With the global aging of the population, menopausal women face higher cardiovascular disease (CVD) risks, with carotid atherosclerosis as the primary pathological basis. However, no effective tools exist for assessing carotid atherosclerosis risk, and this study fills the gap in predictive tools in this field. Using data from 4,446 menopausal women in Shenzhen, we developed and validated a Nomogram model for carotid atherosclerosis risk. The sample was divided into training (2,178), internal validation (934), and external validation (1,334) sets. Variables were selected using logistic regression and LASSO, including age, systolic blood pressure (SBP), lipoprotein a (LPa), non-HDL cholesterol (Non-HDL-C), TC/HDL-C ratio, glycosylated hemoglobin (HbA1c), and blood glucose (GLU). Random Forest validation confirmed the model’s robustness. The Nomogram’s C-index was 0.706 (training), 0.664 (internal), and 0.668 (external), with Random Forest results of 0.721, 0.662, and 0.661, respectively. Calibration and decision curve analyses demonstrated the model’s accuracy and clinical utility. Additionally, a slight negative correlation between age and GLU (OR = 0.689, P = 0.068) suggested reduced glycemic risk with age. This model provides a scientific basis for early risk assessment and personalized interventions for menopausal women, guiding future research on related biological mechanisms.

Cardiovascular disease remains a leading health issue globally, with atherosclerosis being a significant contributor, particularly in patients with type 2 diabetes who face multiple risk factors. This study aims to develop and validate a predictive nomogram for carotid atherosclerosis specifically in patients with type 2 diabetes, addressing the lack of effective risk-stratification tools. A retrospective cohort study involving 1,258 patients with type 2 diabetes was conducted. The 880 diabetic patients diagnosed between 2018 and 2021 were divided into a training set (n = 616) and an internal validation set (n = 264) at a 7:3 ratio. An additional 378 patients from 2022 to 2023 were included as an external validation set. Demographic, clinical, and biochemical data were collected. Risk factors were identified using LASSO regression and multivariate logistic regression, leading to the development of a nomogram. Model performance was evaluated using Receiver Operating Characteristic curves, calibration curves, and decision curve analysis. The nomogram identified age, smoking, drinking, systolic blood pressure, lipoprotein(a), non-high-density lipoprotein cholesterol, and creatinine as independent risk factors for carotid atherosclerosis in diabetic patients. The model demonstrated good discrimination, with area under the curve values of 0.791, 0.725, and 0.721 for the training, internal, and external validation sets, respectively. Calibration curves indicated a strong alignment between predicted probabilities and observed outcomes. Decision curve analysis confirmed the model’s clinical utility, especially when the threshold probability was above 15

At present, the barrier to HIV-1 functional cure is the persistence of HIV-1 reservoirs. The “shock (reversing latency) and kill (antiretroviral therapy)” strategy sheds light on reducing or eliminating the latent reservoir of HIV-1. However, the current limits of latency-reversing agents (LRAs) are their toxicity or side effects, which limit their practicability pharmacologically and immunologically. Our previous research found that HSF1 is a key transcriptional regulatory factor in the reversion of HIV-1 latency. We then constructed the in vitro HSF1-knockout (HSF1-KO) HIV-1 latency models and found that HSF1 depletion inhibited the reactivation ability of LRAs including salubrinal, carfizomib, bortezomib, PR-957 and resveratrol, respectively. Furthermore, bortezomib/carfizomib treatment induced the increase of heat shock elements (HSEs) activity after HSF1-KO, suggesting that HSEs participated in reversing the latent HIV-1. Subsequent investigation showed that latent HIV-1-reversal by H2O2-induced DNA damage was inhibited by PARP1 inhibitors, while PARP1 was unable to down-regulate HSF1-depleted HSE activity, indicating that PARP1 could serve as a replaceable protein for HSF1 in HIV-1 latent cells. In summary, we succeeded in finding the mechanisms by which HSF1 reactivates the latent HIV-1, which also provides a theoretical basis for the further development of LRAs that specifically target HSF1.

This study investigated the effects of hypothermia induced before cardiac arrest or after return of spontaneous circulation (ROSC) on cardiac function and myocardial mitochondrial injury after ROSC in a rat cardiac arrest model. Sixty healthy, male Wistar rats were randomly divided into the Normothermia group, pre-arrest hypothermia (Pre-HT) group, and post-resuscitation hypothermia (Post-HT) group. The rats underwent 8 min of untreated ventricular fibrillation followed by cardiopulmonary resuscitation. Twelve rats in each group were used to evaluate the left ventricular ejection fraction before ventricular fibrillation and 4 h after ROSC. Survival was determined at 24 h after ROSC. The remaining eight rats in each group were used to detect for heart malondialdehyde, reduced glutathione, adenosine triphosphate levels and mitochondrial histology. Oxygen consumption rate and mitochondrial membrane potential were evaluated 4 h after ROSC; 10 of 12 rats in Pre-HT group, 5 of 12 in Post-HT group, and 6 of 12 in normothermia group were successfully resuscitated. The survival rate of each group was 66.7%, 33.3%, and 25%, respectively. Rats in the Pre-HT group showed less alteration of the mitochondrial ultrastructure and oxidative stress injury, better maintenance of adenine nucleotides, and more preservation of the mitochondrial membrane potential and respiratory function when compared with rats in the Post-HT and normothermia groups. Transient hypothermia is an effective preconditioning stimulus to induce ischemic tolerance in a cardiac arrest model and worthy of further evaluation for potential clinical use. Impact statement In this paper, we investigated the effects of hypothermia induced before ischemia or after ROSC on cardiac function, oxidative stress damage, and myocardial mitochondrial ischemia–reperfusion injury after cardiac arrest in a rat model with VF. We demonstrated that pre-arrest hypothermia conferred greater cardio-protective benefits than delayed post-resuscitation hypothermia, reduced the number of defibrillations required and dosages of epinephrine during CPR, decreased oxidative stress, ameliorated mitochondrial dysfunction, and subsequently improved survival rate.

AT‑101, an orally available and well‑tolerated natural pan‑Bcl‑2 family protein inhibitor, has been reported to be effective against a variety of cancers. However, the mechanisms whereby AT‑101 exhibits anticancer activity have not been fully elucidated. In this study, we demonstrated that AT‑101 reduced the cell viability of human esophageal cancer cells by inducing G1/G0 phase arrest and apoptosis. Apoptotic cell death occurred later than cell cycle arrest, as evidenced by an increase in the proportion of Annexin V‑positive cells and cleaved caspase‑3, ‑9 and PARP protein levels. AT‑101 markedly downregulated the protein levels of phospho‑retinoblastoma (Ser 780) and cyclin D1, whereas it elevated protein levels of p53 and p21Waf1/Cip1, contributing to the inhibition of cell cycle progression. Moreover, AT‑101 substantially reduced β‑catenin expression. XAV‑939, a small molecule that inhibits the Wnt/β‑catenin signaling pathway by facilitating β‑catenin degradation, lowered β‑catenin and cyclin D1 protein expression to an extent similar to AT‑101. XAV‑939 alone resulted in G1/G0 phase arrest and further induced cell cycle arrest in combination with AT‑101, suggesting that the β‑catenin/cyclin D1 signaling pathway mediated, at least in part, the cell cycle arrest induced by AT‑101. The present study may shed new light on the anticancer activity of AT‑101 in relation to cell cycle arrest as well as apoptosis in human esophageal cancer cells.

Objective:In the post-HAART era, the incidence of some AIDS-defining cancers declined markedly likely reflecting HAART-related improvements in immunity, whereas incidence of some cancers such as cervical cancer has not been affected. Therefore, it is valuable to find whether antiretroviral drugs or prophylactic microbicides could treat or prevent these cancers, especially the cervical cancer. Design:We screened the anti-HIV drugs, approved or in phase III clinical trials, to identify a potential anticancer drug candidate. Methods:We chose cervical HeLa and SiHa cancer cells and focused on studying the antitumor effects in vitro and in vivo. Cell proliferation was measured by MTT assay, the cytotoxic effect was obtained through apoptosis as evidenced by Annexin V flow cytometry assay because of the arresting of cancer cells in G2/M phase of cell cycle. Nude mice xenograft model was performed to detect the antitumor effect in vivo. Results:TMC120 was identified as a potential anticancer drug candidate. TMC120 displayed potent cytotoxic effect on various human cancer cells, including cervical carcinoma cell line HeLa and SiHa. Further mechanism study showed that TMC120 enhanced the polymerization of microtubules, which was followed by mitotic arrest, as well as abno rmal mitotic spindles. TMC120 also substantially retarded the growth rate of the tumor in vivo. Conclusion:TMC120 is a potential chemoprophylactic and therapeutic agent for cervical cancers in a manner similar to paclitaxel, and could be suitable for helping healthy women to prevent HIV infection and cervical cancer.

The persistent inflammation aggravated by a disordered immune response is considered to be the major cause of CD4+ T cell depletion in lymphoid tissue, which impels the progression of AIDS. Here, we report that heat shock factor 1 (HSF1) works as an innate repressor of HIV-induced inflammation. The activation of HSF1 was found to accompany inflammation during HIV infection. Further research uncovered that HSF1 activation inhibited HIV-induced inflammation. In addition, HSF1 overexpression suppressed the inflammatory response induced by HIV, while HSF1 deficiency exacerbated that inflammation. Mechanistically, HSF1 was found to compete with nuclear factor-κB (NF-κB) in the nucleus. Generally, our report highlights that HSF1 is an important host factor in regulating HIV-induced inflammation and may work as a potential target for curing AIDS.

To investigate long noncoding (lnc)-RNA and mRNA expression profiles in post-cardiac arrest (CA) brains, an external transthoracic electrical current was applied for 8 min to induce CA (the CA group). A total of 4 rats received sham-operations and served as the blank control (BC) group. Upon return of spontaneous circulation (ROSC), lncRNA and mRNA expression in the rat cerebral cortex was assayed with high-throughput Agilent lncRNA and mRNA microarrays. In total, 37 lncRNAs were upregulated and 21 lncRNAs were downregulated in the CA group, and 258 mRNA transcripts were differentially expressed with 177 mRNAs upregulated and 81 mRNAs downregulated in the CA group. The differentially expressed lncRNAs in the CA group were co-expressed with thousands of mRNAs. The differentially expressed lncRNAs could be clustered into >100 signaling pathways and processes according to Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. The most common predicted functions involved metabolic pathways, protein synthesis, transport and degradation during CA-ROSC. CA-ROSC led to significant alterations in cerebral lncRNA and mRNA expression profiles. Thus, lncRNA-mRNA network interactions have the potential to regulate vital metabolic pathways and processes involved in CA-ROSC.

The persistence of latent HIV reservoirs presents a significant challenge to viral eradication. Effective latency reversing agents (LRAs) based on "shock and kill" strategy are urgently needed. The natural phytoalexin resveratrol has been demonstrated to enhance HIV gene expression, although its mechanism remains unclear. In this study, we demonstrated that resveratrol was able to reactivate latent HIV without global T cell activation in vitro. Mode of action studies showed resveratrol-mediated reactivation from latency did not involve the activation of silent mating type information regulation 2 homologue 1 (SIRT1), which belonged to class-3 histone deacetylase (HDAC). However, latent HIV was reactivated by resveratrol mediated through increasing histone acetylation and activation of heat shock factor 1 (HSF1). Additionally, synergistic activation of the latent HIV reservoirs was observed under cotreatment with resveratrol and conventional LRAs. Collectively, this research reveals that resveratrol is a natural LRA and shows promise for HIV therapy.

Objective: Recent studies have shown the existence of autophagy in cerebral ischemia; however, there has been no research on the role of autophagy in cerebral injury after cardiopulmonary resuscitation (CPR). This studywas conducted to determine the role of autophagy in an animal model of ventricular fibrillation (VF)/CPR.Methods: Experiment 1: A total of 48 adult Wistar rats were untreated for 7 minutes after induction of VF using an external transthoracic alternating current, and subsequent CPR was performed to observe the existence of autophagy after the return of spontaneous circulation (ROSC). Experiment 2: A total of 72 rats were pretreated with intracerebroventricular injection of physiologic saline (control group), the autophagy inducer (rapamycin group), or the autophagy inhibitor 3-methyladenine (3-methyladenine group) before ROSC to evaluate the contribution of autophagy to neuronal injury after ROSC.Results: The activation of autophagy was attenuated 2 to 4 hours after ROSC, which was related to the activity decrease of 5'-adenosine monophosphate-activated protein kinase after ROSC. Rapamycin treatment significantly increased the expressions of LC3-II and Beclin-1 after ROSC, attenuated the activation of caspase-3, promoted neuronal survival and decreased neuronal apoptosis, and improved the neurologic deficit score after CPR.Conclusions: The activation of autophagy after ROSC offered a remarkable tolerance to VF/CPR ischemic insult and improved the neurologic outcomes. (C) 2016 Published by Elsevier Inc.

HSF1, a conserved heat shock factor, has emerged as a key regulator of mammalian transcription in response to cellular metabolic status and stress. To our knowledge, it is not known whether HSF1 regulates viral transcription, particularly HIV-1 and its latent form. Here we reveal that HSF1 extensively participates in HIV transcription and is critical for HIV latent reactivation. Mode of action studies demonstrated that HSF1 binds to the HIV 5′-LTR to reactivate viral transcription and recruits a family of closely related multi-subunit complexes, including p300 and p-TEFb. And HSF1 recruits p300 for self-acetylation is also a committed step. The knockout of HSF1 impaired HIV transcription, whereas the conditional over-expression of HSF1 improved that. These findings demonstrate that HSF1 positively regulates the transcription of latent HIV, suggesting that it might be an important target for different therapeutic strategies aimed at a cure for HIV/AIDS.

The persistence of HIV in resting memory CD4(+) T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. Proteasome inhibitors (PIs) were previously reported as latency reversing agents (LRAs) but the mechanism underlying this function is yet unclear. Here we demonstrate that PIs reactivate latent HIV ex vivo without global T cell activation, and may facilitate host innate immune responses. Mechanistically, latent HIV reactivation induced by PIs is mediated by heat shock factor 1 (HSF1) via the recruitment of the heat shock protein (HSP) 90-positive transcriptional elongation factor b (p-TEFb) complex. Specifically, HSP90 downstream HSF1 gives positive feedback to the reactivation process through binding to cyclin-dependent kinase 9 (CDK9) and preventing it from undergoing degradation by the proteasome. Overall, these findings suggest proteasome inhibitors as potential latency reversing agents. In addition, HSF1/HSP90 involved in HIV transcription elongation, may serve as therapeutic targets in HIV eradication.

BACKGROUND:Lung cancer risk is the leading cause of cancer-related deaths worldwide. We conducted a meta-analysis to evaluate the relationship between dairy consumption and lung cancer risk.METHODS:The databases included EMBASE, Medline (PubMed), and Web of Science. The relationship between dairy consumption and lung cancer risk was analyzed by relative risk or odds ratio estimates with 95% confidence intervals (CIs). We identified eight prospective cohort studies, which amounted to 10,344 cases and 61,901 participants.RESULTS:For milk intake, relative risk was 0.95 (95% CI: 0.76-1.15); heterogeneity was 70.2% (P=0.003). For total dairy product intake, relative risk was 0.96 (95% CI: 0.89-1.03), heterogeneity was 68.4% (P=0.004).CONCLUSION:There was no significant association between dairy consumption and lung cancer risk.

OBJECTIVE:To investigate the effect of Euphorbia fischeriana extract on latent HIV reactivation and the pathway involved in this process and discuss the value of Euphorbia fischeriana extract in eliminating HIV.METHODS:Fresh tissues of Euphorbia fischeriana root were crushed into powder after quick freezing with liquid nitrogen and extracted with acetone followed by a three-day vacuum freeze-drying for dehydration of the extract. The extract (EFE) was separated using RP-C18 column with high-performance liquid chromatography (HPLC) and identified with mass spectrometry (MS). The activity of reactivated latent HIV was analyzed by fluorescence-activated cell sorting in a J-Lat 10.6 cell model treated with EFE (50 µg/mL) for 24 h, using TNF-α (10 ng/mL) as the positive control. The effect of a NF-κB pathway inhibitor (Bay 11-7082) on EFE activity was tested. The changes in P65 expression in the cell nuclei within 2 h and HIV protein p24 expression within 24 h were analyzed by Western blotting in cells treated with EFE.RESULTS:EFE was obtained by one-step acetone extraction, and the concentration of prostratin in the extract was around 0.53 mmol/L. About 50% of the cells showed HIV reactivation after treatment with 50 µg/mL EFE for 24 h accompanied by a significantly increased p24 expression. The activity of EFE in reactivating latent HIV was inhibited by Bay 11-7082 in a concentration-dependent manner, and p65 accumulation was detected in the cell nuclei within 2 h.CONCLUSION:EFE we obtained contains the active compounds of prostratin and its analogues and shows a strong capacity to reactivate latent HIV through classical NF-κB pathway.

Objective: The present study was designed to evaluate the effects of ulinastatin (UTI) on cardiac dysfunction after cardiopulmonary resuscitation (CPR).Methods: A total of 48 healthy adult male New Zealand rabbits were untreated for 8 minutes after the induction of ventricular fibrillation (VF) by an external transthoracic alternating current and then treated by CPR. These rabbits were then randomly divided into the control and UTI groups after the return of spontaneous circulation (ROSC) and were observed for 8 hours after the ROSC. Before CPR and after ROSC at 2, 4, and 8 hours, blood samples were collected to determine the levels of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), malondialdehyde (MDA), cardiac troponin I (cTnI), and N-terminal probrain natriuretic peptide (NT-proBNP), and the left ventricular ejection fraction (EF) was measured by echocardiography.Results: Nineteen of 24 rabbits in the control group and 18 of 24 in the UTI group were successfully resuscitated. The plasma levels of TNF-alpha, IL-6, MDA, cTnI, and NT-proBNP were significantly increased, accompanying a deceased EF in the control group, but the cotreatment with UTI decreased the plasma levels of TNF-alpha, IL-6, MDA, cTnI, and NT-proBNP (P < .05), attenuating the myocardial injury and improving the EF in the UTI group. Only 9 of 19 animals in the control group but 14 of 18 animals in the UTI group survived longer than 8 hours (P = .011).Conclusions: The progression of proinflammatory responses, oxidative stress, and myocardial injury have been linked to the reduced EF after VF/CPR, and the administration of UTI at a cardioprotective dosage preserved the cardiac function after VF/CPR. (c) 2013 Elsevier Inc. All rights reserved.

Background: Whether bilevel positive airway pressure (BiPAP) is advantageous compared with continuous positive airway pressure (CPAP) in acute cardiogenic pulmonary edema (ACPO) remains uncertain. The aim of the meta-analysis was to assess potential beneficial and adverse effects of CPAP compared with BiPAP in patients with ACPO.Methods: Randomized controlled trials comparing the treatment effects of BiPAP with CPAP were identified from electronic databases and reference lists from January 1966 to December 2012. Two reviewers independently assessed study quality. In trials that fulfilled inclusion criteria, we critically evaluate the evidence for the use of noninvasive ventilation on rates of hospital mortality, endotracheal intubation, myocardial infarction, and the length of hospital stay. Data were combined using Review Manager 4.3 (The Cochrane Collaboration, Oxford, UK). Both pooled effects and 95% confidence intervals (CIs) were calculated.Results: Twelve randomized controlled trials with a total of 1433 patients with ACPO were included. The hospital mortality (relative risk [RR], 0.86; 95% CI, 0.65-1.14; P = .46; I-2 = 0%) and need for requiring invasive ventilation (RR, 0.89; 95% CI, 0.57-1.38; P = .64; I-2 = 0%) were not significantly different between patients treated with CPAP and those treated with BiPAP. The occurrence of new cases of myocardial infarction (RR, 0.95; 95% CI, 0.77-1.17; P = .53, I-2 = 0%) and length of hospital stay (RR, 1.01; 95% CI, -0.40 to 2.41; P = .98; I-2 = 0%) were also not significantly different between the 2 groups.Conclusions: There are no significant differences in clinical outcomes when comparing CPAP vs BiPAP. Based on the limited data available, our results suggest that there are no significant differences in clinical outcomes when comparing CPAP with BiPAP. (C) 2013 Elsevier Inc. All rights reserved.

Objectives To investigate the effects of activation of Autophagy on cerebral injury after cardiopulmonary resuscitation (CPR) in Wistar rat. Methods First 36 healthy adult male Wistar rats were induced ventricular fibrillation (VF) by alternating current for 7 minutes and then received CPR. Before VF (0) and at 1, 2, 4, 8 and 12 hours after return of spontaneous circulation (ROSC), cerebral cortex were harvested to determine the expressions of beclin-1 and LC3II by Weston blot. Further 60 healthy adult male Wistar rats were used to observe the effects of Autophagy activator Rapamycine (Rapamycine group, 20), Autophagy inhibitor 3-Methyladenine (3-MA group, 20) and Normal saline (Control group, 20) on the expressions of beclin-1, LC3II and the formation of autophagic vacuole in the cerebral cortex after ROSC. The neurologic deficit score (NDS) was used to evaluate the neurologic function at 24, 48 and 72h respectively after ROSC. The numbers of viable neurons and apoptotic neurons in the parietal cortex were counted by H&E staining and TUNEL staining after 72h. One-way ANOVA was used for the expressions of beclin-1 and LC3II and neurons counting. Rank sum test was used for NDS. Results The expressions of beclin-1 and LC3 II were significantly lower at 2 and 4h after ROSC than the levels before VF (P < 0.05). The expressions of beclin-1 and the conversion of LC3 II in cerebral cortex at 2 and 4h after ROSC in the Rapamycine group were significantly higher than that in Control group and 3-MA group (P < 0.05). The numbers of autophagic vacuole in the Rapamycine group at 2 and 4h after ROSC were significantly higher than the Control and 3-MA group. The number of viable neurons at 72h after ROSC in the Rapamycine group was 19 ± 516 ± 4/400pixs, higher than 16 ± 4/400pixs in Control group and 15 ± 3/400pixs in 3-MA group (P < 0.05). The number of the TUNEL positive cells in the Rapamycine group was 12 ± 4/400pixs and was lower than 15 ± 6/400pixs in the Control group and 17 ± 5/400pixs in 3-MA group (P < 0.05). The NDS scores of animals in Control group and 3-MA group at 24, 48 and 72h after ROSC were inferior to Rapamycine group. Conclusions The Autophagy of neurons in the cerebral cortex was attenuated in Wistar rats after ROSC. The activation of Autophagy can decrease the number of apoptotic neurons, preserve viable neurons and improve neurologic function.

Objectives To analysis the effect of milrinone on cor pulmonale with heart failure. Methods 212 patients with cor pulmonale with heart failure were separated into 2 groups randomly: 106 patients of control group were treated with routine therapy, while on this basis, 106 patients of treatment group were given milrinone additionally. Symptoms and signs of heart failure, lung function and adverse side effect were observed. Results The lung function and heat function of the treatment group were improved much better. It can quickly improve respiratory distress in cor pulmonale with acute heart failure patients. The clinic effective rate of the treatment group was 94.34%, the difference between the two groups was statistically significant (P<0.05). Conclusions Milrinone would be effective in treating cor pulmonale with heart failure without adverse side effect.

The world financial crisis is still serious now and the financial supervision has become the focus of attention in the world.The present paper discusses legal mechanism of prudential supervision three years after foreign banks moved all-roundly into China.It puts forward the view that innovation of the legal mechanism of prudential supervision should take internal-control review as the base,operational-risk supervision as the difficulty of prudential supervision,and information disclosure as the security of prudential supervision-a suggestion for the organic integration of the three legal organizations.