The Effect of Bariatric Surgery on PAI-1 Levels: A Systematic Review and Meta-analysis.

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.

Rhus coriaria induces autophagic and apoptotic cell death in pancreatic cancer cells.

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.

Phenotypic switch of vascular smooth muscle cells in COVID-19: Role of cholesterol, calcium, and phosphate.

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.

The differential expression of adipose tissue genes in short, medium and long-term periods after bariatric surgery.

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.

Citrus limon var. pompia Camarda var. nova: A Comprehensive Review of Its Botanical Characteristics, Traditional Uses, Phytochemical Profile, and Potential Health Benefits.

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)-ß-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.

Phytochemical-mediated modulation of autophagy and endoplasmic reticulum stress as a cancer therapeutic approach.

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.

Efficacy of statin therapy in reducing epicardial adipose tissue: a systematic review and meta-analysis.

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 5th, 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.

Enhanced vasorin signaling mitigates adverse cardiovascular remodeling.

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-ß1) 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-ß1, 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-ß1 activation, amplifying arterial fibrosis and calcification in the arterial wall. Importantly, TGF-ß1 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-ß1 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.

Leptin is a potential biomarker of childhood obesity and an indicator of the effectiveness of weight-loss interventions.

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.

Hope on the Horizon: Promising Therapies for Steatotic Liver Disease.

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.

Intermittent Fasting Regulates Metabolic Homeostasis and Improves Cardiovascular Health.

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.

Impact of bariatric surgery on circulating irisin levels: a systematic review and meta­analysis.

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; I2:70.56). 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.

Adrenoceptor Desensitization: Current Understanding of Mechanisms.

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 ß-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, ß-arrestins play a particularly significant role in both short- and long-term desensitization mechanisms. In addition, ß-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 ß adrenoceptors and highlights the role of ß-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.

Angiotensin receptor blocker-neprilysin inhibitor for heart failure with reduced ejection fraction.

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.

Antibody-dependent enhancement (ADE) of SARS-CoV-2 in patients exposed to MERS-CoV and SARS-CoV-2 antigens.

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.

Bariatric Surgery Improves Serum CD40L Levels as a Predictor of Cardiovascular Risk: Systematic Review and Meta-analysis.

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; I2, 87.00). Circulating levels of CD40L are decreased after bariatric surgery which may represent a mechanism for improvement of metabolic profile.

Corrigendum: Cardioprotective effect of Sanguisorba minor against isoprenaline-induced myocardial infarction in rats.

[This corrects the article DOI: 10.3389/fphar.2023.1305816.].

Elucidating the chemical profile and biological studies of Verbascum diversifolium Hochst. extracts.

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 IC50 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.