of vaginal microbiota in modulating this imbalance is unclear. Methods: In this study, we collected vaginal samples from 99 HPV-infected patients across varying degrees of lesions, alongside control groups. These samples underwent bacterial DNA sequencing. Additionally, we employed Elisa kits to quantify the protein expression levels of Th1/Th2 cytokines IL2, IL12, IL5, IL13, and TNFa within the centrifuged supernatant of vaginal-cervical secretions from diverse research subjects. Subsequently, correlation analyses were conducted between inflammatory factors and vaginal microbiota. Results: Our findings highlighted a correlation between decreased Lactobacillus and increased Gardenerella presence with HPV-induced cervical cancer. Functionally, our predictive analysis revealed the predominant enrichment of the ABC transporter within the vaginal microbiota of cervical cancer patients. Notably, these microbiota alterations exhibited correlations with the production of Th1/Th2 cytokines, which are intimately tied to tumor immunity. Conclusions: This study suggests the potential involvement of vaginal microbiota in the progression of HPV-induced cervical cancer through Th1/Th2 cytokine regulation. This novel insight offers a fresh perspective for early cervical cancer diagnosis and future prevention strategies.

Reticulon 3 deficiency ameliorates post-myocardial infarction heart failure by alleviating mitochondrial dysfunction and inflammation.

Multiple molecular mechanisms are involved in the development of heart failure (HF) after myocardial infarction (MI). However, interventions targeting these pathological processes alone remain clinically ineffective. Therefore, it is essential to identify new therapeutic targets for alleviating cardiac dysfunction after MI. Here, gain- and loss-of-function approaches were used to investigate the role of reticulon 3 (RTN3) in HF after MI. We found that RTN3 was elevated in the myocardium of patients with HF and mice with MI. Cardiomyocyte-specific RTN3 overexpression decreased systolic function in mice under physiological conditions and exacerbated the development of HF induced by MI. Conversely, RTN3 knockout alleviated cardiac dysfunction after MI. Mechanistically, RTN3 bound and mediated heat shock protein beta-1 (HSPB1) translocation from the cytosol to the endoplasmic reticulum. The reduction of cytosolic HSPB1 was responsible for the elevation of TLR4, which impaired mitochondrial function and promoted inflammation through toll-like receptor 4 (TLR4)/peroxisome proliferator-activated receptor gamma coactivator-1 alpha(PGC-1α) and TLR4/Nuclear factor-kappa B(NFκB) pathways, respectively. Furthermore, the HSPB1 inhibitor reversed the protective effect of RTN3 knockout on MI. Additionally, elevated plasma RTN3 level is associated with decreased cardiac function in patients with acute MI. This study identified RTN3 as a critical driver of HF after MI and suggests targeting RTN3 as a promising therapeutic strategy for MI and related cardiovascular diseases.

Elevated SLC40A1 impairs cardiac function and exacerbates mitochondrial dysfunction, oxidative stress, and apoptosis in ischemic myocardia.

Iron homeostasis is crucial for optimal cardiac function. Iron deficiency and overload have been linked to the development of cardiomyopathy and heart failure (HF) via intricate mechanisms. Although the crucial role of SLC40A1 in iron metabolism by facilitating the efflux of cellular iron has been confirmed, its specific molecular functions in cardiovascular diseases remain poorly understood. In this study, we generated mice with inducible cardiomyocyte-specific overexpression of SLC40A1 for the first time. The overexpression of SLC40A1 in the cardiomyocytes of adult mice resulted in significant iron deficiency, leading to mitochondrial dysfunction, oxidative stress, and apoptosis, subsequently resulting in the development of fatal HF. Notably, SLC40A1 upregulation was observed in the ischemic region during the initial phase of myocardial infarction (MI), contributing to iron loss in the cardiomyocytes. Conversely, the cardiomyocyte-specific knockdown of SLC40A1 improved cardiac dysfunction after MI by enhancing mitochondrial function, suppressing oxidative stress, and reducing cardiomyocytes apoptosis. Mechanistically, Steap4 interacted with SLC40A1, facilitating SLC40A1-mediated iron efflux from cardiomyocytes. In short, our study presents evidence for the involvement of SLC40A1 in the regulation of myocardial iron levels and the therapeutic benefits of cardiomyocyte-specific knockdown of SLC40A1 in MI in mice.

Predictive Value of Nutritional Risk for All-Cause Death and Functional Outcomes in Chinese Elderly Patients with Acute Stroke: A 3-Year Follow-Up Study.

Purpose: To explore the predictive value of nutritional risk for all-cause death and functional outcomes among elderly acute stroke patients. Patients and Methods: A total of 479 elderly acute stroke patients were enrolled in this study. The nutritional risk of patients was screened by the GNRI and NRS-2002. The primary outcome was all-cause death, and the secondary outcome was poor prognosis defined as a modified Rankin Scale (mRS) score ≥3. Results: Based on the NRS-2002, patients with nutritional risk had a higher risk of all-cause death at 3 months (adjusted OR: 3.642, 95% CI 1.046~12.689) and at 3 years (adjusted OR: 2.266, 95% CI 1.259~4.076) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 2.748, 95% CI 1.518~4.972. Based on the GNRI, compared to those without nutritional risk, patients with mild malnutrition also had a higher risk of all-cause death at 3 months (adjusted OR: 7.186, 95% CI 1.550~33.315) and at 3 years (adjusted OR: 2.255, 95% CI 1.211~4.199) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 1.947, 95% CI 1.030~3.680), so patients with moderate and severe malnutrition had a higher risk of all-cause death at 3 months (adjusted OR: 6.535, 95% CI 1.380~30.945) and at 3 years (adjusted OR: 2.498, 95% CI 1.301~4.799) and a higher risk of adverse functional outcomes at 3 months (adjusted OR: 2.213, 95% CI 1.144~4.279). Conclusion: Nutritional risk increases the risk of poor short-term and long-term outcomes in elderly patients with acute stroke. For elderly stroke patients, we should pay attention to early nutritional risk screening, and effective intervention should be provided to improve the prognosis of such patients.

Exploring the Mechanism of Brucea Javanica against Ovarian Cancer based on Network Pharmacology and the Influence of Luteolin on the PI3K/AKT Pathway.

BACKGROUND: Ovarian cancer (OC) is a commonly diagnosed female cancer around the world. The Chinese herbal medicine Brucea Javanica has an anti-cancer effect. However, there is no relevant report on whether Brucea Javanica is effective in treating OC, and the corresponding mechanism is also unknown. OBJECTIVE: This study was projected to excavate the active components and underpinned molecular mechanisms of Brucea Javanica in treating ovarian cancer (OC) through network pharmacology combined with in vitro experiments. METHODS: The essential active components of Brucea Javanica were selected using the TCMSP database. The OC-related targets were selected by GeneCards, intersecting targets were obtained by Venn Diagram. The core targets were obtained through the PPI network and Cytoscape, and the key pathway was gained through GO and KEGG enrichment analyses. Meanwhile, docking conformation was observed as reflected by molecular docking. MTT, colony formation assay and flow cytometer (FCM) analysis were performed to determine cell proliferation and apoptosis, respectively. Finally, Levels of various signaling proteins were evaluated by western blotting. RESULTS: Luteolin, ß-sitosterol and their corresponding targets were selected as the essential active components of Brucea Javanica. 76 intersecting targets were obtained by Venn Diagram. TP53, AKT1, and TNF were obtained through the PPI network and Cytoscape, and the key pathway PI3K/AKT was gained through GO and KEGG enrichment analyses. A good docking conformation was observed between luteolin and AKT1. Luteolin could hinder A2780 cell proliferation, induce cell apoptosis and enhance the inhibition of the PI3K/AKT pathway. CONCLUSION: It was verified in vitro that luteolin could hinder OC cell proliferation and activate the PI3K/AKT pathway to lead to apoptosis.

Bruceine D and afatinib combination inhibits ovarian cancer cells proliferation and migration through DNA damage repair and EGFR pathway.

Owing to the high rates of relapse and migration, ovarian cancer (OC) has been recognized as the most lethal gynecological malignancy worldwide. The activity of the epidermal growth factor receptor (EGFR) signaling pathway is frequently associated with OC cell proliferation and migration. Despite this knowledge, inhibition of EGFR signaling in OC patients failed to achieve satisfactory therapeutic effects. In this study, we identified that bruceine D (BD) and EGFR inhibitor, afatinib, combination resulted in synergistic anti-OC effects. The results indicated that compared with one of both drugs alone, the combination of BD and afatinib slowed the DNA replication rate, inhibition of cell viability, and proliferation and clone formation. This resulted in cell cycle arrest and cell apoptosis. In addition, the combination of BD and afatinib possessed a stronger ability to inhibit the OC cell adhesion and migration than treatment with BD or afatinib alone. Mechanistically, the combined treatment triggered intense DNA damage, suppressed DNA damage repair, and enhanced the inhibition of the EGFR pathway. These results demonstrated that compared with each pathway inhibition, combined blocking of both DNA damage repair and the EGFR pathway appears to more effective against OC treatment. The results support the potential of BD and afatinib combination as a therapeutic strategy for OC patients.

Relationship between vaginal microecology and human papillomavirus infection as well as cervical intraepithelial neoplasia in 2,147 women from Wenzhou, the southeast of China.

Objective: The female reproductive tract is a significant microecological region, and its micro-environment can directly affect women's cervical health. This research aimed to investigate the effect of vaginal microecology on human papillomavirus (HPV) infection and cervical intraepithelial neoplasia(CIN). Methods: A retrospective cohort study enrolling 2,147 women who underwent a colposcopic examination between August 2021 and August 2022 was conducted. The relationship between vaginal microecology and HPV infection as well as cervical lesions were assessed using the chi-square test, univariate and multivariate logistic regression analyses, and Cochran-Armitage trend test. Results: HPV infection was linked to the imbalance of vaginal microecology [odds ratio (OR)=3.00, 95% confidence interval (CI)=1.66-5.43; P<0.001]. Clue cell (OR=1.59, 95% CI=0.99-2.54; P=0.054) and sialidase (OR=1.54, 95% CI=1.01-2.35; P<0.046) were considered as significant risk factors for HPV infection. Further analysis showed that vaginal microecological disorder was more likely to be detected in patients infected with HPV 16/18 subtypes (OR=9.86, 95% CI=2.37-41.80; P=0.002). Although there was no significant correlation between the incidence of vaginal microecological disorder and the severity of cervical lesions (P > 0.05), the proportions of abnormal PH value (OR=2.6, 95% CI=1.63-10.42; P=0.001) and abnormal vaginal cleanliness (OR=2.6, 95% CI=1.36-4.0; P= 0.004) increased as the histological stage progressed. Conclusion: Vaginal microecology associates with HPV infection and the progression of cervical lesions. Detection of vaginal secretion may contribute to the development of targets for micro-environmental modulation with probiotics and the reduction of the incidence of cervical cancer.

Fasting blood glucose-to-glycated hemoglobin ratio and all-cause mortality among Chinese in-hospital patients with acute stroke: a 12-month follow-up study.

BACKGROUND: Stroke is a leading cause of death and functional impairment in older people. To assess the prospective association between fasting blood glucose-to-glycated hemoglobin ratio and all-cause mortality and poor prognosis in stroke patients. METHODS: A total of 971 Chinese inpatients with acute stroke (mean age of 65.7) were consecutively enrolled in the prospective clinical study and followed up for 12 months after discharge. Stress hyperglycemia was measured using the ratio of fasting blood glucose (FBG, mmol/L)/glycated hemoglobin (HbA1c, %). The primary outcome was all-cause mortality, and secondary outcomes were poor prognosis defined as infectious complications, a National Institutes of Health Stroke Scale (NIHSS) score ≥ 6, a Barthel Index score ≤ 60, or a modified Rankin Scale (mRS) score of 3-6, presented as multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) across the quartiles of the FBG/HbA1c ratio. RESULTS: There were 35 (4.1%) all-cause deaths at 3 months and 85 (11.4%) at 12 months. The inpatients with the highest quartile of the FBG/HbA1c ratio had a higher risk of all-cause death at 3 months (adjusted OR: 5.16, 95% CI: 1.03-25.74) and at 12 months (adjusted OR: 2.59, 95% CI: 1.14-5.89)) and a higher risk of infectious complications (adjusted OR 2.37, 95% CI 1.27-4.43) and dysfunction (adjusted OR 1.79, 95% CI 1.06-3.01) during hospitalization than inpatients with the lowest quartile. CONCLUSIONS: Stress hyperglycemia, measured by the FBG/HbA1c ratio, was associated with an increased risk of adverse outcomes, including all-cause death, infectious complications, and dysfunction after stroke.

The emerging role of WWP1 in cancer development and progression.

Emerging evidence demonstrates that WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) participates into carcinogenesis and tumor progression. In this review article, we will describe the association between dysregulated WWP1 expression and clinical features of cancer patients. Moreover, we summarize the both oncogenic and tumor suppressive functions of WWP1 in a variety of human cancers. Furthermore, we briefly describe the downstream substrates of WWP1 and its upstream factors to regulate the expression of WWP1. Notably, targeting WWP1 by its inhibitors or natural compounds is potentially useful for treating human malignancies. Finally, we provide the perspectives regarding WWP1 in cancer development and therapies. We hope this review can stimulate the research to improve our understanding of WWP1-mediated tumorigenesis and accelerate the discovery of novel therapeutic strategies via targeting WWP1 expression in cancers.

Comparing the prognostic significance of nutritional screening tools and ESPEN-DCM on 3-month and 12-month outcomes in stroke patients.

BACKGROUND AND AIMS: Malnutrition is prevalent among individuals with acute ischaemic stroke (AIS) and may worsen clinical outcomes. There is no consensus on the best tool for nutritional screening in this population. The present study compared four screening tools and one diagnostic tool in terms of their prognostic significance in predicting short-term and long-term outcomes in AIS patients. METHODS: We included patients admitted to five major hospitals in Wenzhou and diagnosed with a primary diagnosis of AIS from October 1 to December 31, 2018. The Controlling Nutritional Status (CONUT) score, the Geriatric Nutritional Risk Index (GNRI), the Malnutrition Universal Screening Tool (MUST), the Nutritional Risk Screening Tool 2002 (NRS-2002) and the European Society for Clinical Nutrition and Metabolism diagnostic criteria for malnutrition (ESPEN-DCM) were assessed at admission. The clinical outcomes were evaluated by the modified Rankin Scale (mRS) and mortality at 3 months and 12 months after discharge. RESULTS: Five hundred and ninety-three patients were included in our prospective study. The mean age was 67.3 ± 12.0 years. Based on the mRS score, 125 patients exhibited poor functional recovery (an mRS ≥3) at 3 months after discharge. Seventeen patients died during the 3-month follow-up period, and the other 25 did not survive 12 months. Multivariate binary logistic regression revealed that inadequate nutritional status at admission, as determined by the CONUT, GNRI, MUST, NRS-2002 and ESPEN-DCM, were independently associated with poor outcomes in AIS patients 3 months after discharge. Both MUST ≥2 and NRS-2002 ≥ 3 showed significant associations with poor outcomes at 12-month post-discharge. Further analysis with the receiver operator characteristic (ROC) curve showed similar results, where all the tools predicted the poor outcomes at 3 months while only the NRS-2002 and MUST scores were significantly associated with the mRS at 12 months post-discharge. Moreover, the area under the curve (AUC) of MUST and NRS-2002 were significantly larger than those for the other tools. The optimal cut-off values of the MUST and NRS-2002 to predict poor outcomes were scores of ≥2 and ≥ 3 points, respectively. CONCLUSIONS: Our data supported a deleterious effect of inadequate nutrition, as evidenced by the nutrition screening tools or ESPEN-DCM, on clinical outcomes during and beyond the acute phase of AIS. We recommended the use of the MUST and NRS-2002 in guiding nutritional support in AIS patients, as they have higher predictive power and can predict both short-term and long-term outcomes.

CaMKII/calpain interaction mediates ischemia/reperfusion injury in isolated rat hearts.

Previous studies indicated that Ca2+/calmodulin-dependent kinase II (CaMKII), a kinase involved in the modulation of ryanodine receptor activity, activates Ca2+-regulated protease µ-calpain to promote myocardial ischemia/reperfusion injury. This study was performed to explore the underlying mechanisms in CaMKII-induced calpain activation to better understand heart injury. To examine the Ca2+ paradox and ischemia/reperfusion injury, isolated rat hearts were subjected to a Ca2+-free solution for 3 min, or left coronary artery occlusion for 40 min, prior to restoration of normal perfusion. Blockade of trans-sarcoplasmic reticulum Ca2+ flux using ryanodine and thapsigargin failed to prevent Ca2+ paradox-induced heart injury. In contrast, the Ca2+ paradox increased CaMKII auto-phosphorylation at Thr287, while the CaMKII inhibitor KN-62 and the Na+/Ca2+ exchanger inhibitor KB-R7943 alleviated heart injury and calpain activity. Intriguingly, the binding of µ-calpain large subunit calpain-1 (CAPN1) to phospho-CaMKII was blunted by both inhibitors. Thus, a Ca2+ leak via the ryanodine receptor is not an essential element in CaMKII-elicited calpain activation. In hearts receiving vector injection, ischemia/reperfusion caused elevated calpain activity and α-fodrin degradation, along with membrane integrity damage, similar to the effects noted in control hearts. Importantly, all these alterations were diminished with delivery of adeno-associated virus expressing mutant CaMKIIδC T287A. Ischemia/reperfusion increased CaMKII auto-phosphorylation and binding of CAPN1 to phospho-CaMKII, and facilitated the translocation of phospho-CaMKII and CAPN1 to the plasma membrane, all of which were reversed by injecting CaMKII mutant. Furthermore, the relocation capacity and the interaction of CaMKII with CAPN1 appeared to be dependent upon CaMKII autophosphorylation, as its mutant delivery increased the level of CaMKII, but did not increase membrane content of CaMKII and CAPN1, or their interactions. Together, CaMKII/calpain interaction represents a new avenue for mediating myocardial ischemia/reperfusion injury, and CaMKII likely serves as both a kinase and a carrier, thereby promoting calpain membrane translocation and activation.

Being at risk of malnutrition predicts poor outcomes at 3 months in acute ischemic stroke patients.

BACKGROUND: Malnutrition is confirmed to be associated with poor outcomes in stroke patients. The present study aimed to confirm that being at risk of malnutrition assessed by Nutritional Risk Screening Tool 2002 (NRS-2002) and the Controlling Nutritional Status (CONUT) score predicts poor outcomes at 3 months in acute ischemic stroke (AIS) patients. METHODS: In total, 682 patients with AIS were recruited within 7 days of stroke onset consecutively and 110 were dropped out. They were screened for risk of malnutrition using NRS-2002 and the CONUT score. The primary outcome is the follow-up modified Rankin Scale (mRS) score. Poor outcomes were defined as an (mRS) score ≥ 3 at 3 months post discharge. RESULTS: There was a significant difference in the mRS score at 3 months between patients at risk of malnutrition compared to those not at risk assessed by NRS-2002(P < 0.001) and CONUT (P = 0.011). The logistic regression model showed that the risk of malnourishment (according to NRS-2002), low risk of malnourishment (according to CONUT), and the moderate-to-severe risk of malnourishment (according to CONUT) were associated with higher risk of poor outcomes at 3 months (P < 0.001, P = 0.033, and P = 0.007). The multivariate logistic regression model (adjusted for confounding factors) demonstrated that the risk of malnourishment, according to the NRS-2002, was associated with the increasing risk of poor outcomes at 3 months (odds ratio = 2.31; 95% CI: 1.24-4.30; P = 0.008). CONCLUSIONS: The risk of malnutrition assessed by NRS-2002 and CONUT can predict poor outcomes at 3 months in AIS patients. NRS-2002 is superior to CONUT in predicting poor outcomes at 3 months.