Endothelium Piezo1 deletion alleviates experimental varicose veins by attenuating perivenous inflammation.

Previous large-scale genetic studies have prioritized the causal genes piezo type mechanosensitive ion channel component 1 (PIEZO1) and castor zinc finger 1 (CASZ1) associated with varicose veins (VVs). This study aims to evaluate their roles in both clinical and experimental VVs. In this study, we investigated abundance of PIEZO1 and CASZ1 in both varicose and normal veins from the same patients. Yoda1 (a selective PIEZO1 agonist, 2.6 mg/kg/day) or vehicle was administered intraperitoneally for 3 weeks to evaluate the effect of PIEZO1 activation on experimental VVs. Subsequently, endothelial Piezo1 deletion mice (Piezo1iΔEC mice) were generated to explored the role of endothelial PIEZO1 on VVs. Laser speckle imaging, flow cytometry, cell tracing with Evans blue or rhodamine-6G, and histopathological staining were utilized to evaluate the pathophysiology of VVs. Our results showed that mRNA expression of PIEZO1, but not CASZ1, was abundant and increased in clinical VVs. The Piezo1tP1-td mice revealed endothelium-specific expression of PIEZO1 in mice veins. By establishing iliac vein ligation-induced VVs in mice, Yoda1 exacerbated experimental VVs with increased inflammatory cell infiltration. Subsequently, endothelial Piezo1 deletion (Piezo1iΔEC mice) alleviated experimental VVs and vascular remodeling by directly reducing vascular permeability and leukocyte-endothelium interactions compared to the control (Piezo1fl/fl mice). PIEZO1 is highly expressed in clinical VVs, meanwhile, activation or inhibition of PIEZO1 exerts a remarkable effect on experimental VVs. Furthermore, Piezo1 may constitute a potential therapeutic approach for the medical treatment of VVs.

NCME-Net: Nuclear cataract mask encoder network for intelligent grading using self-supervised learning from anterior segment photographs.

Cataracts are a leading cause of blindness worldwide, making accurate diagnosis and effective surgical planning critical. However, grading the severity of the lens nucleus is challenging because deep learning (DL) models pretrained using ImageNet perform poorly when applied directly to medical data due to the limited availability of labeled medical images and high interclass similarity. Self-supervised pretraining offers a solution by circumventing the need for cost-intensive data annotations and bridging domain disparities. In this study, to address the challenges of intelligent grading, we proposed a hybrid model called nuclear cataract mask encoder network (NCME-Net), which utilizes self-supervised pretraining for the four-class analysis of nuclear cataract severity. A total of 792 images of nuclear cataracts were categorized into the training set (533 images), the validation set (139 images), and the test set (100 images). NCME-Net achieved a diagnostic accuracy of 91.0 % on the test set, a 5.0 % improvement over the best-performing DL model (ResNet50). Experimental results demonstrate NCME-Net's ability to distinguish between cataract severities, particularly in scenarios with limited samples, making it a valuable tool for intelligently diagnosing cataracts. In addition, the effect of different self-supervised tasks on the model's ability to capture the intrinsic structure of the data was studied. Findings indicate that image restoration tasks significantly enhance semantic information extraction.

Cascade Electrocatalytic Reduction of Nitrate to Ammonia Using a Heterobimetallic Covalent Organic Framework Composed of Cu-Porphyrin and Co-Bipyridine.

The electrocatalytic reduction of nitrate (NO3-) to ammonia (NH3) not only offers an effective solution to environmental problems caused by the accumulation of NO3- but also provides a sustainable alternative to the Haber-Bosch process. However, the conversion of NO3- to NH3 is a complicated process involving multiple steps, leading to a low Faradaic efficiency (FE) for NH3 production. The structural designability of covalent organic frameworks (COFs) renders feasible and precise modulation at the molecular level, facilitating the incorporation of multiple well-defined catalytic sites with different reactivities into a cohesive entity. This promotes the efficiency of the overall reaction through the coupling of multistep reactions. Herein, heterobimetallic CuP-CoBpy was prepared by postmodification, involving the anchoring of cobalt ions to the CuP-Bpy structure. As a result of the cascade effect of the bimetallic sites, CuP-CoBpy achieved an outstanding NH3 yield of 13.9 mg h-1 mgcat.-1 with a high FE of 96.7% at -0.70 V versus the reversible hydrogen electrode and exhibited excellent stability during catalysis. A series of experimental and theoretical studies revealed that the CuP unit facilitates the conversion of NO3- to NO2-, while the CoBpy moiety significantly prompts the reduction of NO2- to NH3. This study demonstrates that tailoring the structural units for the construction of COFs based on each step in the multistep reaction can enhance both the catalytic activity and product selectivity of the overall process.

PI3Kγ promotes neutrophil extracellular trap formation by noncanonical pyroptosis in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is one of the most life-threatening cardiovascular diseases; however, effective drug treatments are still lacking. The formation of neutrophil extracellular traps (NETs) has been shown to be a crucial trigger of AAA, and identifying upstream regulatory targets is thus key to discovering therapeutic agents for AAA. We revealed that phosphoinositide-3-kinase γ (PI3Kγ) acted as an upstream regulatory molecule and that PI3Kγ inhibition reduced NET formation and aortic wall inflammation, thereby markedly ameliorating AAA. However, the mechanism of NET formation regulated by PI3Kγ remains unclear. In this study, we showed that PI3Kγ deficiency inactivated the noncanonical pyroptosis pathway, which suppressed downstream NET formation. In addition, PI3Kγ regulation of noncanonical pyroptosis was dependent on cyclic AMP/protein kinase A signaling. These results clarify the molecular mechanism and crosstalk between PI3Kγ and NETosis in the development of AAA, potentially facilitating the discovery of therapeutic options for AAA.

Fine tuning dual active sites in modulating cascade electrocatalytic nitrate reduction over covalent organic framework.

Conversion of NO3- to NH3 proceeds stepwise in natural system under two different enzymes involving intermediate NO2-. Artificial electro-driven NO3- reduction also faces the obstacle of low faradaic efficiency due to insufficient utilization of this intermediate. Herein, we demonstrate a bimetallic COF-based electrocatalyst for the cascade catalysis of NO3--to-NO2--to-NH3 for the first time. TpBpy-Cu2Co4 exhibits a significantly improved performance, with an enhancement factor of 1.4-2 compared to monometallic TpBpy-M. The NH3 yield rate achieves 25.6 mg h-1 mgcat.-1 at -0.55 V vs RHE over TpBpy-Cu2Co4, together with excellent faradaic efficiency (93.4 %). This achievement demonstrates cascade catalysis between Co and Cu units, and their distinct roles are investigated through electrochemical experiments and theory calculations. In electrocatalytic process, Cu site facilities *NO3-to-*NO3H step, while the Co site significantly decreases the energy barrier of *NHOH-to-*NH. The present work provides a valuable inspiration in designing efficient catalysts for cascade reaction.

A comprehensive review on oat milk: from oat nutrients and phytochemicals to its processing technologies, product features, and potential applications.

Plant-based milk alternatives have become increasingly desirable due to their sustainability and the increased consumer awareness of health. Among many varieties of emerging plant-based milk, the smooth texture and flavor of oat milk make it spread rapidly around the world. Furthermore, as a sustainable source of diet, oats can provide rich nutrients and phytochemicals. Issues on the stability, sensory properties, shelf life, and nutritional quality of oat milk have been highlighted in published studies. In this review, the processing techniques, quality improvement, and product features of oat milk are elaborated, and the potential applications of oat milk are summarized. Besides, the challenges and future perspectives of oat milk production in the future are discussed.

Increased plasma renin by vasodilators promotes the progression of abdominal aortic aneurysm.

Background: It is well-accepted that antihypertensive therapy is the cornerstone of treatment for abdominal aortic aneurysm (AAA) patients with hypertension. Direct-acting vasodilators were used in the treatment of hypertension by directly relaxing vascular smooth muscle but may have destructive effects on the aortic wall by activating the renin-angiotensin system axis. Their roles in AAA disease remain to be elucidated. In this study, we used hydralazine and minoxidil, two classical direct-acting vasodilators, to investigate their influence and potential mechanisms on AAA disease. Methods and results: In this study, we investigated the plasma renin level and plasma renin activity in AAA patients. Simultaneously, age and gender ratio-matched patients diagnosed with peripheral artery disease and varicose veins were selected as the control group using a ratio of 1:1:1. Our regression analysis suggested both the plasma renin level and plasma renin activity are positively associated with AAA development. In view of the well-established relationship between direct-acting vasodilators and increased plasma renin concentration, we established a porcine pancreatic elastase-infused AAA mouse model, followed by oral administration of hydralazine (250 mg/L) and minoxidil (120 mg/L) to investigate effects of direct-acting vasodilators on AAA disease. Our results suggested both hydralazine and minoxidil promoted the progression of AAA with increased aortic degeneration. Mechanistically, the vasodilators aggravated aortic inflammation by increased leukocyte infiltration and inflammatory cytokine secretion. Conclusion and relevance: The plasma renin level and plasma renin activity are positively associated with AAA development. Direct vasodilators aggravated experimental AAA progression, which raised cautionary concerns about their applications in AAA disease.

Comparison of efficiency and safety of open surgery, hybrid surgery and endovascular repair for the treatment of thoracoabdominal aneurysms: a systemic review and network meta-analysis.

Objective: The objective of this study was to perform a network meta-analysis (NMA) to assess the efficacy and safety of three different surgical interventions- open surgical repair (OSR), hybrid surgical repair (HSR), and endovascular repair (EVAR)- for the treatment of thoracoabdominal aortic aneurysms (TAAAs). Methods: Electronic repositories like PubMed, Embase, Web of Science, Scopus, ScienceDirect, the Cochrane library, Clinical trial, and China National Knowledge Infrastructure (CNKI) were systematically searched to identify studies that compared the efficacy of OSR, HSR, and EVAR with endografts for the treatment of TAAAs until December 24th, 2022. Random-effects and fixed-effects models were employed to analyze the data gathered in a network meta-analysis. The study's primary outcomes of interest encompassed in-hospital mortality, long-term survival rate, and postoperative complications. Results: Eleven comparative studies meet inclusion criterias. There were 2,222 patients in OSR, 1,574 patients in EVAR and 537 patients in HSR. EVAR has lower one-month mortality than OSR (RR: 0.31; 95% CI: 0.17-0.70) and HSR (RR: 0.37; 95% CI: 0.22-0.71), and lower incident rate of renal complications than HSR (RR: 0.20; 95% CI: 0.08-0.43) and OSR (RR: 0.34; 95% CI: 0.16-0.65). Nonetheless, there was no noteworthy discrepancy identified in the long-term survival rates of these procedures. Conclusions: As compared with OSR, HSR, and EVAR, EVER has lower one-month mortality, and lower incident rates of complications. Systematic review registration: PROSPERO (CRD42022313829).

Effects of Spermidine on Gut Microbiota Modulation in Experimental Abdominal Aortic Aneurysm Mice.

Accumulating evidence in recent years has demonstrated the important role of gut microbiota in maintaining cardiovascular function. However, their functions in abdominal aortic aneurysm (AAA) are largely unexplored. In this study, we established a porcine pancreatic elastase-infused experimental AAA mouse model and explored gut microbiota modulation using 16S rDNA sequencing. Here, we found that a significant alteration to gut microbiota composition and function occurred in AAA. The functional change in the gut microbiome revealed dysregulated biosynthesis metabolism and transport of spermidine in AAA. Furthermore, exogenous spermidine was administrated via drinking water and attenuated the progression of experimental AAA disease, which supports our recent study that spermidine alleviates systemic inflammation and AAA. These effects were associated with remitted gut microbiota dysbiosis and metabolism in AAA progression as demonstrated by 16S rDNA gene analysis. In addition, several bacterial florae, such as Bacteroides, Parabacteroides and Prevotella, were identified to be associated with the progression of AAA. Our results uncovered altered gut microbial profiles in AAA and highlighted the potential therapeutic use of spermidine in the treatment of gut microbiota dysbiosis and AAA.

Evaluation of ropivacaine combined with dexmedetomidine versus ropivacaine alone for epidural anesthesia: A meta-analysis.

BACKGROUND: Ropivacaine is considered the most commonly used for epidural anesthesia. We compared the efficiency and safety of ropivacaine alone (R group) and ropivacaine combined with dexmedetomidine (RD group). METHOD: PubMed, the Cochrane Library, Google Scholar, Ovid Medline, the Web of Science, Scopus, Embase, and ScienceDirect were searched. We considered sensory and motor block, duration of anesthesia, time to rescue, hemodynamics, and adverse effects as the primary endpoints. RESULTS: Eleven randomized controlled trials were included with 337 patients in the R group and 336 patients in the RD group. The RD group had a shorter time to onset of sensory (mean difference [MD]: 3.97 [1.90-6.04] minutes; P = .0002) and motor (MD: 2.43 [0.70-4.16] minutes; P = .006) block and a longer duration of anesthesia (MD: -164.17 [-294.43 to -33.91]; P = .01) than the R group. Comparison of the time to rescue between the groups showed no significant difference (MD: -119.01[-254.47-16.46] minutes; P = 0.09). The R group showed more stable hemodynamics than the RD group in heart rate and arterial pressure at 10 minutes. The R group had a lower incidence of bradycardia and a higher incidence of shivering than the RD group. CONCLUSION: RD may be a more suitable choice for epidural anesthesia with better anesthetic outcomes than R alone. However, the safety of the combination must be carefully assessed.

A meta-analysis comparing stereotactic body radiotherapy vs conventional radiotherapy in inoperable stage I non-small cell lung cancer.

BACKGROUND: Stereotactic body radiotherapy (SBRT) superseded conventional radiotherapy (CRT) for the treatment of patients with inoperable early stage non-small cell lung cancer (NSCLC) over a decade ago. However, the direct comparisons of the outcomes of SBRT and CRT remain controversial. This meta-analysis was performed to compare the survival and safety of SBRT and CRT in patients with inoperable stage I NSCLC. METHODS: We systematically searched the Cochrane Library, Embase, PubMed, Web of Science, Ovid MEDLINE, ScienceDirect, Scopus and Google Scholar for relevant articles. Overall survival (OS), progression-free survival (PFS), lung cancer-specific survival (LCSS), local control rate (LCR) and adverse effects (AEs) were the primary outcomes. RESULTS: We identified 11,110 articles, 17 of which were eventually included in this study; these 17 articles had 17,973 patients (SBRT: 7395; CRT: 10,578). Compared to CRT for the treatment of inoperable stage I NSCLC, SBRT had superior survival in terms of OS (hazard ratio [HR]: 0.66, 95% confidence interval [CI]: 0.62-0.70, P < .00001), LCSS (HR: 0.42 [0.35-0.50], P < .00001), and PFS (HR: 0.34 [0.25-0.48], P < .00001). The 4-year OS rate (OSR); 4-year LCSS rate (LCSSR); 3-year local control rate (LCR); 5-year PFS rate (PFSR) with SBRT were all higher than those with CRT. With regard to all-grade AEs, the SBRT group had a significantly lower rate of dyspnea, esophagitis and radiation pneumonitis; no significant difference was found in grade 3-5 AEs (risk ratio [RR]: 0.68 [0.30-1.53], P = .35). CONCLUSIONS: With better survival and a lower rate of dyspnea, esophagitis and radiation pneumonitis than CRT, SBRT appears to be more suitable for patients with inoperable stage I NSCLC.

Comparison of transcatheter arterial chemoembolization combined with radiofrequency ablation or microwave ablation for the treatment of unresectable hepatocellular carcinoma: a systemic review and meta-analysis.

Background: Transcatheter arterial chemoembolization (TACE), radiofrequency ablation (RFA), and microwave ablation (MWA) are regarded as effective therapies for treating unresectable hepatocellular carcinoma (HCC). We conducted this study to compare the efficiency and safety of TACE combined with RFA (TR group) or MWA (TM group).Method: PubMed, the Cochrane Library, Ovid Medline, Web of Science, Scopus, Embase, ScienceDirect, and Google Scholar were searched. The primary endpoints were overall survival (OS), progression-free survival (PFS), response rates, and complications.Result: Eight cohort studies and one randomized controlled trial were included. The TM group had better OS (Hazard ratio [HR]: 1.55; 95% confidence interval [CI]: 1.09-2.21, p = 0.01) and a better 2- and 3-year OS rate, 24-month PFS rate (Risk ratio [RR]: 0.67; 95% CI: 0.46-0.96, p = 0.03), and complete response rate (RR: 0.87; 95% CI: 0.79-0.96, p = 0.003) than the TR group. Furthermore, the TM and TR groups did not show significant differences in PFS, the disease control rate or complications. The advantage of TM was mainly reflected in younger patients (50-60 years old) compared with patients aged 60-70 years, as well as in patients with larger tumors (≥3 cm) compared with patients with tumors <3 cm. Moreover, patients treated with conventional TACE (cTACE) in the TM group showed longer OS, while patients treated with drug-eluting bead transarterial chemoembolization (DEB-TACE) in the TR group showed a higher overall response rate.Conclusion: TM seems to be a more effective therapy than TR for unresectable HCC, with better survival and similar safety.

Association of magnesium intake with type 2 diabetes and total stroke: an updated systematic review and meta-analysis.

OBJECTIVE: The detailed associations between type 2 diabetes (T2D) and total stroke and magnesium intake as well as the dose-response trend should be updated in a timely manner. DESIGN: Systematic review and meta-analyses. DATA SOURCES: PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov were rigorously searched from inception to 15 March 2019. ELIGIBILITY CRITERIA: Prospective cohort studies investigating these two diseases were included. DATA SYNTHESIS: Relative risk (RR) and 95% CI in random effects models as well as absolute risk (AR) were pooled to calculate the risk of T2D and stroke. Methodological quality was assessed by the Newcastle-Ottawa Scale. RESULTS: Forty-one studies involving 53 cohorts were included. The magnitude of the risk was significantly reduced by 22% for T2D (RR 0.78 (95% CI 0.75 to 0.81); p<0.001; AR reduction 0.120%), 11% for total stroke (RR 0.89 (95% CI 0.83 to 0.94); p<0.001; AR reduction 0.281%) and 12% for ischaemic stroke (RR 0.88 (95% CI 0.81 to 0.95); p=0.001; AR reduction 0.246%) when comparing the highest magnesium intake to the lowest. The inverse association still existed when studies on T2D were adjusted for cereal fibre (RR 0.79; p<0.001) and those on total stroke were adjusted for calcium (RR 0.89; p=0.040). Subgroup analyses suggested that the risk for total and ischaemic stroke was significantly decreased in females, participants with ≥25 mg/m2 body mass index and those with ≥12-year follow-up; the reduced risk in Asians was not as notable as that in North American and European populations. CONCLUSIONS: Magnesium intake has significantly inverse associations with T2D and total stroke in a dose-dependent manner. Feasible magnesium-rich dietary patterns may be highly beneficial for specific populations and could be highlighted in the primary T2D and total stroke prevention strategies disseminated to the public. PROSPERO REGISTRATION NUMBER: CRD42018092690.

Proton-pump inhibitor and amoxicillin-based triple therapy containing clarithromycin versus metronidazole for Helicobacter pylori: A meta-analysis.

BACKGROUND: Helicobacter pylori (H. pylori) infection is one of the important risk factors of gastric related diseases and antibiotic therapy has become an effective treatment. At present, proton-pump inhibitor and amoxicillin-based triple therapy, including clarithromycin (PAC) and metronidazole (PAM), are two commonly used first-line therapies for H. pylori infection, which has a high incidence and possibly poor prognosis worldwide. METHODS: A systematic literature review was performed using the databases PubMed, the Cochrane Library, Ovid Medline, Science Direct, Embase, Scopus and Web of Science. Only randomized clinical trials with full texts published were included. RESULTS: Eighteen studies involving 3264 patients were included. The pooled risk ratios (RR) between the PAC and PAM groups were comparable in the intention-to-treat (ITT) eradication rates (71.0% versus 75.2%, RR = 0.96, p = 0.38) and per-protocol (PP) eradication rates (79.6% versus 80.1%, RR = 1.02, p = 0.65). PAM is highly effective in clarithromycin-resistant cases (70.4% versus 48.2%, RR = 0.65, p = 0.002) and that PAC showed significant efficacy in metronidazole-resistant cases (87.3% versus 58.6%, RR = 1.43, p = 0.0006). In subgroup analysis, when using low-dose PPI, the PAM group showed greater efficacy than the PAC group. Furthermore, we found that PAM showed higher effectiveness in the studies published in recent years, especially for people over 60 years old (RR = 0.80, 95% CI: 0.71-0.89, p < 0.001). CONCLUSION: In general, both PAC and PAM regimens were effective and comparable in eradicating H. pylori. However, the PAM regimen showed greater efficacy than the PAC regimen in recent years, especially for people over 60 years old.

Three-dimensional vs 2-dimensional laparoscopic gastrectomy for gastric cancer: A systematic review and meta-analysis.

BACKGROUND: Both 3-dimensional (3D) laparoscopic gastrectomy (LG) and 2-dimensional (2D) LG are commonly used for gastric cancer (GC). To investigate their safety and efficacy, we performed this meta-analysis. METHODS: PubMed, The Cochrane Library, Science Direct, Embase, Scopus, and Web of Science were systematically searched to identify relevant studies. The total number of lymph node dissections (LNDs), operation time, blood loss, postoperative hospital stay, postoperative complications, and hospitalization cost were extracted as major endpoints. RESULTS: Among 904 articles that were enrolled, 9 studies were included for analysis. The 3D group was observed to have shorter operation times [95% confidence interval (CI): -0.54 to -0.06; P = .01] and less blood loss (95% CI: -0.41 to -0.19; P < .00001) than the 2D group. Compared with the 2D group, slightly higher hospitalization cost was found in the 3D group (95% CI: 0.06-0.37; P = .008). However, the outcomes among the total LNDs, postoperative hospital stay, and postoperative complications were similar. Subgroup analysis suggested that the 3D LG group had more 11p (2.22 ±â€Š1.80 vs 1.47 ±â€Š1.99, P = .019) and 8a (2.52 ±â€Š1.88 vs 1.48 ±â€Š1.43, P = .001) LNDs compared to the 2D LG group. CONCLUSIONS: 3D LG has advantages for GC, with shorter operation times, less blood loss, and possibly more LNDs. However, the cost was slightly higher than that of 2D LG.

Stereotactic Body Radiotherapy Combined with Transcatheter Arterial Chemoembolization versus Stereotactic Body Radiotherapy Alone as the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Meta-Analysis and Systematic Review.

BACKGROUND: The superiority of stereotactic body radiotherapy (SBRT) combined with transcatheter arterial chemoembolization (TACE) compared to SBRT alone as the first-line therapy for unresectable hepatocellular carcinoma (HCC) remains unclear. We conducted this meta-analysis to compare the efficiency and safety of SBRT combined with TACE (ST group) and SBRT alone (SA group). METHODS: We searched PubMed, Ovid Medline, Web of Science, Scopus, The Cochrane Library, ScienceDirect, EMBASE, Google Scholar, and CNKI (China National Knowledge Infrastructure) for related studies. We analyzed overall survival (OS), local control survival (LCS), progression-free survival (PFS), the response rate and adverse effects (AEs) between the 2 groups. RESULTS: Ten articles were included, with a total of 980 patients. The results showed that the ST (SBRT + TACE) group had a longer OS (95% CIs 0.60-0.85, p = 0.0002), a higher 5-year OS rate (95% CI 1.01-2.04, p = 0.04), a higher rate of complete response (95% CI 1.08-1.90, p = 0.01), and a higher disease control rate (95% CI 1.02-1.16, p = 0.02) than the SA (SBRT alone) group. No significant difference was found in LCS, PFS and total AEs of all grades and grades 3-5 AEs between the 2 groups. In the subgroup analysis, the patients with HCC + PVTT or treated with SBRT followed by TACE in the ST group had the same OS as those in the SA group, and the patients in the ST group had a higher incidence rate of leukopenia and fever than those in the SA group. CONCLUSION: SBRT + TACE appears to be more effective than SBRT alone in treating unresectable HCC. However, its higher incidence rate of leukopenia and fever need to be monitored.

Noncoding transcribed ultraconserved region (T-UCR) UC.48+ is a novel regulator of high-fat diet induced myocardial ischemia/reperfusion injury.

Increasing evidence has suggested high-fat diet (HFD) is an independent risk factor for myocardial ischemia/reperfusion (MI/R) injury. Long noncoding RNAs (lncRNAs) recently attracted much attraction in the study of MI/R injury. However, the functional questions of specific lncRNAs in HFD-induced MI/R injury have not been well elucidated. Uc.48+ is a lncRNA from a transcribed ultraconserved region (T-UCR) of human, mouse, and rat genomes. Here, we explored the aggravating role of uc.48+and identified purinergic P2X7 receptor (P2X7R) as a downstream regulator of uc.48+ in HFD-induced MI/R vulnerability. We demonstrated uc.48+ expression was upregulated, accompanied by the corresponding upregulation of P2X7R in HFD I/R myocardium and HFD-induced MI/R vulnerability. Overexpression of uc.48+enhanced, whereas silencing of uc.48 + decreased the expression of P2X7R, cardiomyocyte apoptosis, and MI/R injury. The functional relevance of uc.48+ regulated P2X7R expression and the subsequent NF-κB signaling to promote cardiomyocyte apoptosis was supported by inhibition of P2X7R with its specific antagonist (A438079) as well as the inhibitor of NF-κB signaling (pyrrolidine dithiocarbamate, PDTC) in H9c2 hypoxia/reoxygenation (H/R) cells transfected with pcDNA3.0-uc.48 + plasmid, and RNA immunoprecipitation (RIP) suggested uc.48+ could interact with transcription factor Sp1. Importantly, Sp1 inhibitor (mithramycin, MIT) was found to suppress uc.48+ -induced P2X7R expression and the NF-κB signaling and cardiomyocyte apoptosis. Our findings provide a potential novel mechanism through which uc.48+ boosts cardiomyocyte apoptosis and MI/R vulnerability to HFD. Thus, uc.48+ is a novel regulator of HFD-induced MI/R injury; targeting uc.48+ may be a novel therapeutic approach of MI/R vulnerability to HFD.

Genetic interaction of purinergic P2X7 receptor and ER-α polymorphisms in susceptibility to osteoporosis in Chinese postmenopausal women.

Osteoporosis (OP) is an increasing public health problem worldwide. Genetic factors are considered to be major contributors to the pathogenesis of OP. The aim of this study was to investigate the association of the purinergic P2X7 receptor (P2X7R) and estrogen receptor-α (ER-α) genes with OP risk, and the effect of the possible interaction between the two genes on predisposition to OP in Chinese postmenopausal women. A total of 596 subjects, including 350 OP patients and 246 controls, were recruited in this case-control study. Five functional single-nucleotide polymorphisms (SNPs) in the P2X7R gene (rs2393799, rs7958311, rs1718119, rs2230911, rs3751143) and two ER-α PvuII and XbaI polymorphisms were genotyped and analyzed. Single-gene variant analysis showed that the carriers of the CC genotype of P2X7R rs3751143 revealed an increased OP risk. Haplotype rs1718119G-rs2230911G-rs3751143C also appeared to be a significant 'risk' haplotype with OP. For the ER-α gene, no evidence of significant association of PvuII or XbaI polymorphism with OP risk was found. Moreover, there was a significant gene-gene interaction between P2X7R rs3751143 and ER-α PvuII; the cross-validation consistency was 10/10 and the testing accuracy was 0.5818 (P = 0.0107). A 1.67-fold-increased risk for OP was detected in individuals carrying the genotypes of AC or CC of rs3751143 and Pp or PP of PvuII compared to subjects with AA of rs3751143 and pp of PvuII. Our findings suggest an important association of the P2X7R rs3751143CC genotype and the rs1718119G-rs2230911G-rs3751143C haplotype with an increased OP risk. Also, the P2X7R rs3751143 and ER-α PvuII two-locus interaction confers a significantly high susceptibility to OP in Chinese postmenopausal women.

Purinergic P2X7 receptor functional genetic polymorphisms are associated with the susceptibility to obesity in Chinese postmenopausal women.

OBJECTIVE: We conducted a case-control study to investigate the associations of functional single-nucleotide polymorphisms in the purinergic P2X7 receptor (P2X7R) gene (rs2393799, rs7958311, rs1718119, rs2230911, and rs3751143) with obesity and overweight in a population of Chinese postmenopausal women. METHODS: Our study included 180 obese women, 179 overweight women, and 204 controls. All participants were genotyped at the P2X7R rs2393799, rs7958311, rs1718119, rs2230911, and rs3751143 loci via allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism procedures. The relationships between P2X7R genetic polymorphisms and their associated haplotypes with obesity (body mass index [BMI] ≥30 kg/m] and overweight (25 kg/m ≤ BMI < 30 kg/m) were evaluated. RESULTS: Our results showed that P2X7R rs2230911G and rs1718119A were associated with an increased risk of obesity; in particular, both carriers of the rs2230911G allele and GG/(CG + GG) genotypes (G vs C, P < 0.001, odds ratio [OR] 2.87, 95% confidence interval [CI] 1.98-4.16; GG vs CC, P < 0.001, OR 8.76, 95% CI 3.29-23.35; CG + GG vs CC, P < 0.001, OR 2.54, 95% CI 1.63-3.95) and carriers of the rs17181191A allele and GA/(GA + AA) genotypes (A vs G, P < 0.001, OR 2.97, 95% CI 1.86-4.74; GA vs GG, P = 0.001, OR 2.72, 95% CI 1.55-4.79; GA + AA vs GG, P < 0.001, OR 3.05, 95% CI 1.79-5.19) were at a higher risk of obesity. No association with obesity or overweight was observed for the other three P2X7R polymorphisms (rs2393799, rs7958311, and rs3751143). Haplotype analysis indicated that P2X7R rs1718119A-rs2230911G-rs3751143C appeared to be a significant risk haplotype with obesity (P = 0.0005, OR 2.37, 95% CI 1.45-3.90). CONCLUSIONS: P2X7R functional genetic polymorphisms and their estimated haplotypes are associated with obesity in Chinese postmenopausal women.