BACKGROUND:Precisely map and ablate the aortorenal ganglion (ARG) using noninvasive ultrasound technology to evaluate therapeutic effects and mechanisms in hypertension and related organ involvement. METHODS:A noninvasive dual-frequency ultrasound with a 3-dimensional targeting system was utilized to precisely map and ablate the ARG in a hypertensive canine model (2-kidney, 1-clip). Blood pressure changes from ultrasound stimulation served as a real-time evaluation metric, leading to an ultrasound stimulation-ablation-re-stimulation-supplementary ablation protocol for comprehensive ablation. Follow-up assessments at 1, 3, and 6 months post-ablation included evaluations of blood pressure, ventricular fibrosis and hypertrophy, cardiac function, and both local and systemic sympathetic nerve activity. RESULTS:One month postultrasound-targeted ARG ablation, there was a significant reduction in systolic blood pressure (∆ = -8.67±2.07 mm Hg; P<0.05), with further decreases at 3 months (∆ = -14.17±3.49 mm Hg; P<0.001) and 6 months (∆ = -24.83±4.49 mm Hg; P<0.001). Histological and echocardiographic assessments indicated improvements in ventricular fibrosis and hypertrophy, along with an enhanced left ventricular ejection fraction. Moreover, a reduction in sympathetic nerve activity was observed in the body, heart, and kidneys. In addition, aortic and adrenal tissue integrity, as well as normal liver and kidney functions, with no significant differences between the hypertension model and ARG ablation groups were observed. CONCLUSIONS:Ultrasound-targeted ablation of the ARG significantly reduces blood pressure, suppresses sympathetic nerve activity in the systemic, cardiac, and renal regions, and alleviates hypertension-induced ventricular remodeling, offering a promising therapeutic strategy for hypertension and related cardiovascular diseases.

Deep vein thrombosis (DVT) treatment remains challenging due to the limited efficacy of conventional thrombolytic agents and the short half-lives of anticoagulants. In this study, we develop a low-molecular-weight heparin (LMWH)-functionalized, ultrasound-responsive nanodroplet with tunable size, designate as LMWH-LA@PFP. Our approach incorporates LMWH itself as an intrinsic carrier scaffold, linked to linoleic acid (LA) for self-assembly and perfluoropentane (PFP) encapsulation. This design integrates three synergistic therapeutic functions including targeted delivery, ultrasound-triggered thrombolysis, and sustained anticoagulation. After intravenous administration, LMWH selectively binds to activated platelets accumulating at the thrombus site. Ultrasound irradiation triggers PFP vaporization, driving nanodroplet expansion from nanoscale dimensions to microbubbles that subsequently collapse, mechanically disrupting the fibrin-rich thrombus matrix while enhancing drug penetration depth. Importantly, LMWH-LA fragmentations reassemble into secondary nanoparticles, thereby prolonging the duration of anticoagulant activity. The nanodroplets demonstrate robust efficacy across acute, chronic, and pregnancy-associated DVT models without evidence of fetal toxicity.

Atherosclerosis and vessel wall trauma induce vascular smooth muscle cell (VSMC) phenotypic modulation, leading to plaque cap growth and postintervention restenosis. Our systems biology approach identified RNA binding protein, mRNA processing factor (RBPMS) as a conserved, VSMC- specific gene associated with VSMC modulation in atherosclerosis. RBPMS gene expression positively correlates with VSMC contractile markers in human and murine atherosclerotic arteries as well as in two vascular injury models during the postinjury intimal hyperplasia phase. RBPMS promotes contractile VSMC differentiation, reduces plaque cap development in high- fat diet- fed apolipoprotein E- null (ApoE-/-) murine atherosclerotic arteries, and inhibits intimal hyperplasia. Mechanistically, the RBPMS protein interacts with the myocardin (MYOCD) pre-mRNA and enhances MYOCD_v3/MYOCD_v1 transcript balance through alternative exon 2a splicing. RBPMS promotes the VSMC contractile phenotype and reduces their fibroproliferative activity in a MYOCD_v3a- dependent manner. RBPMS enhances Myocd_ v3/Myocd_v1 transcript balance in both atherosclerotic and injured vessels. RBPMS may inhibit VSMC- driven plaque cap development and intervention- induced restenosis.

20% acute pancreatitis (AP) develops into severe AP (SAP), a global health crisis, with an increased mortality rate to 30%-50%. Mitochondrial damage and immune disorders are direct factors, which exacerbate the occurrence and progression of AP. So far, mitochondrial and immunity injury in SAP remains largely elusive, with no established treatment options available. Immunomodulation is a promising approach to treat pancreatitis. Herein, we proved that Tuftsin (TN), a vital endogenous immunomodulator, can inhibit SAP, while it is limited by extremely short biological half-life, low bioavailability, and the inconvenience of administration. Nano platform is the positive choice. Interestingly, we found that the activated P2X7 signaling was closely associated with the enhanced pancreatic inflammation via damaging mitochondrial function in SAP. Herein, we engineered a nanoplatform containing a Se-Se bond responsive for ROS to deliver TN, namely, DSPE-Se-Se-MPEG@TN (DSSM@TN), contributing to increases in TN's half-life and bioavailability. We synthesized TN-loaded ROS-responsive DSPE-Se-Se- MPEG@TN liposomes (DSSM@TN NPs) via a one-step emulsification method, which exhibited good biosecurity, high stability, suitable size, favorable ROS responsiveness and biocompatibility, as well as excellent capability for releasing TN during oxidative stress and inflammation environment. Moreover, the Se-Se bond with ROS-responsive ability was first proved to play a vital role for TN-loaded liposomes to enhance its anti-inflammation and antioxidant abilities via targeting damaged mitochondria during SAP progression. Mechanistically, DSSM@TN targeting damaged pancreas simultaneously inhibits mitochondrial dysfunction and inflammation in vivo and vitro via mitochondrial P2X7 signaling-impaired Nrf2/HO-1 signaling-inhibited PINK1/PARKIN pathway. Consequently, such a ROS-responsive immunotherapy nanomedicine targeted mitochondria holds great potential in facilitating substantial clinical progress in SAP treatment.

Osteopontin (OPN), highly expressed in foam cells, serves as a hallmark of atherosclerotic plaques and a potential target for site-specific drug delivery. In this study, we developed OPN-targeted liposomes (OPN LIP) co-loaded with curcumin and perfluoro-n-pentane (PFP) to enhance therapeutic efficacy against atherosclerosis. The liposomes exhibited uniform particle size, colloidal stability, favorable biocompatibility, and minimal cytotoxicity. In vitro experiments demonstrated efficient and time-dependent cellular uptake by ox-LDL-stimulated RAW264.7 foam cells. Upon exposure to low-intensity focused ultrasound (LIFU), the nanocarriers underwent acoustic cavitation-induced rupture, leading to rapid curcumin release and significant induction of apoptosis. OPN LIP treatment notably reduced IL-1 alpha and TNF-alpha levels and aggravated apoptosis in foam cells. Transcriptomic analysis revealed modulation of inflammatory and apoptotic pathways, including TLR, NF-kappa B, and Mapk3 signaling. These findings highlight the potential of OPN LIP as an ultrasound-responsive, targeted nanoplatform capable of suppressing inflammation and foam cell viability, providing a promising approach for the treatment of atherosclerosis through combined physical and pharmacological strategies.

The obesity paradox is common among older adults at risk for various diseases. Although this paradox has also been observed in the association between obesity and osteoporosis, the available evidence remains controversial. This study aimed to investigate the association between obesity and OP risk in an older population. A cross-sectional and prospective study was conducted using data from 177,734 participants in the UK Biobank. The association of body mass index (BMI), waist circumference (WC), and fat percentage with BMD was examined using Spearman correlation analysis with baseline BMD data. Cox proportional hazards regression analysis was used to investigate the association between obesity and OP risk. Restricted cubic spline (RCS) were used to assess the nonlinear associations of BMI, WC, and fat percentage with OP. Baseline cross-sectional analyses revealed a significant positive association between BMI, WC, and fat percentage with BMD in women, whereas this association was very weak in men. A total of 8,998 OP patients were identified during a median follow-up period of 13.7 years. Cox analyses showed that obesity as defined by BMI, WC, and fat percentage was associated with a 33

Objective This study aimed to investigate the influencing factors of self-neglect behavior (SNB) in elderly patients with coronary heart disease (CHD) and provide a basis for clinical intervention. Methods A retrospective analysis was conducted on 400 elderly patients with coronary heart disease who visited our hospital from January 2023 and June 2025.Based on the scores of the Elder Self-Neglect Scale (SESN), the patients were divided into a Low Self-Neglect (LSN) group (n = 179) and a High Self-Neglect (HSN) group (n = 221). Data were collected on the patients' general information, disease-related assessments, psychological evaluations, physical status, cognitive function assessments, and quality of life evaluations. Pearson and Spearman correlation analyses were used to explore the relationship between self-neglect behaviors (SNB) and various factors, while univariate logistic regression analysis was performed to identify the influencing factors of SNB. Results There were no significant differences in age, gender, and education level between the two groups (P > 0.05). However, there was a significant difference in the New York Heart Association (NYHA) functional classification between the two groups ( P < 0.05). The LSN group had significantly higher scores in psychological resilience, optimism, and self-efficacy than the HSN group ( P < 0.05). The LSN group had significantly lower anxiety scores than the HSN group ( P < 0.05). The LSN group also had significantly higher scores in the Fatigue Scale-14, Timed Up and Go (TUG) test, Montreal Cognitive Assessment (MoCA), overall well-being, and social support compared to the HSN group ( P < 0.05). Correlation and logistic regression analyses showed that NYHA functional classification, psychological resilience, optimism, self-efficacy, fatigue, frailty, cognitive function, overall well-being, and social support were independent influencing factors of SNB in elderly patients with CHD. Conclusion SNB in elderly patients with CHD is influenced by multiple factors. Clinical healthcare providers should pay attention to patients’ psychological resilience, anxiety, social support, and cognitive function, and formulate individualized health management plans to improve their health status and quality of life. Clinical trial number not applicable.

Early identification and treatment of ventricular remodeling (VR) are crucial for delaying the progression of heart failure after myocardial infarction. This study aims to develop a dual-responsive phase-shift molecular probe loaded with a cholecystokinin octapeptide (CCK-8) and oxygen, which will provide a new integrated scheme for the assessment and treatment of VR. Biocompatible phospholipid shells were utilized to encapsulate CCK-8 and perfluoropentane (PFP), an efficient oxygen carrier. Surface modification involves reactive oxygen species (ROS)-responsive thioketal (TK) bonds and anti-ICAM-1 antibodies to create CCK-8 and oxygen-carrying phase-shift nanoparticles (PFP-O2-CCK8@lipid/TK-ICAM1 Ab nanoparticles, POC@L/TI NPs). These nanoparticles were designed for coronary artery endothelial cell targeting and responsiveness to dual stimuli. The results demonstrated that delayed myocardial contrast-enhanced echocardiography (DMCE) provided dynamic VR monitoring, with contrast intensity values showing a negative correlation with cardiac function parameter changes. POC@L/TI NPs significantly improved cardiac structural and functional parameters in rats with myocardial infarction and reperfusion and delayed the progression of heart failure by increasing tissue oxygenation, reducing the inflammatory response, inhibiting fibrotic scar formation and preventing myocardial cell apoptosis. This innovative approach combines supersaturated oxygen therapy with the multitarget therapeutic effect of CCK-8 and dynamic monitoring via DMCE to offer an integrated strategy for early detection and comprehensive VR treatment.

Energy metabolism modulation emerges as a highly regarded strategy for tumor therapy. However, the efficacy of targeting energy metabolism in tumor cells remains unsatisfactory due to the alternate energy production pathways by switching between mitochondrial respiration and glycolysis. In addition, tumor cells can hijack mitochondria from peripheral immune cells to maintain their energy metabolism as an extra respiratory pathway. In this study, a CD44 receptor-targeted hyaluronic acid energy metabolism nanoblocker is developed to achieve bidirectional blockade of basal respiration in tumor cells with the loaded mitochondrial oxidative phosphorylation (OXPHOS) inhibitor nebivolol hydrochloride, and the glycolysis inhibitor 3-bromopyruvate. Furthermore, combined intraperitoneal injection of L-778123 hydrochloride inhibits mitochondrial transfer, thus blocking the extra respiratory pathway of tumor cells and the depletion of cytotoxic T lymphocytes. This emerging strategy, which involves depleting tumor cell energy through inhibition of basal respiration (OXPHOS/glycolysis) and extra respiration, while synergistically enhancing effector immune cells to maintain systemic anti-tumor immune effects, demonstrates high efficacy and safety in both in vitro and in vivo experiments. It provides a conceptual paradigm shift in nanomedicine-mediated energy metabolism-based tumor therapy.

Achieving full eradication of residual tumors post photothermal therapy (PTT) hinges on the immune system's activation and response. Nevertheless, the resultant local inflammation attracts a significant influx of aberrant immune cells and fibroblasts, such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), following tumor PTT. This phenomenon exacerbates immune evasion and the persistence of residual tumor cells, culminating in tumor recurrence and advancement. To tackle this challenge, a combined therapeutic approach utilizing multifunctional ICG-SB@Lip-ZA nanosystem has been introduced. Indocyanine green (ICG) as a photothermal-transducer ablated tumor cells, zoledronic acid (ZA) depletes TAMs recruited by the inflammatory tumor microenvironment (mostly M2-like phenotype), SB-505124 affects CAFs proliferation in the tumor microenvironment (TME) by inhibiting the transforming growth factor-β （TGF-β） pathway, thereby removing physical barriers to T cell infiltration. In a breast cancer model, these immunomodulatory nanoliposomes markedly decrease the population of M2-like TAMs in the TME, eliminate physical barriers hindering T cell infiltration, reshape the inflammatory immune-suppressive tumor microenvironment, eventually leading to a rate of tumor eradication of 94%. This multifunctional ICG-SB@Lip-ZA nanosystem (including photothermal conversion, TAM depletion, and TGF-β pathway blockade) offers a promising strategy for mitigating the deteriorating tumor microenvironment following PTT and presents a more efficient approach for clinical photothermal-immune combination therapy.

Osteoarthritis (OA), a prevalent chronic disease among the elderly, presents a complex pathogenesis and currently lacks effective treatment. Traditional observational studies are time-consuming, labor-intensive, susceptible to confounding factors, and cannot establish causal relationships. Mendelian randomization (MR) analysis, leveraging genetic variation to assess causal associations between exposures and outcomes, offers a cost-effective and efficient alternative. Over the past decade, large-scale genome-wide association studies have identified numerous genetic variants linked to OA risk factors, facilitating MR study design. In this review, we systematically identified 52 MR studies meeting specific criteria and evaluated their quality, exploring the impact of lifestyle, nutrition, comorbidities, circulating metabolites, plasma proteins, and other health factors on OA risk. We discuss the results and potential mechanisms of MR findings, addressing conflicting evidence based on existing literature and our prior research. With the ongoing expansion of genome-wide association data, we anticipate MR’s role in future OA studies to broaden, particularly in drug development research using targeted MR approaches. We thus aim for this paper to offer valuable insights for researchers and clinicians in related fields.

BACKGROUND:Antiviral post-exposure prophylaxis with neuraminidase inhibitors can reduce the incidence of influenza and the risk of symptomatic influenza, but the efficacy of the other classes of antiviral remains unclear. To support an update of WHO influenza guidelines, this systematic review and network meta-analysis evaluated antiviral drugs for post-exposure prophylaxis of influenza. METHODS:We systematically searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos, and ClinicalTrials.gov for randomised controlled trials published up to Sept 20, 2023 that evaluated the efficacy and safety of antivirals compared with another antiviral or placebo or standard care for prevention of influenza. Pairs of reviewers independently screened studies, extracted data, and assessed the risk of bias. We performed network meta-analyses with frequentist random effects model and assessed the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The outcomes of interest were symptomatic or asymptomatic infection, admission to hospital, all-cause mortality, adverse events related to antivirals, and serious adverse events. This study is registered with PROSPERO, CRD42023466450. FINDINGS:Of 11 845 records identified by our search, 33 trials of six antivirals (zanamivir, oseltamivir, laninamivir, baloxavir, amantadine, and rimantadine) that enrolled 19 096 individuals (mean age 6·75-81·15 years) were included in this systematic review and network meta-analysis. Most of the studies were rated as having a low risk of bias. Zanamivir, oseltamivir, laninamivir, and baloxavir probably achieve important reductions in symptomatic influenza in individuals at high risk of severe disease (zanamivir: risk ratio 0·35, 95% CI 0·25-0·50; oseltamivir: 0·40, 0·26-0·62; laninamivir: 0·43, 0·30-0·63; baloxavir: 0·43, 0·23-0·79; moderate certainty) when given promptly (eg, within 48 h) after exposure to seasonal influenza. These antivirals probably do not achieve important reductions in symptomatic influenza in individuals at low risk of severe disease when given promptly after exposure to seasonal influenza (moderate certainty). Zanamivir, oseltamivir, laninamivir, and baloxavir might achieve important reductions in symptomatic zoonotic influenza in individuals exposed to novel influenza A viruses associated with severe disease in infected humans when given promptly after exposure (low certainty). Oseltamivir, laninamivir, baloxavir, and amantadine probably decrease the risk of all influenza (symptomatic and asymptomatic infection; moderate certainty). Zanamivir, oseltamivir, laninamivir, and baloxavir probably have little or no effect on prevention of asymptomatic influenza virus infection or all-cause mortality (high or moderate certainty). Oseltamivir probably has little or no effect on admission to hospital (moderate certainty). All six antivirals do not significantly increase the incidence of drug-related adverse events or serious adverse events, although the certainty of evidence varies. INTERPRETATION:Post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir, or baloxavir probably decreases the risk of symptomatic seasonal influenza in individuals at high risk for severe disease after exposure to seasonal influenza viruses. Post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir, or baloxavir might reduce the risk of symptomatic zoonotic influenza after exposure to novel influenza A viruses associated with severe disease in infected humans. FUNDING:World Health Organization.

The biomacromolecule silk fibroin (SF) may be constructed to promote biomimetic nucleation and nanostructures of inorganic nanomaterials, offering it a promising candidate for use in various biomimetic applications. We combined SF-NPs and ZIF-8-NPs to fabricate new drug vehicles that effectively release the drug. SF nanoparticles (SF-NPs) were assembled into quercetin (QCT), a myocardial drug added to fabricate QSF-NPs. By acting as a template for the ZIF-8 nucleation onto the surface, the QSF-NPs fabricated core-shell-structured nanocomposites (named QSF@Z-NCs) with ZIF-8 as the core-shell and the QSF-NPs. The biocompatibility analysis using the MTT assay revealed that the developed QCT, SF-NPs, and QSF@Z-NCs are not harmful to cardiac myoblast (H9C2) cells. The in vivo model demonstrated that H9C2 cells encouraged cardiomyocyte fibre regeneration in myocardial infarction rats. We fabricated a brand-new technique using H9C2 cells and QSF@Z-NCs that might encourage the healing processes in myocardial ischemia cells. This study's results demonstrate that it successfully treats myocardial injury.

Heterogeneity of antibody responses has been reported in SARS‐CoV‐2 vaccination recipients with underlying diseases. We investigated the impact of the presence of comorbidities on the humoral response to SARS‐CoV‐2 vaccination in patients with chronic disease (PWCD) and assessed the effect of the number of comorbidities on the humoral response to vaccination. In this study, neutralizing antibodies (NAbs) and IgG antibodies against the receptor‐binding domain (RBD‐IgG) were monitored following a full‐course vaccination. In total, 1400 PWCD (82.7%, inactivated vaccines; 17.3%, subunit recombinant vaccine) and 245 healthy controls (65.7% inactivated vaccines, 34.3% subunit recombinant vaccine) vaccinated with inactivated or subunit recombinant SARS‐CoV‐2 vaccines, were included. The seroconversion and antibody levels of the NAbs and RBD‐IgG were different in the PWCD group compared with those in the control group. Chronic hepatitis B (odds ratio [OR]: 0.65; 95% confidence interval [CI]: 0.46–0.93), cancer (OR: 0.65; 95% CI: 0.42–0.99), and diabetes (OR: 0.50; 95% CI: 0.28–0.89) were associated with lower seroconversion of NAbs. Chronic kidney disease (OR: 0.29; 95% CI: 0.11–0.76), cancer (OR: 0.38; 95% CI: 0.23–0.62), and diabetes (OR: 0.37; 95% CI: 0.20–0.69) were associated with lower seroconversion of RBD‐IgG. Only the presence of autoimmune disease showed significantly lower NAbs and RBD‐IgG titers. Patients with most types of chronic diseases showed similar responses to the controls, but humoral responses were still significantly associated with the presence of ≥2 coexisting diseases. Our study suggested that humoral responses following SARS‐CoV‐2 vaccination are impaired in patients with certain chronic diseases.

Background: Stroke accelerates inflammatory monocyte recruitment to the endothelium and consequent atheroprogression via high-mobility group box 1-receptor for advanced glycation end products signaling. Notably, Hmgb1 interacts with multiple tolllike receptors (TLRs) and promotes TLR4-mediated proinflammatory myeloid cell activation. Therefore, TLR-associated mechanism(s) within monocytes may play a role in Hmgb1-driven poststroke atheroprogression. Objectives: We aimed to elucidate the TLR-associated mechanism(s) within monocytes that contribute to stroke-induced exacerbation of atherosclerotic disease. Methods: A weighted gene coexpression network analysis on the whole blood transcriptomes of stroke model mice identified hexokinase 2 (HK2) as a key gene associated with TLR signaling in ischemic stroke. We conducted a cross-sectional analysis of monocyte HK2 levels in patients with ischemic stroke patients. We performed in vitro and in vivo studies using high-cholesterol diet-fed myeloid-specific Hk2-null ApoE-/- (ApoE-/-;Hk2 & UDelta;M & phi;) mice and ApoE-/-;Hk2fl/fl controls. Results: We found markedly higher monocyte HK2 levels in patients with ischemic stroke patients during the acute and subacute phases poststroke. Similarly, stroke model mice displayed a profound increase in monocyte Hk2 levels. Using aortas and aortic valve samples collected from high-cholesterol diet-fed ApoE-/-;Hk2 & UDelta;M & phi; mice and ApoE-/-;Hk2fl/fl controls, we found that stroke-induced monocyte Hk2 upregulation enhanced poststroke atheroprogression and inflammatory monocyte recruitment to the endothelium. Stroke-induced monocyte Hk2 upregulation induced inflammatory monocyte activation, systemic inflammation, and atheroprogression via Il-1 & beta;. Mechanistically, we demonstrated that stroke-induced monocyte Hk2 upregulation was dependent upon Hmgb1-driven p38-dependent hypoxia-inducible factor-1 & alpha; stabilization. Conclusion: Stroke-induced monocyte Hk2 upregulation is a key mechanism underlying poststroke vascular inflammation and atheroprogression.

Atherosclerosis is the leading cause of mortality globally. RBC–platelet hybrid membrane-coated nanoparticles ([RBC-P]NPs), which biologically mimic platelets in vivo, display evidence of anti-atherosclerotic activity. The efficacy of a targeted RBC–platelet hybrid membrane-coated nanoparticles ([RBC-P]NP)-based approach was investigated as a primary preventive measure against atherosclerosis. A ligand-receptor interactome analysis conducted with circulating platelets and monocytes derived from CAD patients and healthy controls identified CXCL8-CXCR2 as a key platelet ligand-monocyte receptor dyad in CAD patients. Based on this analysis, a novel anti-CXCR2 [RBC-P]NP that specifically binds to CXCR2 and blocks the interaction between CXCL8 and CXCR2 was engineered and characterized. Administering anti-CXCR2 [RBC-P]NPs to Western diet-fed Ldlr−/− mice led to diminished plaque size, necrosis, and intraplaque macrophage accumulation relative to control [RBC-P]NPs or vehicle. Importantly, anti-CXCR2 [RBC-P]NPs demonstrated no adverse bleeding/hemorrhagic effects. A series of in vitro experiments was conducted to characterize anti-CXCR2 [RBC-P]NP's mechanism of action in plaque macrophages. Mechanistically, anti-CXCR2 [RBC-P]NPs inhibited p38α (Mapk14)-mediated, pro-inflammatory M1 skewing and corrected efferocytosis in plaque macrophages. This targeted [RBC-P]NP-based approach, in which the cardioprotective effects of anti-CXCR2 [RBC-P]NP therapy overweighs its bleeding/hemorrhagic risks, could potentially be used to proactively manage atherosclerotic progression in at-risk populations.

Objectives Ultrasound (US) technology has recently made advances that have led to the development of modalities including elastography and contrast-enhanced ultrasound. The use of different US modalities in combination may increase the accuracy of PCa diagnosis. This study aims to assess the diagnostic accuracy of multiparametric ultrasound (mpUS) in the PCa diagnosis. Methods Through September 2023, we searched through Cochrane CENTRAL, PubMed, Embase, Scopus, Web of Science, ClinicalTrial.gov, and Google Scholar for relevant studies. We used standard methods recommended for meta-analyses of diagnostic evaluation. We plot the SROC curve, which stands for summary receiver operating characteristic. To determine how confounding factors affected the results, meta-regression analysis was used. Results Finally, 1004 patients from 8 studies that were included in this research were examined. The diagnostic odds ratio for PCa was 20 (95% confidence interval (CI), 8–49) and the pooled estimates of mpUS for diagnosis were as follows: sensitivity, 0.88 (95% CI, 0.81–0.93); specificity, 0.72 (95% CI, 0.59–0.83); positive predictive value, 0.75 (95% CI, 0.63–0.87); and negative predictive value, 0.82 (95% CI, 0.71–0.93). The area under the SROC curve was 0.89 (95% CI, 0.86–0.92). There was a significant heterogeneity among the studies ( p < 0.01). According to meta-regression, both the sensitivity and specificity of mpUS in the diagnosis of clinically significant PCa (csPCa) were inferior to any PCa. Conclusion The diagnostic accuracy of mpUS in the diagnosis of PCa is moderate, but the accuracy in the diagnosis of csPCa is significantly lower than any PCa. More relevant research is needed in the future. Critical relevance statement This study provides urologists and sonographers with useful data by summarizing the accuracy of multiparametric ultrasound in the detection of prostate cancer. Key points • Recent studies focused on the role of multiparametric ultrasound in the diagnosis of prostate cancer. • This meta-analysis revealed that multiparametric ultrasound has moderate diagnostic accuracy for prostate cancer. • The diagnostic accuracy of multiparametric ultrasound in the diagnosis of clinically significant prostate cancer is significantly lower than any prostate cancer. Graphical Abstract

Abstract Background: Hepatic ischemia-reperfusion injury (IRI) is a major unavoidable clinical problem often occurs during various liver surgery and transplantation. D-Pinitol, a cyclic polyol, showed its hepatoprotective efficacy in clinical and experimental settings. Aim: To determine the potential and possible mechanism of pinitol against ER stress regulation-mediated hepatic IRI in experimental rats.Materials and methods: Male SD rats were pre-treated with pinitol for 21 days and then subjected to 60 min. of partial hepatic ischemia followed by 24 h. of reperfusion. Various parameters were evaluated, including liver function tests, inflammatory release, endoplasmic reticulum (ER) stress, apoptosis, and structural modifications.Results: Pre-treatment with pinitol (10 and 20 mg/kg) effectively protected IRI-induced hepatic damage reflected by attenuation of elevated AST, ALT, oxidative stress (SOD, GSH, MDA and NO) and pro-inflammatory cytokines (TNF-α and IL’s) release. Interestingly, western blot and ELISA analysis suggested that pinitol significantly down-regulated the expression of ER stress apoptotic markers, namely GRP78, CHOP, AFT-4, AFT-6α, XBP-1, and caspase-3, 9 and 12. Additionally, pinitol pre-treatment improved mitochondrial function and phosphorylation of ERK1/2 and P38. Pinitol markedly protected IRI-induced hepatic apoptosis determined by flow cytometry. The hepatic histological and ultrastructural aberration induced by IRI was effectively protected by pinitol. Conclusion: Findings of the present investigation suggested that pinitol offered protection against ER stress-mediated phosphorylation of ERK1/2 and p38, thereby inhibited AFT4-CHOP/GRP78 signaling response and induction of caspase-3 induced hepatocellular apoptosis during hepatic ischemia-reperfusion insults.

Objective To investigate the effects and mechanisms of ghrelin on plaque stability and endothelial funtion in ApoE-/- mice after myocardial infarction. Methods The ApoE-/- mice were divided into control group, double model group and ghrelin-treated group. All ApoE-/- mice were fed with a high-fat diet for 12 weeks to induce atherosclerotic vulnerable plaques. The atherosclerotic vulnerable plaque model was the control group.At the 8th week of this study, the double model group and the ghrelin group were subjected to acute myocardial infarction model(AMI). After modeling of AMI, the ghrelin group was administered with ghrelin (100 μg/kg,bid) until the end of the 12th week. Body weight and blood lipids were detected. Left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were recorded by echocardiography; NO level was measured by Griess method; the percentage of aortic sinus plaque area was evaluated by HE microscopy. The plaque content of lipid and collagen was observed by Oil Red 0 and Sirius red staining; The distribution of macrophages and smooth muscle cells in plaques were determined by RAM-11 and α-actin immunohistochemical staining and microscopy; And then the vulnerability index was calculated; Myocardial infarct size was measured by Masson staining and microscopy; The vascular endothelial growth factor (VEGF) was detected by quantitative real-time PCR and Western blot. Results Compared with the control group, the level of LVEF and LVFS and NO2-/NO3- concentration in the double model group were all decreased(P＜0.05), and the expression of VEGF was increased(P＜0.05), significantly. However, the ghrelin group had significantly reduced plasma TG level and also the myocardial infarct size(P＜0.05), LVEF, LVFS, NO2-/NO3- level, the expression of VEGF, and the plaque content of collagen and smooth muscle cells were all increased(P＜0.05), and reduced the percentage of aortic sinus plaque area, the distribution of lipid and macrophages(P＜0.05), and the vulnerability index as compared with the double model group(P＜0.05). Conclusions 1)Ghrelin may improve the endothelial function and improve heart function in ApoE-/- mice after myocardial infarction. 2)Ghrelin may stabilize vulnerable plaque and reduce the occurrence of reinfarction.

Toll-like receptor 2 and 4 (TLR2, TLR4) signaling is implicated in atherosclerotic plaque formation. The two-stage master regulator Virtual Inference of Protein-activity by Enriched Regulon (VIPER) analysis of macrophage TLR2 and TLR4 signature genes integrated with coexpression network genes derived from 371 patient-derived carotid specimens identifies activated RNA polymerase II transcriptional coactivator p15 (SUB1/Sub1, PC4) as a master regulon in the atherogenic TLR response. It is found that TLR2 and TLR4 signaling is proinflammatory and proatherosclerotic in chow-fed apolipoprotein E-deficient (ApoE-/- ) mice. Through transgenic myeloid-specific Sub1 knockout in ApoE-/- mice, it is discovered that these proatherosclerotic effects of TLR2 and TLR4 signaling are mediated by Sub1. Sub1 knockout in macrophages enhances anti-inflammatory M2 macrophage polarization and cholesterol efflux. Irradiated low density lipoprotein receptor-deficient (Ldlr-/- ) mice transplanted with Sub1-/- murine bone marrow display reduced atherosclerosis. Promoter analysis reveals Sub1-dependent activation of interferon regulatory factor 1 (Irf1) transcription in a casein kinase 2 (Ck2)-dependent manner, and Sub1-knockout macrophages display decreased Irf1 expression. Artificial Irf1 overexpression in Sub1-knockout macrophages enhances proinflammatory M1 skewing and lowers cholesterol clearance. In conclusion, the TLR master regulon Sub1, and its downstream effect on the transcription factor Irf1, promotes a proinflammatory M1 macrophage phenotype and enhances atherosclerotic burden in vivo.