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Abstract The palladium anchored to BisPyP@bilayer-SiO2@NMP organic–inorganic hybrid was employed as an effective and recyclable organometallic catalyst in Suzuki and Stille C–C coupling reactions. The structure of this magnetic nanocatalyst was determined using various techniques such as SEM, TEM, FT-IR, EDS, ICP-OES, VSM, N2 adsorption–desorption isotherms, XRD, and TGA. In both of the mentioned coupling paths, the yields of the products were very favorable and ranged from 90 to 98%. Also, they had significant features compared to previous reports, such as very short reaction time (5–15 and 7–20 min respectively in the Suzuki and Stille reactions), easy work-up, broad substrate scope, ease of separation of the catalyst using a magnet, suitable reproducibility of the catalyst in 6 runs, heterogeneous nature of the catalyst and not washing it during consecutive runs with confirmation of hot filtration and ICP-OES methods.

The biomass filtrate containing various metabolites of endophytic bacterial strain, Brevibacillus brevis PI-5 was used as a biocatalyst for reducing and stabilizing copper oxide nanoparticles (CuO-NPs). UV-Vis spectroscopy, Fourier transform infrared, transmission electron microscopy, scanning electron microscopy with energy-dispersive X-ray (SEM-EDX), X-ray diffraction, and X-ray photoelectron spectroscopy were used for CuO-NPs characterization. A spherical, well-dispersed, and crystallographic structure with sizes of 2–28 nm was formed. The SEM-EDX confirmed the presence of Cu and O with weight percentages of 27.62% and 48.88%, respectively. The biological activities including antifungal, anticancer, and larvicidal of synthesized CuO-NPs were assessed using the fungal radial growth inhibition, MTT assay method, and mortality percentages, respectively. The obtained data showed that the CuO-NPs exhibit high activity in a dose-dependent manner. The growth of three phytopathogenic fungi, Fusarium oxysporum, Alternaria alternata, and Aspergillus niger was decreased by percentages of 64.5% ± 4.1%, 62.9% ± 0.3%, and 70.2% ± 2.3%, respectively at 300 µg·mL–1. Also, various clinical Candida spp. were successfully inhibited with varied zones of inhibition and minimum inhibitory concentration values in ranges of 6.25–50 µg·mL–1. The in vitro cytotoxicity exhibits target-orientation to breast cancer cells (T47D) at low concentration compared to normal cells (HFB4) with IC50 values of 122.3 ± 5.4 and 229.9 ± 5.7 μg·mL–1, respectively. The mortality percentages of I, II, III, and IV instar larvae of Culex antennatus were 60% ± 1.4%, 43.1% ± 1.1%, 36.2% ± 1%, and 32.1% ± 0.9%, at 10 mg·L–1 and increased to 86.9% ± 2.1%, 68.1% ± 1.7%, 64.4% ± 1.9%, and 53.1% ± 1.4% at 50 mg·L–1, respectively.

a series of benzodioxole compounds were synthesized and evaluated for their cytotoxic activity against cervical (Hela), colorectal (Caco-2), and liver (Hep3B) cancer cell lines. Compounds 5a, 5b, 6a, 6b, 7a and 7b showed very weak or negligible anticancer activity with IC50 3.94-9.12 mM. On the contrary, carboxamide containing compounds 2a and 2b showed anticancer activity. Both 2a and 2b reduced Hep3B secretions of α-fetoprotein (α-FP) to 1625.8 ng/ml and 2340 ng/ml, respectively, compared to 2519.17 ng/ml in untreated cells. The results also showed that compound 2a has potent anticancer activity against Hep3B cancer cell line. Furthermore, in cell cycle analysis, compound 2a induced arrest in the G2-M phase in value of 8.07% that was very close to the activity of doxorubicin (7.4%). These results indicate that compound 2a has a potent and promising antitumor activity. However, benzodiazepine derivatives (7a and 7b) showed moderate antioxidant activity with IC50 values of 39.85 and 79.95 μM, respectively compared with the potent antioxidant agent Trolox (IC50 = 7.72 μM).

The purpose of this meta-analysis was to determine the effect of bariatric surgery on circulating PAI-1. The meta-analysis was provided by comprehensive meta-analysis (CMA) V4 software. Meta-analysis of 33 studies showed a significant decrease in circulating PAI-1 after bariatric surgery (p < 0.001). A significant reduction was observed for two types of surgery) (p < 0.001 for LSG and p < 0.001 for RYGB). Furthermore, there was a significant change in circulating PAI-1 based on the follow-up duration (p < 0.001 for follow-up < 12 months and p < 0.001 for follow-up ≥ 12). We showed that bariatric surgery changed PAI-1 level significantly and changes in BMI after surgery were not related to PAI-1 alteration. Furthermore, this result was consistent based on follow-up duration and type of surgery., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Bariatric surgery is an approved treatment for obesity that consistently improves metabolic syndrome, with well-documented beneficial effects on dyslipidemia, cardiovascular risk, nonalcoholic fatty liver disease and glucose homeostasis. In this study, we determined the differential expression genes in three periods after bariatric surgery: short-term (4-months), medium-term (1- and 2-years), and long-term (5-years) periods. Two microarray profiles were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by comparing the expression of adipose tissue genes before surgery compared to short, medium and long-term periods following surgery. Shared DEGs for the medium-term were evaluated by comparing the DEGs for both 1 and 2 years. 165, 65, and 59 DEGs were identified in short-medium-long periods. The protein-protein interactions were analyzed by STRING. A co-expression network was constructed by mapping the DEGs onto the GeneMANIA plugin of Cytoscape. Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) and wikipathway analysis were done for each group of DEGs. Interleukin-8 receptor activity, complement receptor activity and opsonin receptor activity/N-formyl peptide receptor activity in GO Function enrichment and cellular response to interleukin-8, positive regulation of hippocampal neuron apoptotic process, and positive regulation of hippocampal neuron apoptotic process in GO Process showed the best scores in short-, medium-, and long-term periods, respectively. Eight genes, including CCL2 (Chemokine ligand 2), CXCR4 (CXC motif chemokine receptor 4), EGR2 (Early Growth Response 2), FPR1 (Formyl Peptide Receptor 1), IL6 (interleukin-6), RGS2 (regulator of gene protein signaling2), SELPLG (Selectin P Ligand), and THBS1 (Thrombospondin 1) were identified as shared DEGs in the three periods after surgery. Importantly, results of DAVID database analysis showed 7, 6, 4, and 4 of these genes have roles in immune/ cancer/cardiovascular diseases, type 2 diabetes, myocardial infarct, and atherosclerosis, respectively., (© 2024. The Author(s).)

Although the novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily manifests as severe respiratory distress, its impact on the cardiovascular system is also notable. Studies reveal that COVID-19 patients often suffer from certain vascular diseases, partly attributed to increased proliferation or altered phenotype of vascular smooth muscle cells (VSMCs). Although the association between COVID-19 and VSMCs is recognized, the precise mechanism underlying SARS-CoV-2's influence on VSMC phenotype remains largely under-reviewed. In this context, while there is a consistent body of literature dissecting the effect of COVID-19 on the cardiovascular system, few reports delve into the potential role of VSMC switching in the pathophysiology associated with COVID-19 and the molecular mechanisms involved therein. This review dissects and critiques the link between COVID-19 and VSMCs, with particular attention to pathways involving cholesterol, calcium, and phosphate. These pathways underpin the interaction between the virus and VSMCs. Such interaction promotes VSMC proliferation, and eventually potentiates vascular calcification as well as worsens prognosis in patients with COVID-19., (© 2024 The Author(s). Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Citrus limon var. pompia Camarda var. nova , commonly known as pompia, is a distinctive citrus ecotype native to Sardinia, notable for its unique botanical, phytochemical, and potential health benefits. It holds cultural significance as a traditional food product of Sardinia, recognized by the Italian Ministry of Agricultural Food and Forestry Policies. This comprehensive review examines pompia's traditional uses, taxonomic classification, pomological characteristics, phytochemical profile, and potential health benefits. Pompia phytochemical analyses reveal a rich composition of flavonoids and terpenoids, with notable concentrations of limonene, myrcene, and various oxygenated monoterpenes. Pompia essential oils are primarily extracted from its peel and leaves. Peel essential oils exhibit a high concentration of the monoterpene limonene (82%) and significantly lower quantities of myrcene (1.8%), geranial (1.7%), geraniol (1.5%), and neral (1.4%). In its rind extract, flavanones such as naringin (23.77 µg/mg), neoeriocitrin (46.53 µg/mg), and neohesperidin (44.57 µg/mg) have been found, along with gallic acid (128.3 µg/mg) and quinic acid (219.67 µg/mg). The main compounds detected in the essential oils from pompia leaves are oxygenated monoterpenes (53.5%), with limonene (28.64%), α-terpineol (41.18%), geranial (24.44%), (E)-β-ocimene (10.5%), linalool (0.56%), and neryl acetate (13.56%) being particularly prominent. In pompia juice, the presence of phenolic compounds has been discovered, with a composition more similar to lemon juice than orange juice. The primary flavonoid identified in pompia juice is chrysoeriol-6,8-di-C-glucoside (stellarin-2) (109.2 mg/L), which has not been found in other citrus juices. The compound rhoifolin-4-glucoside (17.5 mg/L) is unique to pompia juice, whereas its aglycone, rhoifolin, is found in lemon juice. Other flavonoids identified in pompia juice include diosmetin 6,8-C-diglucoside (54.5 mg/L) and isorhamnetin 3-O-rutinoside (79.4 mg/L). These findings support the potential of pompia in developing nutraceuticals and natural health products, further confirmed by its compounds' antioxidant, anti-inflammatory and antibacterial properties. Future research should focus on optimizing extraction methods, conducting clinical trials to evaluate efficacy and safety, and exploring sustainable cultivation practices. The potential applications of pompia extracts in food preservation, functional foods, and cosmetic formulations also warrant further investigation. Addressing these areas could significantly enhance pompia's contribution to natural medicine, food science, and biotechnology.

Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Pancreatic cancer is a leading cause of cancer-related mortality worldwide with increasing global incidence. We previously reported the anticancer effect of Rhus coriaria ethanolic extract (RCE) in triple negative breast and colon cancer cells. Herein, we investigated the anticancer effect of RCE on human pancreatic cancer cells. Methods: Cell viability was measured using Cell Titer-Glo and staining of viable and dead cells based on differential permeability to two DNA binding dyes. Cell cycle distribution and annexin V staining was carried out in Muse cell analyzer. Protein level was determined by Western blot. Tumor growth was assessed by in ovo chick embryo chorioallantoic membrane assay. Results: We found that RCE significantly inhibited the viability and colony growth of pancreatic cancer cells (Panc-1, Mia-PaCa-2, S2-013, AsPC-1). The antiproliferative effects of RCE in pancreatic cancer cells (Panc-1 and Mia-PaCa-2) were mediated through induction of G1 cell cycle arrest, Beclin-1-independent autophagy, and apoptosis. RCE activated both the extrinsic and intrinsic pathways of apoptosis and regulated the Bax/Bcl-2 apoptotic switch. Mechanistically, we found that RCE inhibited the AKT/mTOR pathway, downstream of which, inactivation of the cell cycle regulator p70S6K and downregulation of the antiapoptotic protein survivin was observed. Additionally, we found that RCE-induced autophagy preceded apoptosis. Further, we confirmed the anticancer effect of RCE in a chick embryo xenograft model and found that RCE inhibited the growth of pancreatic cancer xenografts without affecting embryo survival. Conclusion: Collectively, our findings demonstrate that Rhus coriaria exerts potent anti-pancreatic cancer activity though cell cycle impairment, autophagy, and apoptosis, and is hence a promising source of anticancer phytochemicals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 El Mahi, Nizami, Wali, Al Neyadi, Magramane, Al Azzani, Arafat, Attoub, Eid and Iratni.)

Childhood obesity represents a significant public health concern, imposing a substantial burden on the healthcare system. Furthermore, weight-loss programs often exhibit reduced effectiveness in adults who have a history of childhood obesity. Therefore, early intervention against childhood obesity is imperative. Presently, the primary method for diagnosing childhood obesity relies on body mass index (BMI), yet this approach has inherent limitations. Leptin, a satiety hormone produced by adipocytes, holds promise as a superior tool for predicting both childhood and subsequent adulthood obesity. In this review, we elucidate the tools employed for assessing obesity in children, delve into the biological functions of leptin, and examine the factors governing its expression. Additionally, we discuss maternal and infantile leptin levels as predictors of childhood obesity. By exploring the relationship between leptin levels and weight loss, we present leptin as a potential indicator of the effectiveness of obesity interventions., (© 2024 The Author(s). Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Autophagy and endoplasmic reticulum (ER) stress are conserved processes that generally promote survival, but can induce cell death when physiological thresholds are crossed. The pro-survival aspects of these processes are exploited by cancer cells for tumor development and progression. Therefore, anticancer drugs targeting autophagy or ER stress to induce cell death and/or block the pro-survival aspects are being investigated extensively. Consistently, several phytochemicals have been reported to exert their anticancer effects by modulating autophagy and/or ER stress. Various phytochemicals (e.g., celastrol, curcumin, emodin, resveratrol, among others) activate the unfolded protein response to induce ER stress-mediated apoptosis through different pathways. Similarly, various phytochemicals induce autophagy through different mechanisms (namely mechanistic target of Rapamycin [mTOR] inhibition). However, phytochemical-induced autophagy can function either as a cytoprotective mechanism or as programmed cell death type II. Interestingly, at times, the same phytochemical (e.g., 6-gingerol, emodin, shikonin, among others) can induce cytoprotective autophagy or programmed cell death type II depending on cellular contexts, such as cancer type. Although there is well-documented mechanistic interplay between autophagy and ER stress, only a one-way modulation was noted with some phytochemicals (carnosol, capsaicin, cryptotanshinone, guangsangon E, kaempferol, and δ-tocotrienol): ER stress-dependent autophagy. Plant extracts are sources of potent phytochemicals and while numerous phytochemicals have been investigated in preclinical and clinical studies, the search for novel phytochemicals with anticancer effects is ongoing from plant extracts used in traditional medicine (e.g., Origanum majorana). Nonetheless, the clinical translation of phytochemicals, a promising avenue for cancer therapeutics, is hindered by several limitations that need to be addressed in future studies., (© 2024 The Author(s). Phytotherapy Research published by John Wiley & Sons Ltd.)

Arterial stiffening is a critical risk factor contributing to the exponential rise in age-associated cardiovascular disease incidence. This process involves age-induced arterial proinflammation, collagen deposition, and calcification, which collectively contribute to arterial stiffening. The primary driver of proinflammatory processes leading to collagen deposition in the arterial wall is the transforming growth factor-beta1 (TGF-β1) signaling. Activation of this signaling is pivotal in driving vascular extracellular remodeling, eventually leading to arterial fibrosis and calcification. Interestingly, the glycosylated protein vasorin (VASN) physically interacts with TGF-β1, and functionally restraining its proinflammatory fibrotic signaling in arterial walls and vascular smooth muscle cells (VSMCs). Notably, as age advances, matrix metalloproteinase type II (MMP-2) is activated, which effectively cleaves VASN protein in both arterial walls and VSMCs. This age-associated/MMP-2-mediated decrease in VASN levels exacerbates TGF-β1 activation, amplifying arterial fibrosis and calcification in the arterial wall. Importantly, TGF-β1 is a downstream molecule of the angiotensin II (Ang II) signaling pathway in the arterial wall and VSMCs, which is modulated by VASN. Indeed, chronic administration of Ang II to young rats significantly activates MMP-2 and diminishes the VASN expression to levels comparable to untreated older control rats. This review highlights and discusses the role played by VASN in mitigating fibrosis and calcification by alleviating TGF-β1 activation and signaling in arterial walls and VSMCs. Understanding these molecular physical and functional interactions may pave the way for establishing VASN-based therapeutic strategies to counteract adverse age-associated cardiovascular remodeling, eventually reducing the risk of cardiovascular diseases., Competing Interests: None., (© 2024 The Author(s). Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.)

Steatotic liver disease (SLD) is a highly prevalent chronic liver disease with significant challenges for global health. The pathophysiology of SLD involves an interplay among genetic, endocrine, and metabolic factors. Successful management of SLD entails accurate diagnosis and disease monitoring through noninvasive methods such as advanced imaging techniques and biomarkers. Many emerging pharmacotherapies for SLD are now in the pipeline, which target different pathways like collagen turnover, fibrogenesis, inflammation, and metabolism. The recent approval of resmetirom for noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) has been a milestone in addressing the unmet medical need for an efficacious SLD treatment. Finally, the potential of personalized medicine approaches and interdisciplinary cooperation in improving patient outcomes and reducing disease burden should be strongly pursued. SIGNIFICANCE STATEMENT: The healthcare burden due to steatotic liver disease (SLD) is enormous. This perspective sheds light on the recent advances in understanding the pathophysiology and diagnosis of SLD as well as promising drug development approaches., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Obesity is a leading cause of morbidity and mortality globally. While the prevalence of obesity has been increasing, the incidence of its related complications including dyslipidemia and cardiovascular disease (CVD) has also been rising. Recent research has focused on modalities aimed at reducing obesity. Several modalities have been suggested including behavioral and dietary changes, medications, and bariatric surgery. These modalities differ in their effectiveness and invasiveness, with dietary changes gaining more interest due to their minimal risks compared to other modalities. Specifically, intermittent fasting (IF) has been gaining interest in the past decade. IF is characterized by cycles of alternating fasting and eating windows, with several different forms practiced. IF has been shown to reduce weight and alleviate obesity-related complications. Our review of clinical and experimental studies explores the effects of IF on the lipid profile, white adipose tissue (WAT) dynamics, and the gut microbiome. Notably, IF corrects dyslipidemia, reduces WAT accumulation, and decreases inflammation, which reduces CVD and obesity. This comprehensive analysis details the protective metabolic role of IF, advocating for its integration into public health practices., (© 2024. The Author(s).)

Introduction: Understanding the effect of statins on epicardial adipose tissue (EAT) is important as it may help reduce the negative impact of EAT-derived molecules on the cardiovascular system and consequently on coronary artery disease. Thus, we aimed to perform a systematic review and meta-analysis to assess the impact of statin therapy on EAT., Methods: The study utilized Scopus, PubMed, Embase, and Web of Science to gather relevant studies on the impacts of statins on EAT until September 5 th , 2023. The data collected underwent meta-analysis using Comprehensive Meta-Analysis (CMA) V4 software., Results: In the meta-analysis, three studies involving 512 subjects were ultimately incorporated. The findings indicated a significant decrease in EAT after treatment with statins (standardized mean difference (SMD = -0.507, 95% CI: -2.536, 1.521, p = 0.021)., Conclusions: Statins appear to exert an additional cardiovascular therapeutic effect by reducing EAT., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 Termedia & Banach.)

Heart failure with reduced ejection fraction (HFrEF) is a clinical syndrome characterized by volume overload, impaired exercise capacity, and recurrent hospital admissions. A major contributor to the pathophysiology and clinical presentation of heart failure is the activation of the renin-angiotensin-aldosterone system (RAAS). Normally, RAAS is responsible for the homeostatic regulation of blood pressure, extracellular fluid volume, and serum sodium concentration. In HFrEF, RAAS gets chronically activated in response to decreased cardiac output, further aggravating the congestion and cardiotoxic effects. Hence, inhibition of RAAS is a major approach in the pharmacologic treatment of those patients. The most recently introduced RAAS antagonizing medication class is angiotensin receptor blocker/ neprilysin inhibitor (ARNI). In this paper, we discuss ARNIs' superiority over traditional RAAS antagonizing agents in reducing heart failure hospitalization and mortality. We also tease out the evidence that shows ARNIs' renoprotective functions in heart failure patients including those with chronic or end stage kidney disease. We also discuss the evidence showing the added benefit resulting from combining ARNIs with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor. Moreover, how ARNIs decrease the risk of arrhythmias and reverse cardiac remodeling, ultimately lowering the risk of cardiovascular death, is also discussed. We then present the positive outcome of ARNIs' use in patients with diabetes mellitus and those recovering from acute decompensated heart failure. ARNIs' side effects are also appreciated and discussed. Taken together, the provided insight and critical appraisal of the evidence justifies and supports the implementation of ARNIs in the guidelines for the treatment of HFrEF., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Despite being an effective chemotherapeutic agent, the clinical use of doxorubicin (DOX) is limited by several organ toxicities including hepatic injury. Pentoxifylline (PTX) is a methylxanthine derivative with marked anti-inflammatory and anti-apoptotic features. It is unknown, however, whether PTX can mitigate DOX-evoked hepatotoxicity. This study aims to explore the potential hepatoprotective impact of PTX in DOX-induced hepatic injury and the underlying molecular mechanisms. Histopathology, immunohistochemistry, and ELISA were used to examine liver tissues. The current findings revealed that PTX administration to DOX-intoxicated rats mitigated the pathological manifestations of hepatic injury, reduced microscopical damage scores, and improved serum ALT and AST markers, revealing restored hepatic cellular integrity. These favorable effects were attributed to PTX's ability to mitigate inflammation by reducing hepatic IL-1β and TNF-α levels and suppressing the pro-inflammatory HMGB1/TLR4/NF-κB axis. Moreover, PTX curtailed the hepatic apoptotic abnormalities by suppressing caspase 3 activity and lowering the Bax/Bcl-2 ratio. In tandem, PTX improved the defective autophagy events by lowering hepatic SQSTM-1/p62 accumulation and enhancing the AMPK/mTOR pathway, favoring autophagy and hepatic cell preservation. Together, for the first time, our findings demonstrate the ameliorative effect of PTX against DOX-evoked hepatotoxicity by dampening the hepatic HMGB1/TLR4/NF-κB pro-inflammatory axis and augmenting hepatic AMPK/mTOR-driven autophagy. Thus, PTX could be utilized as an adjunct agent with DOX regimens to mitigate DOX-induced hepatic injury.

This systematic review and meta-analysis evaluated changes in circulating irisin levels after bariatric surgery. A systematic search was performed across Embase, Scopus, PubMed, and Web of Science for this study. The meta-analysis was conducted using Comprehensive Meta-Analysis (CMA) V4 software. The overall effect size was depicted through a random-effects meta-analysis and the leave-one-out method. The meta-analysis, which included 13 studies with a total of 407 participants, showed a statistically non-significant reduction in circulating irisin levels following bariatric surgery (SMD:  - 0.089, 95% CI  - 0.281, 0.102, 95% PI:  - 0.790, 0.611, p = 0.360; I 2 :70.56). Our research found no significant change in irisin levels after bariatric surgery. Moreover, these findings were not associated with the type of surgery or the duration of follow-up., (© 2024. Italian Society of Surgery (SIC).)

G-protein coupled receptors (GPCRs) transduce a wide range of extracellular signals. They are key players in the majority of biologic functions including vision, olfaction, chemotaxis, and immunity. However, as essential as most of them are to body function and homeostasis, overactivation of GPCRs has been implicated in many pathologic diseases such as cancer, asthma, and heart failure (HF). Therefore, an important feature of G protein signaling systems is the ability to control GPCR responsiveness, and one key process to control overstimulation involves initiating receptor desensitization. A number of steps are appreciated in the desensitization process, including cell surface receptor phosphorylation, internalization, and downregulation. Rapid or short-term desensitization occurs within minutes and involves receptor phosphorylation via the action of intracellular protein kinases, the binding of β -arrestins, and the consequent uncoupling of GPCRs from their cognate heterotrimeric G proteins. On the other hand, long-term desensitization occurs over hours to days and involves receptor downregulation or a decrease in cell surface receptor protein level. Of the proteins involved in this biologic phenomenon, β -arrestins play a particularly significant role in both short- and long-term desensitization mechanisms. In addition, β -arrestins are involved in the phenomenon of biased agonism, where the biased ligand preferentially activates one of several downstream signaling pathways, leading to altered cellular responses. In this context, this review discusses the different patterns of desensitization of the α 1 -, α 2 - and the β adrenoceptors and highlights the role of β -arrestins in regulating physiologic responsiveness through desensitization and biased agonism. SIGNIFICANCE STATEMENT: A sophisticated network of proteins orchestrates the molecular regulation of GPCR activity. Adrenoceptors are GPCRs that play vast roles in many physiological processes. Without tightly controlled desensitization of these receptors, homeostatic imbalance may ensue, thus precipitating various diseases. Here, we critically appraise the mechanisms implicated in adrenoceptor desensitization. A better understanding of these mechanisms helps identify new druggable targets within the GPCR desensitization machinery and opens exciting therapeutic fronts in the treatment of several pathologies., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

This study evaluated the potential for antibody-dependent enhancement (ADE) in serum samples from patients exposed to Middle East respiratory syndrome coronavirus (MERS-CoV). Furthermore, we evaluated the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination on ADE in individuals with a MERS infection history. We performed ADE assay in sera from MERS recovered and SARS-CoV-2-vaccinated individuals using BHK cells expressing FcgRIIa, SARS-CoV-2, and MERS-CoV pseudoviruses (PVs). Further, we analyzed the association of ADE to serum IgG levels and neutralization. Out of 16 MERS patients, nine demonstrated ADE against SARS-CoV-2 PV, however, none of the samples demonstrated ADE against MERS-CoV PV. Furthermore, out of the seven patients exposed to SARS-CoV-2 vaccination after MERS-CoV infection, only one patient (acutely infected with MERS-CoV) showed ADE for SARS-CoV-2 PV. Further analysis indicated that IgG1, IgG2, and IgG3 against SARS-CoV-2 S1 and RBD subunits, IgG1 and IgG2 against the MERS-CoV S1 subunit, and serum neutralizing activity were low in ADE-positive samples. In summary, samples from MERS-CoV-infected patients exhibited ADE against SARS-CoV-2 and was significantly associated with low levels of neutralizing antibodies. Subsequent exposure to SARS-CoV-2 vaccination resulted in diminished ADE activity while the PV neutralization assay demonstrated a broadly reactive antibody response in some patient samples., (© 2024 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

C-peptide, a byproduct of insulin synthesis believed to be biologically inert, is emerging as a multifunctional molecule. C-peptide serves an anti-inflammatory and anti-atherogenic role in type 1 diabetes mellitus (T1DM) and early T2DM. C-peptide protects endothelial cells by activating AMP-activated protein kinase α, thus suppressing the activity of NAD(P)H oxidase activity and reducing reactive oxygen species (ROS) generation. It also prevents apoptosis by regulating hyperglycemia-induced p53 upregulation and mitochondrial adaptor p66shc overactivation, as well as reducing caspase-3 activity and promoting expression of B-cell lymphoma-2. Additionally, C-peptide suppresses platelet-derived growth factor (PDGF)-beta receptor and p44/p42 mitogen-activated protein (MAP) kinase phosphorylation to inhibit vascular smooth muscle cells (VSMC) proliferation. It also diminishes leukocyte adhesion by virtue of its capacity to abolish nuclear factor kappa B (NF-kB) signaling, a major pro-inflammatory cascade. Consequently, it is envisaged that supplementation of C-peptide in T1DM might ameliorate or even prevent end-organ damage. In marked contrast, C-peptide increases monocyte recruitment and migration through phosphoinositide 3-kinase (PI-3 kinase)-mediated pathways, induces lipid accumulation via peroxisome proliferator-activated receptor γ upregulation, and stimulates VSMC proliferation and CD4 + lymphocyte migration through Src-kinase and PI-3K dependent pathways. Thus, it promotes atherosclerosis and microvascular damage in late T2DM. Indeed, C-peptide is now contemplated as a potential biomarker for insulin resistance in T2DM and linked to increased coronary artery disease risk. This shift in the understanding of the pathophysiology of diabetes from being a single hormone deficiency to a dual hormone disorder warrants a careful consideration of the role of C-peptide as a unique molecule with promising diagnostic, prognostic, and therapeutic applications., (© 2024 Wiley Periodicals LLC.)

CD40 and its ligand have been recently implicated in the pathogenesis of cardiovascular disease (CVD). This meta-analysis examined the effect of bariatric surgery in reducing circulating CD40L levels. A systematic review was performed using Embase, Google Scholar, PubMed, Scopus, and Web of Science. The meta-analysis was provided by Comprehensive Meta-Analysis (CMA) V4 software. The overall effect size was detected by a random-effects meta-analysis and the leave-one-out approach. Random-effects meta-analysis of 7 studies including 191 subjects showed a significant reduction in CD40L after bariatric surgery (standardized mean difference (SMD), - 0.531; 95% CI, - 0.981, - 0.082; p = 0.021; I 2 , 87.00). Circulating levels of CD40L are decreased after bariatric surgery which may represent a mechanism for improvement of metabolic profile., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Vascular smooth muscle cells (VSMCs) play a critical role in regulating vasotone, and their phenotypic plasticity is a key contributor to the pathogenesis of various vascular diseases. Two main VSMC phenotypes have been well described: contractile and synthetic. Contractile VSMCs are typically found in the tunica media of the vessel wall, and are responsible for regulating vascular tone and diameter. Synthetic VSMCs, on the other hand, are typically found in the tunica intima and adventitia, and are involved in vascular repair and remodeling. Switching between contractile and synthetic phenotypes occurs in response to various insults and stimuli, such as injury or inflammation, and this allows VSMCs to adapt to changing environmental cues and regulate vascular tone, growth, and repair. Furthermore, VSMCs can also switch to osteoblast-like and chondrocyte-like cell phenotypes, which may contribute to vascular calcification and other pathological processes like the formation of atherosclerotic plaques. This provides discusses the mechanisms that regulate VSMC phenotypic switching and its role in the development of vascular diseases. A better understanding of these processes is essential for the development of effective diagnostic and therapeutic strategies., (© 2024 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

The cardiovascular and renovascular complications of metabolic deterioration are associated with localized adipose tissue dysfunction. We have previously demonstrated that metabolic impairment delineated the heightened vulnerability of both the perivascular (PVAT) and perirenal adipose tissue (PRAT) depots to hypoxia and inflammation, predisposing to cardioautonomic, vascular and renal deterioration. Interventions either addressing underlying metabolic disturbances or halting adipose tissue dysfunction rescued the observed pathological and functional manifestations. Several lines of evidence implicate adipose tissue thromboinflammation, which entails the activation of the proinflammatory properties of the blood clotting cascade, in the pathogenesis of metabolic and cardiovascular diseases. Despite offering valuable tools to interrupt the thromboinflammatory cycle, there exists a significant knowledge gap regarding the potential pleiotropic effects of anticoagulant drugs on adipose inflammation and cardiovascular function. As such, a systemic investigation of the consequences of PVAT and PRAT thromboinflammation and its interruption in the context of metabolic disease has not been attempted. Here, using an established prediabetic rat model, we demonstrate that metabolic disturbances are associated with PVAT and PRAT thromboinflammation in addition to cardioautonomic, vascular and renal functional decline. Administration of rivaroxaban, a FXa inhibitor, reduced PVAT and PRAT thromboinflammation and ameliorated the cardioautonomic, vascular and renal deterioration associated with prediabetes. Our present work outlines the involvement of PVAT and PRAT thromboinflammation during early metabolic derangement and offers novel perspectives into targeting adipose tissue thrombo-inflammatory pathways for the management its complications in future translational efforts., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Hypertension is a major harbinger of cardiovascular morbidity and mortality. It predisposes to higher rates of myocardial infarction, chronic kidney failure, stroke, and heart failure than most other risk factors. By 2025, the prevalence of hypertension is projected to reach 1.5 billion people. The pathophysiology of this disease is multifaceted, as it involves nitric oxide and endothelin dysregulation, reactive oxygen species, vascular smooth muscle proliferation, and vessel wall calcification, among others. With the advent of new biomolecular techniques, various studies have elucidated a gaping hole in the etiology and mechanisms of hypertension. Indeed, epigenetics, DNA methylation, histone modification, and microRNA-mediated translational silencing appear to play crucial roles in altering the molecular phenotype into a hypertensive profile. Here, we critically review the experimentally determined associations between microRNA (miRNA) molecules and hypertension pharmacotherapy. Particular attention is given to the epigenetic mechanisms underlying the physiological responses to antihypertensive drugs like candesartan, and other relevant drugs like clopidogrel, aspirin, and statins among others. Furthermore, how miRNA affects the pharmaco-epigenetics of hypertension is especially highlighted., (© 2024. The Author(s).)

Natural products have long been utilized in traditional medicine as remedies to improve health and treat illnesses, and have had a key role in modern drug discovery. Recently, there has been a revived interest in the search for bioactives from natural sources as alternative or complementary modalities to synthetic medicines; especially for cancer treatment, which incidence and mortality rates are on the rise worldwide. Ziziphus nummularia has been widely used in traditional medicine for the treatment of various diseases. Its traditional uses and numerous ethnopharmacological properties may be attributed to its richness in bioactive metabolites. However, its phytochemical composition or chemopreventive effects against the aggressive triple-negative breast cancer (TNBC) are still poorly explored. Here, phytochemical composition of an ethanolic extract of Z. nummularia leaves (ZNE) and its chromatographically isolated fractions was identified both qualitatively by spectrophotometric assays and analytically by HPLC-PDA-MS/MS. The anti-proliferative effects of ZNE were tested in several cancer cell lines, but we focused on its anti-TNBC effects since they were not explored yet. The anti-cancerous potential of ZNE and its fractions was tested in vitro in MDA-MB-231, a TNBC cell line. Results showed that ZNE and its Fraction 6 (F6) reduced the viability of MDA-MB-231 cells. F6 decreased MDA-MB-231 viability more than crude ZNE or its other fractions. ZNE and F6 are rich in phytochemicals and HPLC-PDA-MS/MS analysis identified several metabolites that were previously reported to have anti-cancerous effects. Both ZNE and F6 showed potent antioxidant capacity in the DPPH assay, but promoted reactive oxygen species (ROS) production in MDA-MB-231 cells; an effect which was blunted by the antioxidant N-acetyl cysteine (NAC). NAC also blunted ZNE- and F6-induced reduction in TNBC cell viability. We also demonstrated that ZNE and F6 induced an arrest of the cell cycle, and triggered apoptosis- and autophagy-mediated cell death. ZNE and F6 inhibited metastasis-related cellular processes by modifying cell migration, invasion, and adhesion. Taken together, our findings reveal that Z . nummularia is rich in phytochemicals that can attenuate the malignant phenotype of TNBC and may offer innovative avenues for the discovery of new drug leads for treatment of TNBC and other cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Abdallah, Shaito, Badran, Baydoun, Sobeh, Ouchari, Sahri, Eid, Mesmar and Baydoun.)

The present study was designed to evaluate the chemical composition, antioxidant, enzyme inhibition and cytotoxic properties of different extracts from aerial parts of V. diversifolium (family Scrophulariaceae), a plant that is native to Lebanon, Syria and Turkey. Six extracts, namely, hexane, dichloromethane (DCM), ethyl acetate (EtOAc), ethanol (EtOH), 70% EtOH, and water (aqueous) were prepared by maceration. The EtOH extract was predominated by the presence of rutin (4280.20 μg g -1 ) and p -coumaric acid (3044.01 μg g -1 ) while the highest accumulation of kaempferol-3-glucoside (1537.38 μg g -1 ), caffeic acid (130.13 μg g -1 ) and 4-hydroxy benzoic acid (465.93 μg g -1 ) was recorded in the 70% EtOH, aqueous, and EtOAc extracts, respectively. The EtOH (46.86 mg TE/g) and 70% EtOH (46.33 mg TE/g) extracts displayed the highest DPPH radical scavenging result. Both these extracts, along with the aqueous one, exerted the highest ABTS radical scavenging result (73.03-73.56 mg TE/g). The EtOH and 70% EtOH extracts revealed the most potent anti-AChE (2.66 and 2.64 mg GALAE/g) and anti-glucosidase (1.07 and 1.09 mmol ACAE/g) activities. The aqueous extract was the most efficacious in inhibiting the proliferation of prostate cancer (DU-145) cells with an IC 50 of 8.71 μg/mL and a Selectivity Index of 3.7. In conclusion, this study appraised the use of V. diversifolium aerial parts as a potential therapeutic source for future development of phytopharmaceuticals that target specific oxidative stress-linked diseases including diabetes, cancer, cardiovascular disease, and Alzheimer's disease among others., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Yagi, Nilofar, Uba, Caprioli, Mustafa, Angeloni, Koyuncu, Seker, Polat, Supti, Tasnim, Al Dhaheri, Zengin and Eid.)

Atherosclerosis remains a leading contributor to cardiovascular disease-associated morbidity and mortality. Interestingly, atherosclerosis-associated mortality rate is higher in men than women. This suggested a protective role for estrogen in the cardiovasculature. These effects of estrogen were initially thought to be mediated by the classic estrogen receptors, ER alpha, and beta. However, genetic knockdown of these receptors did not abolish estrogen's vasculoprotective effects suggesting that the other membranous Gprotein coupled estrogen receptor, GPER1, maybe the actual mediator. Indeed, in addition to its role in vasotone regulation, this GPER1 appears to play important roles in regulating vascular smooth cell phenotype, a critical player in the onset of atherosclerosis. Moreover, GPER1-selective agonists appear to reduce LDL levels by promoting the expression of LDL receptors as well as potentiating LDL re-uptake in liver cells. Further evidence also show that GPER1 can downregulate Proprotein Convertase Subtilisin/ Kexin type 9, leading to suppression of LDL receptor breakdown. Here, we review how selective activation of GPER1 might prevent or suppress atherosclerosis, with less side effects than those of the non-selective estrogen., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

One of the main causes of atherosclerosis is a disruption in cellular cholesterol hemostasis. The low-density lipoprotein receptor (LDLR) is an important factor in maintaining cholesterol homeostasis by the receptor-mediated endocytosis of LDL particles. Defective hepatic LDLR activity and uptake of LDL particles lead to elevated blood levels of low-density lipoprotein cholesterol (LDL-C), which is associated with a higher risk of atherosclerotic cardiovascular disease. LDLR expression can be affected by microRNAs (miRNAs). Some miRNAs, like miR-148a, miR-185, miR-224, miR-520, miR-128-1, miR-27a/b, miR-130b, and miR-301 seem to be important post-transcriptional regulators of LDLR related genes. These findings indicate the critical role of miRNAs in regulating LDL metabolism. The aim of this review was to provide insight into the miRNAs involved in LDLR activity and their potential roles in the treatment of cardiovascular disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background and Aim: Mucopolysaccharidosis type III (MPS III) is a rare autosomal recessive lysosomal storage disease (LSD) caused by a deficiency of lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs), mainly in the central nervous system. Trehalose has been proposed as a potential therapeutic agent to attenuate neuropathology in MPS III. We conducted a single- arm, open-label study to evaluate the efficacy of trehalose treatment in patients with MPS IIIA and MPS IIIB., Methods: Five patients with MPS III were enrolled. Trehalose was administrated intravenously (15 g/week) for 12 weeks. Health-related quality of life and cognitive function, serum biomarkers, liver, spleen, and lung imaging were assessed to evaluate trehalose efficacy at baseline and trial end (week 12)., Results: TNO-AZL Preschool children Quality of Life (TAPQOL) scores increased in all patients, and the mean scores for quality of life were increased after the intervention. Serum GAG levels were reduced in all treated patients (however, the differences were not statistically significant). Alanine aminotransferase (ALT) levels were reduced in all patients post-treatment (p=0.0039). The mean levels of aspartate transaminase (AST) were also decreased after 12 weeks of treatment with Trehalose. Decreased serum pro-oxidant-antioxidant balance and increased GPX activity were observed at the end of the study. Decreases in mean splenic length were observed, whereas the liver volume did not change., Conclusion: Improvements in health-related quality of life and serum biomarkers (GAGs, liver aminotransferase levels, antioxidant status), as well as liver and spleen size, were found following 3 months of trehalose administration in patients with MPS IIIA and MPS IIIB., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Oxidative stress is a major instigator of various cardiovascular diseases, including myocardial infarction (MI). Despite available drugs, there is still an increased need to look for alternative therapies or identify new bioactive compounds. Sanguisorba minor ( S. minor ) is a native herb characterized by its potent antioxidant activity. This study was designed to evaluate the effect of S. minor against isoprenaline-induced MI. Methods: Rats were treated with the hydro-ethanolic extract of the aerial parts of S. minor at doses of 100 or 300 mg/kg orally for 9 days. Isoprenaline was injected subcutaneously at the dose of 85 mg/kg on days 8 and 9. Then, the activities of various cardiac injury markers including cardiac troponin (cTnT), lactate dehydrogenase (LDH), creatinine kinase muscle brain (CK-MB), creatinine phosphokinase (CPK), and antioxidant enzymes in serum were determined. Malondialdehyde (MDA) and thiol content were measured in cardiac tissue, and histopathological analysis was conducted. Results: Our results show that isoprenaline increased the serum levels of cTnT, LDH, CK-MB, and CPK ( p < 0.001) and elevated MDA levels ( p < 0.001) in cardiac tissue. Isoprenaline also reduced superoxide dismutase (SOD), catalase, and thiol content ( p < 0.001). Importantly, the extract abolished isoprenaline-induced MI by elevating SOD and catalase ( p < 0.001), reducing levels of MDA, and diminishing levels of cTnT, LDH, CK-MB, and CPK cardiac markers ( p < 0.001). Histopathological studies of the cardiac tissue showed isoprenaline-induced injury that was significantly attenuated by the extract. Conclusion: Our results suggest that S. minor could abrogate isoprenaline-induced cardiac toxicity due to its ability to mitigate oxidative stress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that they were editorial board members of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Hosseini, Ghorbani, Alavi, Forouhi, Rajabian, Boroumand-Noughabi, Sahebkar and Eid.)

Competing Interests: Declaration of competing interest None.

Abstract: Raynaud's phenomenon, which results from exaggerated cold-induced vasoconstriction, is more prevalent in females than males. We previously showed that estrogen increases the expression of alpha 2C-adrenoceptors (α 2C -AR), the sole mediator of cold-induced vasoconstriction. This effect of estrogen is reproduced by the cell-impermeable form of the hormone (E 2 :bovine serum albumin [BSA]), suggesting a role of the membrane estrogen receptor, G-protein-coupled estrogen receptor [GPER], in E 2 -induced α 2C -AR expression. We also previously reported that E 2 upregulates α 2C -AR in microvascular smooth muscle cells (VSMCs) via the cAMP/Epac/Rap/JNK/AP-1 pathway, and that E 2 :BSA elevates cAMP levels. We, therefore, hypothesized that E 2 uses GPER to upregulate α 2C -AR through the cAMP/Epac/JNK/AP-1 pathway. Our results show that G15, a selective GPER antagonist, attenuates the E 2 -induced increase in α 2C -AR transcription. G-1, a selective GPER agonist, induced α 2C -AR transcription, which was concomitant with elevated cAMP levels and JNK activation. Pretreatment with ESI09, an Epac inhibitor, abolished G-1-induced α 2C -AR upregulation and JNK activation. Moreover, pretreatment with SP600125, a JNK-specific inhibitor, but not H89, a PKA-specific inhibitor, abolished G-1-induced α 2C -AR upregulation. In addition, transient transfection of an Epac dominant negative mutant (Epac-DN) attenuated G-1-induced activation of the α 2C -AR promoter. This inhibitory effect of Epac-DN on the α 2C -AR promoter was overridden by the cotransfection of constitutively active JNK mutant. Furthermore, mutation of AP-1 site in the α 2C -AR promoter abrogated G1-induced expression. Collectively, these results indicate that GPER upregulates α 2C -AR through the cAMP/EPAC/JNK/AP-1 pathway. These findings unravel GPER as a new mediator of cold-induced vasoconstriction, and present it as a potential target for treating Raynaud's phenomenon in estrogen-replete females., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Adipose tissue is now recognized as an endocrine organ that secretes bioactive molecules called adipokines. These biomolecules regulate key physiological functions, including insulin sensitivity, energy metabolism, appetite regulation, endothelial function and immunity. Dysregulated secretion of adipokines is intimately associated with obesity, and translates into increased risk of obesity-related cardiovasculo-metabolic diseases. In particular, emerging evidence suggests that adipokine imbalance contributes to the pathogenesis of atherosclerosis. One of the promising diet regimens that is beneficial in the fight against obesity and cardiometabolic disorders is intermittent fasting (IF). Indeed, IF robustly suppresses inflammation, meditates weight loss and mitigates many aspects of the cardiometabolic syndrome. In this paper, we review the main adipokines and their role in atherosclerosis, which remains a major contributor to cardiovascular-associated morbidity and mortality. We further discuss how IF can be employed as an effective management modality for obesity-associated atherosclerosis. By exploring a plethora of the beneficial effects of IF, particularly on inflammatory markers, we present IF as a possible intervention to help prevent atherosclerosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Meningiomas are the most prevalent primary intracranial tumors. The majority are benign but can undergo dedifferentiation into advanced grades classified by World Health Organization (WHO) into Grades 1 to 3. Meningiomas' tremendous variability in tumor behavior and slow growth rates complicate their diagnosis and treatment. A deeper comprehension of the molecular pathways and cellular microenvironment factors implicated in meningioma survival and pathology is needed. This review summarizes the known genetic and epigenetic aberrations involved in meningiomas, with a focus on neurofibromatosis type 2 ( NF2 ) and non- NF2 mutations. Novel potential biomarkers for meningioma diagnosis and prognosis are also discussed, including epigenetic-, RNA-, metabolomics-, and protein-based markers. Finally, the landscape of available meningioma-specific animal models is overviewed. Use of these animal models can enable planning of adjuvant treatment, potentially assisting in pre-operative and post-operative decision making. Discovery of novel biomarkers will allow, in combination with WHO grading, more precise meningioma grading, including meningioma identification, subtype determination, and prediction of metastasis, recurrence, and response to therapy. Moreover, these biomarkers may be exploited in the development of personalized targeted therapies that can distinguish between the 15 diverse meningioma subtypes.

Cognitive decline and Alzheimer-like neuropathology are common manifestations of cadmium toxicity. Thanks to its antioxidant/anti-apoptotic features, dapagliflozin has demonstrated promising neuroprotective actions. However, its effect on cadmium-induced neurotoxicity is lacking. The present work aimed to examine whether dapagliflozin could protect rats from cadmium-evoked cognitive decline. In this study, the behavioral disturbances and hippocampal biomolecular alterations were studied after receiving dapagliflozin. Herein, cadmium-induced memory/learning decline was rescued in the Morris water maze, novel object recognition task, and Y-shaped maze by dapagliflozin. Meanwhile, the hippocampal histopathological abnormalities were mitigated. The molecular mechanisms revealed that dapagliflozin lowered hippocampal expression of p-tau and Aβ42 neurotoxic proteins while augmenting acetylcholine. The cognitive enhancement was triggered by hippocampal autophagy stimulation, as indicated by decreased SQSTM-1/p62 and Beclin 1 upregulation. Meanwhile, a decrease in p-mTOR/total mTOR and an increase in p-AMPK/total AMPK ratio were observed in response to dapagliflozin, reflecting AMPK/mTOR cascade stimulation. Dapagliflozin, on the other hand, dampened the pro-apoptotic processes in the hippocampus by downregulating Bax, upregulating Bcl-2, and inactivating GSK-3β. The hippocampal oxidative insult was mitigated by dapagliflozin as seen by lipid peroxide lowering, antioxidants augmentation, and SIRT1/Nrf2/HO-1 pathway activation. In conclusion, dapagliflozin's promising neuroprotection was triggered by its pro-autophagic, anti-apoptotic, and antioxidant properties.

Background: Evidence on the effectiveness of vaccination-induced immunity compared to SARS-CoV-2 natural immunity is warranted to inform vaccination recommendations., Aim: In this study, we aimed to conduct a comparative assessment of antibody responses between vaccinated naïve (VN) and unvaccinated naturally infected individuals (NI) over 10 Months., Method: The study comprised fully-vaccinated naïve individuals (VN; n = 596) who had no history of SARS-CoV-2 infection, and received two doses of either BNT162b2 or mRNA-1273, and naturally infected individuals who had a documented history of SARS-CoV-2 infection and no vaccination record (NI cohort; n = 218). We measured the levels of neutralizing total antibodies (NtAbs), anti-S-RBD IgG, and anti-S1 IgA titers among VN and NI up to ∼10 months from administration of the first dose, and up to ∼7 months from SARS-CoV-2 infection, respectively. To explore the relationship between the antibody responses and time, Spearman's correlation coefficient was computed. Furthermore, correlations between the levels of NtAbs/anti-S-RBD IgG and NtAbs/anti-S1 IgA were examined through pairwise correlation analysis., Results: Up to six months, VN individuals had a significantly higher NtAb and anti-S-RBD IgG antibody responses compared to NI individuals. At the 7th month, there was a significant decline in antibody responses among VN individuals, but not NI individuals, with a minimum decrease of 3.7-fold (p < 0.001). Among VN individuals, anti-S1 IgA levels began to decrease significantly (1.4-fold; p = 0.007) after two months, and both NtAb and S-RBD IgG levels began to decline significantly (NtAb: 2.0-fold; p = 0.042, S-RBD IgG: 2.4-fold; p = 0.035) after three months. After 10 months, the most significant decline among VN individuals was observed for S-RBD-IgG (30.0-fold; P < 0.001), followed by NtAb (15.7-fold; P < 0.001) and S-IgA (3.7-fold; P < 0.001) (most stable). Moreover, after 5 months, there was no significant difference in the IgA response between the two groups., Conclusion: These findings have important implications for policymakers in the development of vaccination strategies, particularly in the consideration of booster doses to sustain long-lasting protection against COVID-19., Competing Interests: Declaration of Competing Interest There are no known conflicts of interest associated with this publication., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Obesity is a chronic inflammatory condition and this meta-analysis evaluated the impact of bariatric surgery on SAA., Methods: Studies included all types of bariatric surgery where SAA was measured before and after the surgical procedure., Results: Meta-analysis of 11 clinical studies (n = 394 individuals) confirmed a significant reduction in SAA following bariatric surgery (SMD: - 0.971, 95% CI: - 2.721, 0.779, p < 0.001). Meta-regression did not show any association between the changes in BMI and the absolute difference in SAA levels. No relationship between the changes in SAA and the length of follow-up was found., Conclusion: Bariatric surgery significantly improved SAA. The decrease in SAA was not related to time after surgery or changes in BMI. Bariatric surgery may thus have an independent effect on SAA., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cardiovascular complications of diabetes and obesity remain a major cause for morbidity and mortality worldwide. Despite significant advances in the pharmacotherapy of metabolic disease, the available approaches do not prevent or slow the progression of complications. Moreover, a majority of patients present with significant vascular involvement at early stages of dysfunction prior to overt metabolic changes. The lack of disease-modifying therapies affects millions of patients globally, causing a massive economic burden due to these complications. Significantly, adipose tissue inflammation was implicated in the pathogenesis of metabolic syndrome, diabetes, and obesity. Specifically, perivascular adipose tissue (PVAT) and perirenal adipose tissue (PRAT) depots influence cardiovascular and renal structure and function. Accumulating evidence implicates localized PVAT/PRAT inflammation as the earliest response to metabolic impairment leading to cardiorenal dysfunction. Increased mitochondrial uncoupling protein 1 (UCP1) expression and function lead to PVAT/PRAT hypoxia and inflammation as well as vascular, cardiac, and renal dysfunction. As UCP1 function remains an undruggable target so far, modulation of the augmented UCP1-mediated PVAT/PRAT thermogenesis constitutes a lucrative target for drug development to mitigate early cardiorenal involvement. This can be achieved either by subtle targeted reduction in UCP-1 expression using innovative proteolysis activating chimeric molecules (PROTACs) or by supplementation with cyclocreatine phosphate, which augments the mitochondrial futile creatine cycling and thus decreases UCP1 activity, enhances the efficiency of oxygen use, and reduces hypoxia. Once developed, these molecules will be first-in-class therapeutic tools to directly interfere with and reverse the earliest pathology underlying cardiac, vascular, and renal dysfunction accompanying the early metabolic deterioration. SIGNIFICANCE STATEMENT: Adipose tissue dysfunction plays a major role in the pathogenesis of metabolic diseases and their complications. Although mitochondrial alterations are common in metabolic impairment, it was only recently shown that the early stages of metabolic challenge involve inflammatory changes in select adipose depots associated with increased uncoupling protein 1 thermogenesis and hypoxia. Manipulating this mode of thermogenesis can help mitigate the early inflammation and the consequent cardiorenal complications., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Gut microbiota is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) through the metabolites, which can induce atherogenesis. One of these metabolites is trimethylamine N-oxide (TMAO). Some studies indicate that statins do not only decrease LDL-cholesterol and thus ASCVD risk, but they also affect gut microbiota. There are only a few studies on humans suggesting that statins might also decrease TMAO, but their results are not unanimous. This meta-analysis aimed to provide an answer as to whether statins do affect decreasing the plasma levels of atherogenic TMAO., Methods: A systematic literature search in PubMed, Scopus, Embase, and Web of Science was performed from inception to January 1st, 2023. To assess the quality of each study included in the meta-analysis, the Cochrane Quality Assessment tool 1 (ROB 1) was used. Comprehensive Meta-Analysis V3 software was used to perform the meta-analysis. The weighted mean difference was also used. A random effects meta-analysis was used to calculate the overall estimate of effect size. In the leave-one-out approach, one study was excluded from each analysis to evaluate the effect of each study on the overall effect size., Results: Random-effects meta-analysis of 3 studies including 244 patients demonstrated a significant decrease in plasma TMAO levels after statin treatment (WMD: -1.839, 95% CI: -2.391, -1.287, p<0.001; I2 :0). The reduction in TMAO was robust in the leaveone-out sensitivity analysis., Conclusion: Statins might reduce TMAO levels, but there is a need for further evidence from long-term studies taking into account different types and doses of statins., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)