Ticagrelor versus Clopidogrel in Patients with left main Coronary Artery Stenting.

PURPOSE: The left main (LM) coronary artery disease poses high risks for its special anatomical characteristics. Optimal antiplatelet therapy is still controversial in this disease. We aimed to investigate the efficacy and safety of ticagrelor and clopidogrel in patients with stent implantation in the LM coronary artery. METHODS: We analyzed 3221 patients with stent implantation in the LM coronary artery from January 2011 to June 2022. Patients were separated into two groups: the ticagrelor group (n = 1550) and the clopidogrel group (n = 1671). Baseline data were balanced by propensity score matching. The primary endpoint was all-cause mortality, and secondary endpoints included cardiovascular death, myocardial infarction, stroke, stent thrombosis, or target vessel revascularization. The primary safety endpoint was major bleeding, defined as BARC 3, 5 bleeding. RESULTS: After propensity score matching (n = 1228 in each group), ticagrelor was linked to a lower incidence of all-cause mortality compared with clopidogrel after a three-year follow-up (5.7% vs. 8.5%; HR:0.728; 95%CI:0.537-0.985, P = 0.040). Ticagrelor treatment reduced target lesion revascularization (3.3% vs. 6.4%; HR: 0.542; 95%CI: 0.371-0.791, P = 0.001) and stent thrombosis (1.6% vs. 3.7%; HR: 0.459; 95%CI: 0.271-0.776, P = 0.004). There was no significant difference in major bleeding between the two groups. Multivariate COX analysis suggested that age, heart rate, diabetes, prior myocardial infarction, hemoglobin, serum creatinine, ticagrelor, DAPT duration, LM true-bifurcation, LM stent diameters, and IVUS were independent predictive parameters of all-cause death. CONCLUSIONS: Ticagrelor was associated with lower all-cause mortality and no increased risk of major bleeding compared to clopidogrel in LM stenting patients. Thus, ticagrelor can be considered a viable substitute for clopidogrel in LM disease.

Reproductive factors and risk of cardiovascular diseases and all-cause and cardiovascular mortality in American women: NHANES 2003-2018.

BACKGROUND: The evidence regarding the association of reproductive factors with cardiovascular diseases (CVDs) is limited. AIMS: To investigate the relationship of reproductive factors with the risk of CVDs, as well as all-cause and cardiovascular mortality. METHODS: This study included 16,404 adults with reproductive factors from the National Health and Nutrition Examination Survey (NHANES) and followed up until 31 December 2019. Logistic models and restricted cubic spline models were used to assess the association of reproductive factors with CVDs. COX proportional hazards models and restricted cubic spline models, with adjustment for potential confounding, were employed to analyze the relation between reproductive factors and cardiovascular and all-cause death. RESULTS: There is a nonlinear relationship between age at menarche and CVDs. Age at menopause ≤ 11(OR 1.36, 95% CI 1.10-1.69) was associated with an increased risk of CVDs compared to ages 12-13 years. Age at Menopause ≤ 44 (OR 1.69, 95% CI 1.40-2.03) was associated with increased CVDs compared to age 35-49 years. Number of pregnancies ≥ 5(OR 1.26, 95% CI 1.02-1.55) was associated with an increased risk of CVDs compared to one pregnancy. In continuous variable COX regression models, a later age at menopause (HR 0.98, 95% CI 0.97-0.99) and a longer reproductive lifespan (HR 0.98, 95% CI 0.97-0.99) were associated with a decreased risk of all-cause death. A later age at menopause (HR 0.98, 95% CI 0.97-0.99) and a longer reproductive lifespan (HR 0.98, 95% CI 0.97-0.99) were associated with a decreased risk of cardiac death. CONCLUSIONS: Female reproductive factors are significant risk factors for CVDs American women.

Unveiling the efficient state of Pd catalyst for robust electrocatalytic hydrodechlorination.

The application of electrochemical hydrodechlorination has been impeded due to the low utilization and activity of Pd catalyst. Herein, a series of Pd catalysts were prepared via the controllable evolution of Zn state during the pyrolysis of ZIF-8 nanosheet. Various forms of Pd with different chemical surroundings were generated upon the combined use of galvanic displacement and ion exchange process. Electrocatalytic hydrodechlorination of 4-chlorophenol was performed and the electrocatalytic hydrodechlorination efficiency of Pd/CN reaches 100% within 3 h at extra low Pd concentration. The coexistence of zero-valent Pd (Pd0) and nitrogen coordinated Pd (Pd-N) was verified by XAFS which provide multiple active sites for focusing on adsorbing H* and cracking C-Cl respectively. The synergetic effect between different chemical state of Pd for efficient hydrodechlorination of chloroaromatics and scheme for dexterous preparation of Pd based electrocatalyst are proposed and discussed.

Minimally Invasive Surgery for Spontaneous Intracerebral Hemorrhage With or Without Intraventricular Hemorrhage.

Objective: The treatment effect of minimally invasive surgery (MIS) for spontaneous intracerebral hemorrhage (sICH) remains controversial. Intracerebral hemorrhage patients with intraventricular hemorrhage (IVH) seemingly have a worse prognosis. So we aim to verify the efficacy of MIS for small and medium cerebral hemorrhage (15-30ml) using the propensity score matching (PSM)method which could reduce the heterogeneity, and further analyze the different treatment effects of MIS for sICH with or without IVH. Methods: We collected the data of patients with sICH from January 2016 to March 2021 retrospectively. The propensity score matching method was used to compare the clinical outcomes of surgery and conservative treatments. The primary outcome was neurological prognosis. The second outcomes were the rate of complications, length of stay, and hospitalization expenses. Furthermore, we use the binary logistic regression analysis to explore the influence of MIS on patients' prognosis. Results: For all sICH patients, the Modified Rankin Scale (MRS) and Glasgow Outcome Scale (GOS) of the surgery group were worse than those of the conservative group. The length of stay (P = .001), hospitalization expenses (P < .01), pneumonia incidence (P < 0.01), and history of tracheotomy (P = .002) of the surgery group were higher than those of the conservative group. For sICH patients without IVH, the GOS and MRS of surgery patients were statistically better than those of conservative patients at 3 months. The length of stay (P = .046), hospitalization expenses (P < .001), and pneumonia incidence (P < .001) of the surgery group were also higher than the conservative group. Binary logistic analysis showed that MIS is the protective factor for patients' neurological function, especially for intracerebral hemorrhage patients without IVH (OR = 66.636). Conclusions: For small and medium cerebral hemorrhage, stereotactic puncture drainage minimally invasive surgery could result in better functional outcomes, especially for the sICH patients without IVH.Nevertheless, surgery cannot reduce the occurrence of complications, hospitalization length, and expenses.

BNP and NT-proBNP Concentrations in Paired cerebrospinal Fluid and Plasma Samples of Patients with Traumatic Brain Injury.

BACKGROUND: The aim of this study was to investigate the secretion patterns of brain natriuretic peptide (BNP) and N-terminal-proBNP (NT-proBNP) after traumatic brain injury (TBI) and to analyze the source of them in cerebrospinal fluid (CSF). MATERIALS AND METHODS: We synchronously measured BNP and NT-proBNP concentrations in paired CSF and plasma samples from 22 moderate to severe TBI patients and 40 healthy control patients. The CSF and/or plasma ratio of albumin (QAlbumin) was calculated daily. The BNP and NT-proBNP levels of CSF and plasma were compared between TBI patients and control patients. RESULTS: CSF BNP and NT-proBNP levels peaked on day 3 after injury, as did the plasma BNP and NT-proBNP levels. The CSF BNP and NT-proBNP levels in TBI patients were elevated from day 1, which was significantly higher than control group (P < 0.05 and P < 0.01, respectively). However, in plasma, only NT-proBNP levels were significantly higher than in the control group from day 2 (P < 0.05). In addition, QBNP, defined as CSF BNP concentration and/or plasma BNP concentration, was significantly higher in TBI patients than in the control group (P < 0.01). However, QAlbumin remained within ranges of a mild to moderate dysfunction of blood-brain-barrier in TBI patients. CONCLUSIONS: CSF BNP concentrations are elevated and peak on day 3 after moderate to severe TBI. CSF BNP may originate from the brain and may be a potential biomarker of TBI.

Association of Plaque Features with Infarct Patterns in Patients with Acutely Symptomatic Middle Cerebral Artery Atherosclerotic Disease.

BACKGROUND AND PURPOSE: Understanding the stroke mechanism of middle cerebral artery (MCA) atherosclerosis is important for stroke triage and future trial design. The aim of this study was to characterize intrinsic MCA plaque and acute cerebral infarct in vivo by using high-resolution black-blood (BB) and diffusion-weighted magnetic resonance (MR) imaging and to investigate the relationship between plaque features and infarct patterns. METHODS: A single-center retrospective study was conducted at a tertiary referral center between March 2017 and August 2019. Patients consecutively admitted for acute ischemic stroke with MCA stenosis underwent diffusion-weighted and BB MR imaging. Plaque features and infarct patterns were assessed. The association between plaque features and infarct patterns (binary variable: single/multiple) was evaluated using a multivariate logistic regression model. RESULTS: Of 49 patients with MCA atherosclerotic stenosis, diffusion-weighted MR imaging showed that 28 patients (57%) had multiple acute cerebral infarcts and 21 patients had single acute cerebral infarcts. In contrast to single infarct, multiple infarcts were associated with greater plaque burden (81.9±7.24 versus 71.3±13.7; P=0.012). A multivariate logistic regression model adjusted for 7 potential confounders confirmed a statistically significant positive association between plaque burden and multiple acute infarcts (adjusted R2 =0.432, P< 0.001). The rate of plaque surface irregularity was significantly greater in patients with multiple infarcts than those with single infarct (71% versus 43%, P=0.044). For single acute penetrating artery infarct, patients with infarct size > 2cm had greater plaque burden compared with patients with infarct size < 2cm (75.3±13.4 versus 63.4±10.9; P = 0.016). CONCLUSIONS: Increased plaque burden, plaque surface irregularity in patients with MCA stenosis is associated with its likelihood to have caused an artery-to-artery embolism that produces multiple cerebral infarcts, especially along the border zone region, and increased plaque burden may promote subcortical single infarct size by occluding penetrating arteries. Our results provide important insight into stroke mechanism of MCA atherosclerosis.

DJ-1 Mediates the Delayed Cardioprotection of Hypoxic Preconditioning Through Activation of Nrf2 and Subsequent Upregulation of Antioxidative Enzymes.

We have recently shown that DJ-1 is implicated in the delayed cardioprotective effect of hypoxic preconditioning (HPC) against hypoxia/reoxygenation (H/R) injury as an endogenous protective protein. This study aims to further investigate the underlying mechanism by which DJ-1 mediates the delayed cardioprotection of HPC against H/R-induced oxidative stress. Using a well-characterized cellular model of HPC from rat heart-derived H9c2 cells, we found that HPC promoted nuclear factor erythroid 2-related factor 2 (Nrf2) and its cytoplasmic inhibitor Kelch-like ECH-associated protein-1 (Keap1) dissociation and resulted in increased nuclear translocation, antioxidant response element-binding, and transcriptional activity of Nrf2 24 hours after HPC, with subsequent upregulation of manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1), which provided delayed protection against H/R-induced oxidative stress in normal H9c2 cells. However, the aforementioned effects of HPC were abolished in DJ-1-knockdown H9c2 cells, which were restored by restoration of DJ-1 expression. Importantly, we showed that inhibition of the Nrf2 pathway in H9c2 cells mimicked the effects of DJ-1 knockdown and abolished HPC-derived induction of antioxidative enzymes (MnSOD and HO-1) and the delayed cardioprotection. In addition, inhibition of Nrf2 also reversed the effects of restored DJ-1 expression on induction of antioxidative enzymes and delayed cardioprotection by HPC in DJ-1-knockdown H9c2 cells. Taken together, this work revealed that activation of Nrf2 pathway and subsequent upregulation of antioxidative enzymes could be a critical mechanism by which DJ-1 mediates the delayed cardioprotection of HPC against H/R-induced oxidative stress in H9c2 cells.

Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for hypoxic preconditioning-mediated delayed cardioprotection.

It has been well demonstrated that hypoxic preconditioning (HPC) can attenuate hypoxia/reoxygenation (H/R)-induced oxidant stress and elicit delayed cardioprotection by upregulating the expression of multiple antioxidative enzymes such as heme oxygenase-1 (HO-1), manganese superoxide dismutase (MnSOD) and so on. However, the underlying mechanisms of HPC-induced upregulation of antioxidative enzymes are not fully understood. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an essential transcription factor that regulates expression of several antioxidant genes via binding to the antioxidant response element (ARE) and plays a crucial role in cellular defence against oxidative stress. Here, we wondered whether activation of the Nrf2-ARE pathway is responsible for the induction of antioxidative enzymes by HPC and contributes to the delayed cardioprotection of HPC. Cellular model of HPC from rat heart-derived H9c2 cells was induced 24 h prior to H/R. The results showed that HPC efficiently attenuated H/R-induced viability loss and lactate dehydrogenase leakage. In addition, HPC increased nuclear translocation and ARE binding of Nrf2 during the late phase, upregulated the expression of antioxidative enzymes (HO-1 and MnSOD), inhibited H/R-induced oxidant stress. However, when Nrf2 was specifically knocked down by siRNA, the induction of antioxidative enzymes by HPC was completely abolished and, as a result, the inhibitory effect of HPC on H/R-induced oxidant stress was reversed, and the delayed cardioprotection induced by HPC was also abolished. These results suggest that HPC upregulates antioxidative enzymes through activating the Nrf2-ARE pathway and confers delayed cardioprotection against H/R-induced oxidative stress.

Association Between Systemic Immune Inflammation Index and Diabetes Mellitus in the NHANES 2003-2018 Population.

Objects: This study aimed to explore the association between the Systemic Immune-Inflammation Index (SII) and diabetes mellitus (DM) and to assess its influence on the prognosis of the DM and no-DM groups. Methods: The study used data from the National Health and Nutrition Examination Survey; 9643 participants were included. Logistic regression analysis was employed to evaluate connections between SII and DM. We used the Cox proportional hazards model, restricted cubic spline, and Kaplan-Meier curve to analyze the relationship between SII and mortality. Results: The logistic regression analysis indicated that a significant increase in the likelihood of developing DM with higher SII levels (odds ratio, 1.31; 95% CI, 1.09-1.57, P = .003). The Cox model showed that there is a positive association between increased SII and higher all-cause mortality. The hazard ratios for SII were 1.53 (1.31, 1.78), 1.61 (1.31, 1.98), and 1.41 (1.12, 1.78) in the total, DM and non-DM groups, respectively. We observed a linear correlation between SII and all-cause mortality in DM participants, whereas non-DM participants and the total population showed a nonlinear correlation. Conclusion: Elevated SII levels are linked to an augmented risk of DM. Those with DM and higher SII levels demonstrated an elevated risk of mortality.

Treatment Effects of Acetazolamide on Ischemic Stroke: A Meta-Analysis and Systematic Review.

BACKGROUND: Ischemic stroke significantly contributes to high mortality and disability rates. Cerebral edema is a common consequence of ischemic stroke and can lead to aggravation or even death. Current treatment strategies are limited to decompressive craniectomy and the intravascular administration of hypertonic drugs, which have significant side effects. Acetazolamide (ACZ) plays a therapeutic role in cerebral edema by inhibiting aquaporin-4 (AQP-4) and improving collateral circulation. This study aimed to perform a meta-analysis and systematic review of ACZ therapy for ischemic stroke and evaluate its efficacy in animal models. METHODS: We searched Embase, Cochrane Library, PubMed, Web of Science, Chinese National Knowledge Infrastructure, Wanfang Database, and Chinese Biomedical Literature Database until April 2023 for studies on ACZ in ischemic animal models. The quality of the animal trials was assessed using the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Stroke. RESULTS: After screening 376 articles, only 5 studies were included. We found that ACZ reduced brain edema in cerebral ischemia 24 hours after onset (standard mean difference, -2.00; 95% confidence interval, -3.57 to -0.43, P = 0.01). ACZ also inhibited AQP-4 expression 24 hours after onset (standard mean difference-1.46; 95% confidence interval, -2.01 to -0.91, P < 0.001). Brain edema and AQP-4 expression also showed a declining trend on the third day after onset, although there were not enough data to support this. The effect of ACZ on brain ischemia in animals' neurological function is uncertain because of the limited research data. CONCLUSIONS: ACZ inhibited AQP-4 and alleviated brain edema after ischemic stroke in the early stages but seemingly could not improve the neurological function.

Pharmacokinetics and bioequivalence of two formulations of mifepristone tablets in healthy Chinese subjects under fasting conditions: a single-center, open, randomized, single-dose, double-period, two-sequence, crossover trial.

Objective: A bioequivalence (BE) study was performed to evaluate the pharmacokinetics, safety, and bioequivalence of two formulations of mifepristone tablets in healthy Chinese volunteers under fasting conditions. Methods: A single-center, open, randomized, single-dose, double-period, two-sequence, crossover study in healthy subjects under fasting conditions was performed. The subjects received a single fasting dose of mifepristone (10 mg/tablet) during the first and second periods, followed by a 14-day washout period, during which frequent pharmacokinetic (PK) sampling occurred up to 120 h. The pharmacokinetic parameters of mifepristone were calculated based on the plasma drug concentration-time profile. Primary endpoints were the BE of major pharmacokinetic parameters (AUC0-t and AUC0-∞) and the maximum observed serum concentration (Cmax). Secondary endpoints were safety parameters. Results: Forty subjects (34 male and 6 female subjects) were randomly assigned to treatment, with 39 completing the two-period study. After the single administration of mifepristone tablets (test preparation vs. reference preparation) under fasting conditions, the geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ were 98.76%, 104.28%, and 104.83%, respectively. The primary metabolites of mifepristone (RU42633 and RU42698),the GMRs of Cmax, AUC0-t, AUC0-∞ were 102.33% and 100.97%, 103.17% and 103.71%, 104.02% and 103.84%, respectively. Similarly, for another metabolite of mifepristone (RU42698), the GMRs of Cmax, AUC0-t, and AUC0-∞ were 100.97%, 103.71%, and 103.84%, respectively. All 90% confidence intervals (CIs) for the test/reference AUC ratio and Cmax ratio were within the acceptable range (80%-125%) for BE, which met the requirements of bioequivalence. No serious adverse events (AEs) occurred, and all AEs were classified as level 1 or 2. Conclusion: The PK parameters of mifepristone and its metabolites (RU42633 and RU42698) were measured using the (GMRs) of AUC0-t, AUC0-∞, and Cmax and were similar between the test and reference drug. The two formulations of mifepristone showed good tolerability and a similar safety profile. Clinical Trial Registration: chinadrugtrials.org.cn, identifier CTR20182413.

[Corrigendum] DJ­1 is involved in the peritoneal metastasis of gastric cancer through activation of the Akt signaling pathway.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that the western blot data shown for the MMP­9 experiment in Fig. 4 on p. 1493 were strikingly similar to the western blots shown for the total­Akt experiments in Fig. 6 on p. 1494. After having re­examined their original data files, the authors realized that Fig. 6 had been inadvertently assembled incorrectly. The revised version of Fig. 6, containing the correct data for the total­Akt experiments, is shown below. Note that the corrections made to this figure do not affect the overall conclusions reported in the paper. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this Corrigendum, and apologize to the readership for any inconvenience caused. [Oncology Reports 31: 1489­1497, 2014; DOI: 10.3892/or.2013.2961].

RNA interference-mediated secretory clusterin gene silencing inhibits proliferation and promotes apoptosis of human non-small cell lung cancer cells.

BACKGROUND/AIMS: Non-small cell lung cancer (NSCLC) constitutes around 85% of lung cancer cases and is frequently beyond surgical intervention. METHODOLOGY: Secretory clusterin (sCLU) is found in diverse types of human cancers and is unregulated in a variety of cell lines in response to stress, and enhances cancer cell survival. However, the roles of sCLU in NSCLC are still to be elucidated. RESULTS: Here we show that RNA interference (RNAi)-mediated sCLU gene silencing with short interference RNA (siRNA) strongly decreased the sCLU mRNA and protein levels, as well as suppressed cell proliferation and induced cell apoptosis. In addition, sCLU siRNA also blocked the PI3K/AKT signaling pathway, and decreased the AKT phosphorylation level, but no change was found in total AKT level. More importantly, PI3K/AKT signaling pathway inhibitor, LY294002, also reduced tumor cell proliferation, which is similar to the result with or without sCLU siRNA treatment. CONCLUSIONS: These results suggest that sCLU plays a positive role in NSCLC cell proliferation, which may be mediated by the PI3K/AKT signaling pathway. Our work in this study demonstrates RNAi-mediated sCLU gene silencing may provide a novel therapeutic strategy in the treatment of NSCLC.

Deficiency of filamin A in smooth muscle cells protects against hypoxia­mediated pulmonary hypertension in mice.

Filamin A (FLNA) is a high molecular weight cytoskeleton protein important for cell locomotion. A relationship between FLNA mutations and pulmonary arterial hypertension (PAH) has previously been reported; however, the detailed mechanism remains unclear. The present study aimed to explore the role of FLNA in vascular smooth muscle cells during the development of PAH. Smooth muscle cell (SMC)­specific FLNA­deficient mice were generated and the mice were then exposed to hypoxia for 28 days to build the mouse model of PAH. Human pulmonary arterial smooth muscle cells (PASMCs) were also cultured and transfected with FLNA small interfering RNA or overexpression plasmids to investigate the effects of FLNA on PASMC proliferation and migration. Notably, compared with control individuals, the expression levels of FLNA were increased in lung tissues from patients with PAH, and it was obviously expressed in the PASMCs of pulmonary arterioles. FLNA deficiency in SMCs attenuated hypoxia­induced pulmonary hypertension and pulmonary vascular remodeling. In vitro studies suggested that absence of FLNA impaired PASMC proliferation and migration, and produced lower levels of phosphorylated (p)­PAK­1 and RAC1 activity. However, FLNA overexpression promoted PASMC proliferation and migration, and increased the expression levels of p­PAK­1 and RAC1 activity. The present study highlights the role of FLNA in pulmonary vascular remodeling; therefore, it could serve as a potential target for the treatment of PAH.

Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases.

ATP-sensitive potassium channels (KATP channels) play pivotal roles in excitable cells and link cellular metabolism with membrane excitability. The action potential converts electricity into dynamics by ion channel-mediated ion exchange to generate systole, involved in every heartbeat. Activation of the KATP channel repolarizes the membrane potential and decreases early afterdepolarization (EAD)-mediated arrhythmias. KATP channels in cardiomyocytes have less function under physiological conditions but they open during severe and prolonged anoxia due to a reduced ATP/ADP ratio, lessening cellular excitability and thus preventing action potential generation and cell contraction. Small active molecules activate and enhance the opening of the KATP channel, which induces the repolarization of the membrane and decreases the occurrence of malignant arrhythmia. Accumulated evidence indicates that mutation of KATP channels deteriorates the regulatory roles in mutation-related diseases. However, patients with mutations in KATP channels still have no efficient treatment. Hence, in this study, we describe the role of KATP channels and subunits in angiocardiopathy, summarize the mutations of the KATP channels and the functional regulation of small active molecules in KATP channels, elucidate the potential mechanisms of mutant KATP channels and provide insight into clinical therapeutic strategies.

CircFOXM1 promotes the proliferation, migration, invasion, and glutaminolysis of glioblastoma by regulating the miR-577/E2F5 axis.

Circular RNA (circRNA) is a key regulator of tumor progression. However, the role of circFOXM1 in glioblastoma (GBM) progression is unclear. The aim of this study was to investigate the role of circFOXM1 in GBM progression. The expression levels of circFOXM1, miR-577, and E2F transcription factor 5 (E2F5) were examined by real-time quantitative polymerase chain reaction. Cell counting kit 8 assay, EdU staining, and transwell assay were used to detect cell proliferation, migration, and invasion. The levels of glutamine, glutamate, and α-ketoglutarate were determined to evaluate the glutaminolysis ability of cells. Protein expression was tested by Western blot analysis. Dual-luciferase reporter assay, RNA pull-down assay, and RNA immunoprecipitation assay were employed to verify the interaction between miR-577 and circFOXM1 or E2F5. Mice xenograft model for GBM was constructed to perform in vivo experiments. Our results showed that circFOXM1 was highly expressed in GBM tumor tissues and cells. Silencing of cir FOXM1 inhibited GBM cell proliferation, migration, invasion, glutaminolysis, as well as tumor growth. MiR-577 could be sponged by circFOXM1, and its inhibitor could reverse the suppressive effect of circFOXM1 downregulation on GBM progression. E2F5 was a target of miR-577, and the effect of its knockdown on GBM progression was consistent with that of circFOXM1 silencing. CircFOXM1 positively regulated E2F5 expression, while miR-577 negatively regulated E2F5 expression. In conclusion, our data confirmed that circFOXM1 could serve as a sponge of miR-577 to enhance the progression of GBM by targeting E2F5, which revealed that circFOXM1 might be a biomarker for GBM treatment.

Comprehensive analysis of the cuproptosis-related model to predict prognosis and indicate tumor immune infiltration in lung adenocarcinoma.

Background: Cuproptosis is a novel form of programmed cell death termed as Cu-dependent cytotoxicity. However, the roles of cuproptosis-associated genes (CAGs) in lung adenocarcinoma (LUAD) have not been explored comprehensively. Methods: We obtained CAGs and utilized consensus molecular clustering by "non-negative matrix factorization (NMF)" to stratify LUAD patients in TCGA (N = 511), GSE13213 (N = 117), and GSE31210 (N = 226) cohorts. The ssGSEA and CIBERSORT algorithms were used to evaluate the relative infiltration levels of immune cell types in tumor microenvironment (TME). The risk score based on CAGs was calculated to predict patients' survival outcomes. Results: We identified three cuproptosis-associated clusters with different clinicopathological characteristics. We found that the cuproptosis-associated cluster with the worst survival rates exhibited a high enrichment of activated CD4/8+ T cells. In addition, we found that the cuproptosis-associated risk score could be used for patients' prognosis prediction and provide new insights in immunotherapy of LUAD patients. Eventually, we constructed a nomogram-integrated cuproptosis-associated risk score with clinicopathological factors to predict overall survival in LUAD patients, with 1-, 3-, and 5-year area under curves (AUCs) being 0.771, 0.754, and 0.722, respectively, all of which were higher than those of the TNM stage. Conclusions: In this study, we uncovered the biological function of CAGs in the TME and its correlations with clinicopathological parameters and patients' prognosis in LUAD. These findings could provide new angles for immunotherapy of LUAD patients.

Interaction of acetic acid bacteria and lactic acid bacteria in multispecies solid-state fermentation of traditional Chinese cereal vinegar.

The microbial community plays an important role on the solid-state fermentation (SSF) of Chinese cereal vinegar, where acetic acid bacteria (AAB) and lactic acid bacteria (LAB) are the dominant bacteria. In this study, the top-down (in situ) and bottom-up (in vitro) approaches were employed to reveal the interaction of AAB and LAB in SSF of Shanxi aged vinegar (SAV). The results of high-throughput sequencing indicates that Acetobacter pasteurianus and Lactobacillus helveticus are the predominant species of AAB and LAB, respectively, and they showed negative interrelationship during the fermentation. A. pasteurianus CGMCC 3089 and L. helveticus CGMCC 12062, both of which were isolated from fermentation of SAV, showed no nutritional competition when they were co-cultured in vitro. However, the growth and metabolism of L. helveticus CGMCC 12062 were inhibited during SSF due to the presence of A. pasteurianus CGMCC 3089, indicating an amensalism phenomenon between these two species. The transcriptomic results shows that there are 831 differentially expressed genes (|log2 (Fold Change)| > 1 and, p ≤ 0.05) in L. helveticus CGMCC 12062 under co-culture condition comparing to its mono-culture, which are mainly classified into Gene Ontology classification of molecular function, biological process, and cell composition. Of those 831 differentially expressed genes, 202 genes are up-regulated and 629 genes are down-regulated. The down-regulated genes were enriched in KEGG pathways of sugar, amino acid, purine, and pyrimidine metabolism. The transcriptomic results for A. pasteurianus CGMCC 3089 under co-culture condition reveals 529 differentially expressed genes with 393 up-regulated and 136 down-regulated, and the genes within KEGG pathways of sugar, amino acid, purine, and pyrimidine metabolism are up-regulated. Results indicate an amensalism relationship in co-culture of A. pasteurianus and L. helveticus. Therefore, this work gives a whole insight on the interaction between the predominant species in SSF of cereal vinegar from nutrient utilization, endogenous factors inhibition and the regulation of gene transcription.

Nobiletin mitigates hepatocytes death, liver inflammation, and fibrosis in a murine model of NASH through modulating hepatic oxidative stress and mitochondrial dysfunction.

This study aimed to investigate the therapeutic effects of nobiletin (NOB) on nonalcoholic steatohepatitis (NASH) and liver fibrosis in mice and to elucidate its underlying molecular mechanisms. BALB/c mice were fed a normal chow diet or a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 8 wks and treated with NOB (50 mg/kg) or vehicle by daily intraperitoneally injection for the last 4 wks. In vitro, we used palmitate (PA) stimulated AML12 cells as the model of hepatocyte lipotoxicity to dissect the effect and molecular mechanisms of NOB' action. Our results exhibited that NOB dramatically reduced hepatic steatosis, lipid accumulation and hepatocyte apoptosis, and inhibited the infiltration of F4/80+ macrophages into the NASH livers. Furthermore, NOB limited liver fibrosis and hepatic stellate cells activation in NASH mice. In parallel, NOB alleviated hepatocytes apoptosis and lipid accumulation in PA-treated AML12 cells. Most importantly, these histological ameliorations in NASH and fibrosis in NOB-treated NASH mice were associated with improvement hepatic oxidative stress, lipid peroxidation product, mitochondrial respiratory chain complexes I and restored ATP production. Similarly, NOB attenuated PA-induced reactive oxygen species (ROS) generation and mitochondrial disfunction in cultured AML12 cells. Additionally, NOB diminished the expression of mitochondrial Ca2+ uniporter (MCU) both in NASH livers and in PA-treated AML12. Taken together, our results indicate that NOB mitigated NASH development and fibrosis through modulating hepatic oxidative stress and attenuating mitochondrial dysfunction. Therefore, NOB might be a novel and promising agent for treatment of NASH and liver fibrosis.

Transferrin receptor-mediated reactive oxygen species promotes ferroptosis of KGN cells via regulating NADPH oxidase 1/PTEN induced kinase 1/acyl-CoA synthetase long chain family member 4 signaling.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Abnormal ovarian folliculogenesis is the main factor responsible for PCOS. Iron metabolism plays a vital role in endocrine disorder. This study aimed to investigate the potentials of iron metabolism in PCOS and the underlying molecular mechanisms. Mice were injected with dehydroepiandrosterone (DHEA) to establish the PCOS model in-vivo. H & E staining was performed for histological analysis; qRT-PCR and western blot were employed to determine the mRNA and protein expressions. Immunofluorescence was used for mitochondrial staining. Cellular functions were detected using CCK-8 and PI staining assays. Ferric ammonium citrate (FAC) activates the transferrin receptor (TFRC), increases the iron content, and suppresses the cell viability of the human granulosa-like tumor cell line (KGN). However, TFRC knockdown suppressed ferroptosis of KGN cells. Iron uptake mediated the activation of NADPH oxidase 1 (NOX1) signaling, which induced the release of reactive oxygen species (ROS) and mitochondrial damage. Moreover, TFRC activated PTEN induced kinase 1 (PINK1) signaling and induced mitophagy; iron-uptake-induced upregulation of acyl-CoA synthetase long chain family member 4 (ACSL4) was required for mitophagy activation and glutathione peroxidase 4 (GPX4) degradation. Additionally, FAC increased iron uptake and suppressed the folliculogenesis in-vivo. In conclusion, TFRC increased the iron content, mediated the release of ROS, activated mitophagy, and induced lipid peroxidation, which further promoted the ferroptosis of KGN cells. Therefore, the inhibitory effects of TFRC/NOX1/PINK1/ACSL4 signaling on folliculogenesis can be a potential target for PCOS.[Figure: see text].