Investigating the association between the triglyceride-glucose index and peripheral artery disease: a systematic review and meta-analysis.

BACKGROUND: Peripheral artery disease (PAD) is a common disease associated with atherosclerosis, leading to significant mortality and morbidity worldwide. Our study focuses on the association between insulin resistance (IR) and PAD, specifically investigating the triglyceride-glucose index (TyG) as a potential surrogate marker of IR in the context of PAD by pooling the existing studies on this topic. METHODS: Online databases, including PubMed, Embase, Scopus, and the Web of Science, were searched to find the studies comparing the TyG index in PAD vs. control, reporting the TyG index among PAD severities, and assessing the association of increase in TyG with PAD prevalence. Random-effect meta-analysis was performed to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) for TyG level comparison and to calculate pooled odds ratio (ORs) for a 1-unit increase in TyG and higher vs. lower quartile/tertile of TyG association with PAD. RESULTS: In the final review, 22 studies comprising 73,168 cases were included. Random-effect meta-analysis showed that patients with PAD had significantly higher levels of the TyG index compared with controls (SMD 0.76, 95%CI 0.65-0.88, P < 0.001). Also, higher severities of PAD were associated with higher TyG levels (SMD 0.48, 95%CI 0.22-0.74, P = 0.0003). Additionally, a 1-unit increase in TyG was associated with a 60% increase in odds of PAD (OR 1.60, 95%CI 1.41-1.80, P < 0.001). Finally, the highest quartile (Q4) of TyG had significantly higher odds of PAD compared to Q1 (OR 1.94, 95%CI 1.49-2.54, P < 0.001). CONCLUSION: Our meta-analysis has identified a significant association between TyG levels and PAD and its severity. These findings not only contribute to our understanding of the role of IR in PAD pathology but also offer clinicians an exact index for evaluating PAD risk and its complications. This could potentially lead to more effective prevention and management strategies in the future.

Polyunsaturated fatty acid status and markers of oxidative stress and inflammation across the lifespan: A cross-sectional study in a cohort with long-lived individuals.

Polyunsaturated fatty acids (PUFA) are known to have a regulatory effect on oxidative and inflammatory processes. This study aimed to identify the relationship between blood PUFA status and circulatory markers of oxidative stress and inflammation in a cohort of 172 subjects. The population was divided by sex and into three age groups: adults (18-64 years old, n = 69), older adults (65-89 years old, n = 54), and long-lived individuals (LLIs, 90-111 years old, n = 49). Whole blood PUFA content was quantified using gas chromatography. Additionally, serum levels of C-reactive protein (CRP), paraoxonase (PON), Trolox equivalent antioxidant capacity (TEAC), and malondialdehyde (MDA) were measured. Our results showed that a higher omega-3 (n-3) index in adult females was a predictor of lower MDA concentrations (p = 0.038). Conversely, total n-3 PUFA and total n-6 PUFA were positively related to MDA values among older adult females and LLI men (p < 0.05), while total n-6 PUFA was inversely correlated with MDA levels in LLI females (p < 0.05). Interestingly, increased concentrations of total n-3 PUFA and n-3 index were positively correlated with higher TEAC values in LLI men (p = 0.007), while the arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio was inversely correlated with TEAC values among LLI females (p = 0.006). These findings suggest that cellular antioxidant capacity is inversely correlated with changes in the AA/EPA ratio in long-lived females, whereas n-3 PUFA may enhance blood antioxidant capacity in long-lived men. Overall, our study highlights the complex, sex-specific interactions between PUFA profiles and oxidative stress and inflammatory markers across different age groups.

Porphyromonas gingivalis virulence factors induce toxic effects in SH-SY5Y neuroblastoma cells: GRK5 modulation as a protective strategy.

Periodontitis (PDS) is a chronic inflammatory disease initiated by a dysbiosis of oral pathogenic bacterial species, such as Porphyromonas gingivalis (Pg). These bacteria can penetrate the bloodstream, releasing various endo and exotoxins that fuel the infection, and stimulate toxic inflammation in different compartments, including the brain. However, the specific mechanisms by which PDS/Pg contribute to brain disorders, such as Alzheimer's disease (AD), remain unclear. This study assessed the effects of Pg's virulence factors - lipopolysaccharide (LPS-Pg) and gingipains (gps) K (Kgp) and Rgp - on SH-SY5Y cells. Our results demonstrated that LPS-Pg activated signaling through the Toll-like receptor (TLR)-2/4 induced a significant downregulation of G protein-coupled receptor kinase 5 (GRK5). Additionally, LPS-Pg stimulation resulted in a robust increase in Tau phosphorylation (pTau) and p53 levels, while causing a marked reduction in Bcl2 and increased cell death compared to unstimulated cells (Ns). LPS-Pg also elevated inducible nitric oxide synthase (iNOS) expression, leading to oxidative damage. In cells overexpressing GRK5 via Adenovirus, LPS-Pg failed to increase iNOS and pTau levels compared to GFP control cells. High GRK5 levels also prevented the nuclear accumulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Furthermore, the overexpression of a GRK5 mutant form lacking the nuclear localization signal (ΔNLS) nearly abolished LPS-Pg induced p53 and iNOS upregulation. Finally, we tested whether Kgp and Rgp mediated similar effects and our data showed that both gps caused a marked downregulation of GRK5 leading to increased p53 and pTau levels. In conclusion, this study provides further insight into the toxic effects elicited by Pg in cells and suggests that preventing GRK5 deficiency may be a valid strategy to mitigate Pg-induced toxic effects (i.e. cell death, oxidative damage, and Tau hyperphosphorylation) in SH-SY5Y cells, which are typical molecular hallmarks of neurodegenerative disorders.

Circulating brain-derived neurotrophic factor levels and heart failure: A systematic review and meta-analysis.

AIMS: Biomarkers are paramount for managing heart failure (HF) patients as prognostic and therapeutic efficacy index tools. Systemic levels of brain-derived neurotrophic factor (BDNF) can add to the HF biomarker scenario, allowing for potentiated efficacy in diagnosis, prognostic stratification, and prediction of patient response to a given therapeutic intervention because BDNF is one of the primary rulers of myocardial function. Yet, whether BDNF is a reliable clinical biomarker awaits clinical validation. Hence, we aimed to answer this relevant question via a systematic review and meta-analysis of existing studies. METHODS AND RESULTS: International databases, including PubMed, Scopus, Embase, and the Web of Science, were comprehensively searched for studies assessing BDNF levels in patients with HF versus non-HF controls or as a prognostic factor for HF complications. Data were extracted and analysed by random-effect meta-analysis. Standardized mean difference (SMD) and 95% confidence intervals (CIs) were computed to pool the results of studies. We included 11 studies in the final review, among which six underwent meta-analysis. These studies analysed 1420 HF patients, with a mean age of 65.4 ± 11.2 years. Meta-analysis revealed that patients with HF had significantly lower circulating BDNF levels than healthy controls (SMD -2.47, 95% CI -4.39 to -0.54, P-value = 0.01). Moreover, patients with higher New York Heart Association functional classification had lower levels of BDNF. Adverse clinical outcomes such as all-cause mortality and HF rehospitalization were also associated with lower levels of BDNF in individual studies. CONCLUSIONS: BDNF levels are decreased in patients with HF. Most importantly, we observed an association between lower BDNF levels and poor prognosis in patients with HF. Our study supports BDNF as an easy-to-dose diagnostic and prognostic biomarker to be implemented in clinical practice for HF. Further studies are warranted to address this ability specifically.

Age and sex mediated effects of estrogen and Β3-adrenergic receptor on cardiovascular pathophysiology.

Sex differences are consistently identified in determining the prevalence, manifestation, and response to therapies in several systemic disorders, including those affecting the cardiovascular (CV), skeletal muscle, and nervous system. Interestingly, such differences are often more noticeable as we age. For example, premenopausal women experience a lower risk of CV disease than men of the same age. While at an advanced age, with menopause, the risk of cardiovascular diseases and adverse outcomes increases exponentially in women, exceeding that of men. However, this effect appears to be reversed in diseases such as pulmonary hypertension, where women are up to seven times more likely than men to develop an idiopathic form of the disease with symptoms developing ten years earlier than their male counterparts. Explaining this is a complex question. However, several factors and mechanisms have been identified in recent decades, including a role for sex hormones, particularly estrogens and their related receptors. Furthermore, an emerging role in these sex differences has also been suggested for ß-adrenergic receptors (ßARs), which are essential regulators of mammalian physiology. It has in fact been shown that ßARs interact with estrogen receptors (ER), providing further demonstration of their involvement in determining sexual differences. Based on these premises, this review article focused on the ß3AR subtype, which shows important activities in adipose tissue but with new and interesting roles in regulating the function of cardiomyocytes and vascular cells. In detail, we examined how ß3AR and ER signaling are intertwined and whether there would be sex- and age-dependent specific effects of these receptor systems.

Assessing the association between triglyceride-glucose index and atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: An essential relationship between insulin resistance (IR) and atrial fibrillation (AF) has been demonstrated. Among the methods used to assess IR, the triglyceride-glucose (TyG) index is the more straightforward, dimensionless, and low-cost tool. However, the possible usage of this index in clinical practice to predict and diagnose AF has yet to be determined and consolidated. OBJECTIVE AND RATIONALE: Herein, we performed a systematic review and meta-analysis to assess the association between the TyG index and AF. METHODS: Databases (PubMed, Embase, Scopus, and Web of Science) were systematically searched for studies evaluating the TyG index in AF. The inclusion criteria were observational studies investigating AF and TyG index correlation in individuals older than 18 years, while preclinical studies and those without the relevant data were excluded. Random effect meta-analyses comparing TyG levels between AF and non-AF cases, AF recurrence after radiofrequency ablation, and post-procedural AF were performed using standardized mean differences (SMD) with their matching 95% confidence intervals (CIs). RESULTS: Our screening identified nine studies to be analyzed, including 6,171 participants including 886 with AF. The meta-analysis demonstrated that the TyG index resulted higher in patients with AF than non-AF counterparts (SMD 1.23, 95% CI 0.71 to 1.75, I2 98%, P < 0.001). Subgroup analysis showed the same results for post-procedure AF (SMD 0.99, 95% CI 0.78 to 1.20, I2 10%, P < 0.001) and post-ablation AF (SMD 1.25, 95% CI 1.07 to 1.43, I2 46%, P < 0.001), while no difference was found in population-based cohorts (SMD 1.45, 95% CI - 0.41 to 3.31, I2 100%, P = 0.13). Publication year (P = 0.036) and sample size (P = 0.003) showed significant associations with the effect size, using multivariable meta-regression. CONCLUSION: The TyG index is an easy-to-measure surrogate marker of IR in patients with AF. Further clinical studies are warranted to demonstrate its ability for routine clinical use and as a screening tool.

The importance of assessing the triglyceride-glucose index (TyG) in patients with depression: A systematic review.

Insulin resistance (IR) has been proposed as a potential risk factor for depression, a major common disorder affecting a significant proportion of adults worldwide. Based on this premise, this study systematically investigated all the studies examining the triglyceride-glucose (TyG) index, a surrogate marker of IR, in patients with depression or suicidal ideas/attempts. Four online databases (PubMed, Scopus, Embase, and Web of Science) were comprehensively searched. After screening, seven studies were included, comprised of 58,981 participants and 46.4% male. While there were some discrepancies among the reports of studies, most of the included studies reported higher levels of TyG index in patients with depression. Moreover, in most cases, a 1-unit increase in the TyG index was associated with significantly higher odds of depression. At last, higher TyG levels were associated with suicidal ideation and attempts. Therefore, this study emphasizes the critical need to further research in this regard and possibly integrate the TyG index measure with routine depression screening to avoid fatal events in the future.

Triglyceride-glucose index and obstructive sleep apnea: a systematic review and meta-analysis.

BACKGROUND: Obstructive sleep apnea (OSA) has a bidirectional association with metabolic syndrome, and insulin resistance (IR). The triglyceride-glucose (TyG) index could be a simply calculated marker of IR in OSA. However, its clinical application appears still limited. Hence, this systematic review and meta-analysis aimed to respond to this question by analyzing all the existing studies showing an association between OSA and the TyG index. METHODS: Four online databases, including PubMed, Scopus, the Web of Science, and Embase were searched for studies evaluating the TyG index in OSA. After screening and data extraction, a random-effect meta-analysis was performed to compare the TyG index in OSA patients vs. healthy controls by calculating standardized mean difference (SMD) and 95% confidence interval (CI) and pooling the area under the curves (AUCs) for diagnosis of OSA based on this index. RESULTS: Ten studies involving 16,726 individuals were included in the current systematic review. Meta-analysis indicated that there was a significantly higher TyG index in patients with OSA, compared with the healthy controls (SMD 0.856, 95% CI 0.579 to 1.132, P < 0.001). Also, TyG had a diagnostic ability for OSA representing a pooled AUC of 0.681 (95% CI 0.627 to 0.735). However, based on the two studies' findings, no difference between different severities of OSA was observed. Finally, our data showed that the TyG index is a good potential predictor of adverse outcomes in these patients. CONCLUSION: Our study revealed that the TyG index is an easy-to-measure marker of IR for assessing OSA, both in diagnosis and prognosis. Our study supports its implementation in routine practice to help clinicians in decision-making and patient stratification.

Insights into the Role of Galectin-3 as a Diagnostic and Prognostic Biomarker of Atrial Fibrillation.

Atrial fibrillation (AF) is an irregular atrial activity and the most prevalent type of arrhythmia. Although AF is easily diagnosed with an electrocardiogram, there is a keen interest in identifying an easy-to-dose biomarker that can predict the prognosis of AF and its recurrence. Galectin-3 (Gal-3) is a beta-galactoside binding protein from the lectin family with pro-fibrotic and -inflammatory effects and a pivotal role in a variety of biological processes, cell proliferation, and differentiation; therefore, it is implicated in the pathogenesis of many cardiovascular (e.g., heart failure (HF)) and noncardiovascular diseases. However, its specificity and sensitivity as a potential marker in AF patients remain debated and controversial. This article comprehensively reviewed the evidence regarding the interplay between Gal-3 and patients with AF. Clinical implications of measuring Gal-3 in AF patients for diagnosis and prognosis are mentioned. Moreover, the role of Gal-3 as a potential biomarker for the management of AF recurrence is investigated. The association of Gal-3 and AF in special populations (coronary artery disease, HF, metabolic syndrome, chronic kidney disease, and diabetes mellitus) has been explored in this review. Overall, although further studies are needed to enlighten the role of Gal-3 in the diagnosis and treatment of AF, our study demonstrated the high potential of this molecule to be used and focused on by researchers and clinicians.

Triglyceride-glucose index and heart failure: a systematic review and meta-analysis.

BACKGROUND: Insulin resistance (IR) is a major metabolic disorder observed in heart failure (HF) and is tightly associated with patients' poor prognosis. The triglyceride-glucose index (TyG) has been proposed as a surrogate marker of IR in HF. Yet, whether TyG is a reliable clinical marker is still under debate. Hence, we aimed to respond to this relevant question via a systematic review and meta-analysis of existing studies. METHODS: A systematic search was conducted in PubMed, Embase, Scopus, and Web of Science to find studies investigating the TyG index in patients with HF or its association with the incidence of HF. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were pooled through random-effect meta-analysis. HRs were calculated using TyG as a continuous variable (1 unit increase) and by comparing the group with the highest TyG to the lowest TyG group. RESULTS: Thirty studies, involving 772,809 participants, were included in this systematic review. Meta-analysis of seven studies comparing the highest-TyG to the lowest-TyG group showed a significantly increased risk of HF in the former group (HR 1.21, 95% CI 1.14 to 1.29, P < 0.01). The same result was found when pooling the HRs for a one-unit increase in the TyG index (HR 1.17, 95% CI 1.08 to 1.26). Similarly, a more elevated TyG index was associated with a higher incidence of HF in patients with type 2 diabetes or coronary artery disease. Additionally, the incidence of adverse events (readmission and mortality) in patients with HF was associated with TyG. CONCLUSION: Our findings support the TyG index as a valuable marker to assess the risk of HF incidence in different populations and as a prognostic marker in patients with HF. Further studies should be conducted to confirm these associations and investigate the clinical utility of the TyG index.

Equol and Resveratrol Improve Bone Turnover Biomarkers in Postmenopausal Women: A Clinical Trial.

Estrogen deficiency is a major cause of loss of postmenopausal bone mineral density (BMD). This study aimed to evaluate the effects of equol and resveratrol on bone turnover biomarkers in postmenopausal women. Sixty healthy postmenopausal women were randomly assigned to receive 200 mg fermented soy containing 10 mg equol and 25 mg resveratrol or a placebo for 12 months. Whole-body BMD and bone turnover biomarkers, such as deoxypyridinoline (DPD), tartrate-resistant acid phosphatase 5b (TRACP-5b), osteocalcin, and bone-specific alkaline phosphatase (BAP), were measured at baseline and after 12 months of treatment. At the end of treatment, DPD, osteocalcin, and BAP significantly improved in the active group (p < 0.0001 for all) compared to the placebo group. Conversely, TRACP-5b levels were unaffected by supplementation (p = 0.051). Statistically significant changes in the concentrations of DPD (p < 0.0001), osteocalcin (p = 0.0001), and BAP (p < 0.0001) compared to baseline were also identified. Overall, the intervention significantly increased BMD measured in the whole body (p = 0.0220) compared with the placebo. These data indicate that the combination of equol and resveratrol may positively modulate bone turnover biomarkers and BMD, representing a potential approach to prevent age-related bone loss in postmenopausal women.

Molecular Mechanisms Underlying Chronic and Degenerative Diseases.

The Special Issue entitled "Molecular Mechanisms Underlying Chronic and Degenerative Diseases" contains eight articles: six original studies and two reviews [...].

Endocan as a marker of endothelial dysfunction in hypertension: a systematic review and meta-analysis.

Hypertension is one of the foremost risk factors for cardiovascular disease and a significant cause of death worldwide. Importantly, endothelial dysfunction (ED) is one of the primary manifestations that may precede the development of hypertension. Endocan is a novel endothelial dysfunction and inflammation biomarker secreted from endothelial cells. Whether endocan may serve as a biomarker of hypertension is currently debated. This systematic review and meta-analysis aimed at linking endocan to ED in hypertensive patients. International databases, including PubMed, Scopus, Embase, and Web of Science, were systematically searched for studies investigating Endocan serum or plasma levels in hypertensive patients and healthy controls. Random effect meta-analysis was performed to calculate the standardized mean difference (SMD) and 95% confidence interval (CI). A total of 20 studies assessing the association between endocan levels and hypertension were included in which 3130 individuals with a mean age of 50.48 ± 8.45 years were assessed. Hypertensive patients presented with higher circulating endocan levels (SMD 0.91, 95% CI 0.44-1.38, p-value < 0.01) compared with healthy controls. Interestingly, our data demonstrated that removing three studies assessing endocan levels in hypertensive patients with different comorbidities or special populations resulted in the same statistically higher endocan levels (SMD 1.16, 95% CI 0.66-1.65, p-value < 0.01). Overall, this systematic review and meta-analysis indicated that in hypertensive patients circulating endocan levels are significantly elevated. Thus, suggesting endocan as an easy-to-use biomarker to detect ED in hypertension. Despite this, more research is warranted to address this potential ability specifically.

ß3AR-Dependent Brain-Derived Neurotrophic Factor (BDNF) Generation Limits Chronic Postischemic Heart Failure.

BACKGROUND: Loss of brain-derived neurotrophic factor (BDNF)/TrkB (tropomyosin kinase receptor B) signaling accounts for brain and cardiac disorders. In neurons, ß-adrenergic receptor stimulation enhances local BDNF expression. It is unclear if this occurs in a pathophysiological relevant manner in the heart, especially in the ß-adrenergic receptor-desensitized postischemic myocardium. Nor is it fully understood whether and how TrkB agonists counter chronic postischemic left ventricle (LV) decompensation, a significant unmet clinical milestone. METHODS: We conducted in vitro studies using neonatal rat and adult murine cardiomyocytes, SH-SY5Y neuronal cells, and umbilical vein endothelial cells. We assessed myocardial ischemia (MI) impact in wild type, ß3AR knockout, or myocyte-selective BDNF knockout (myoBDNF KO) mice in vivo (via coronary ligation [MI]) or in isolated hearts with global ischemia-reperfusion (I/R). RESULTS: In wild type hearts, BDNF levels rose early after MI (<24 hours), plummeting at 4 weeks when LV dysfunction, adrenergic denervation, and impaired angiogenesis ensued. The TrkB agonist, LM22A-4, countered all these adverse effects. Compared with wild type, isolated myoBDNF KO hearts displayed worse infarct size/LV dysfunction after I/R injury and modest benefits from LM22A-4. In vitro, LM22A-4 promoted neurite outgrowth and neovascularization, boosting myocyte function, effects reproduced by 7,8-dihydroxyflavone, a chemically unrelated TrkB agonist. Superfusing myocytes with the ß3AR-agonist, BRL-37344, increased myocyte BDNF content, while ß3AR signaling underscored BDNF generation/protection in post-MI hearts. Accordingly, the ß1AR blocker, metoprolol, via upregulated ß3ARs, improved chronic post-MI LV dysfunction, enriching the myocardium with BDNF. Last, BRL-37344-imparted benefits were nearly abolished in isolated I/R injured myoBDNF KO hearts. CONCLUSIONS: BDNF loss underscores chronic postischemic heart failure. TrkB agonists can improve ischemic LV dysfunction via replenished myocardial BDNF content. Direct cardiac ß3AR stimulation, or ß-blockers (via upregulated ß3AR), is another BDNF-based means to fend off chronic postischemic heart failure.

Galectins can serve as biomarkers in COVID-19: A comprehensive systematic review and meta-analysis.

Background: Galectins are an eleven-member class of lectins in humans that function as immune response mediators and aberrancies in their expression are commonly associated with immunological diseases. Several studies have focused on galectins as they may represent an important biomarker and a therapeutic target in the fight against COVID-19. This systematic review and meta-analysis examined the usefulness of clinical assessment of circulating galectin levels in patients with COVID-19. Methods: International databases including PubMed, Scopus, Web of Science, and Embase were systematically used as data sources for our analyses. The random-effect model was implemented to calculate the standardized mean difference (SMD) and a 95% confidence interval (CI). Results: A total of 18 studies, comprising 2,765 individuals, were identified and used in our analyses. We found that Gal-3 is the most widely investigated galectin in COVID-19. Three studies reported significantly higher Gal-1 levels in COVID-19 patients. Meta-analysis revealed that patients with COVID-19 had statistically higher levels of Gal-3 compared with healthy controls (SMD 0.53, 95% CI 0.10 to 0.96, P=0.02). However, there was no significant difference between severe and non-severe cases (SMD 0.45, 95% CI -0.17 to 1.07, P=0.15). While one study supports lower levels of Gal-8 in COVID-19, Gal-9 was measured to be higher in patients and more severe cases. Conclusion: Our study supports Gal-3 as a valuable non-invasive biomarker for the diagnosis and/or prognosis of COVID-19. Moreover, based on the evidence provided here, more studies are needed to confirm a similar diagnostic and prognostic role for Gal-1, -8, and -9.

Are Skeletal Muscle Changes during Prolonged Space Flights Similar to Those Experienced by Frail and Sarcopenic Older Adults?

Microgravity exposure causes several physiological and psychosocial alterations that challenge astronauts' health during space flight. Notably, many of these changes are mostly related to physical inactivity influencing different functional systems and organ biology, in particular the musculoskeletal system, dramatically resulting in aging-like phenotypes, such as those occurring in older persons on Earth. In this sense, sarcopenia, a syndrome characterized by the loss in muscle mass and strength due to skeletal muscle unloading, is undoubtedly one of the most critical aging-like adverse effects of microgravity and a prevalent problem in the geriatric population, still awaiting effective countermeasures. Therefore, there is an urgent demand to identify clinically relevant biological markers and to underline molecular mechanisms behind these effects that are still poorly understood. From this perspective, a lesson from Geroscience may help tailor interventions to counteract the adverse effects of microgravity. For instance, decades of studies in the field have demonstrated that in the older people, the clinical picture of sarcopenia remarkably overlaps (from a clinical and biological point of view) with that of frailty, primarily when referred to the physical function domain. Based on this premise, here we provide a deeper understanding of the biological mechanisms of sarcopenia and frailty, which in aging are often considered together, and how these converge with those observed in astronauts after space flight.

Special Issue: "G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2.0".

The second volume of this Special Issue, entitled "G Protein-Coupled Receptor and Their Kinases in Cell Biology and Disease 2 [...].

Beta-3 adrenergic receptor overexpression reverses aortic stenosis-induced heart failure and restores balanced mitochondrial dynamics.

Aortic stenosis (AS) is associated with left ventricular (LV) hypertrophy and heart failure (HF). There is a lack of therapies able to prevent/revert AS-induced HF. Beta3 adrenergic receptor (ß3AR) signaling is beneficial in several forms of HF. Here, we studied the potential beneficial effect of ß3AR overexpression on AS-induced HF. Selective ß3AR stimulation had a positive inotropic effect. Transgenic mice constitutively overexpressing human ß3AR in the heart (c-hß3tg) were protected from the development of HF in response to induced AS, and against cardiomyocyte mitochondrial dysfunction (fragmented mitochondria with remodeled cristae and metabolic reprogramming featuring altered substrate use). Similar beneficial effects were observed in wild-type mice inoculated with adeno-associated virus (AAV9) inducing cardiac-specific overexpression of human ß3AR before AS induction. Moreover, AAV9-hß3AR injection into wild-type mice at late disease stages, when cardiac hypertrophy and metabolic reprogramming are already advanced, reversed the HF phenotype and restored balanced mitochondrial dynamics, demonstrating the potential of gene-therapy-mediated ß3AR overexpression in AS. Mice with cardiac specific ablation of Yme1l (cYKO), characterized by fragmented mitochondria, showed an increased mortality upon AS challenge. AAV9-hß3AR injection in these mice before AS induction reverted the fragmented mitochondria phenotype and rescued them from death. In conclusion, our results step out that ß3AR overexpression might have translational potential as a therapeutic strategy in AS-induced HF.

Relationship between COVID-19 Mortality, Hospital Beds, and Primary Care by Italian Regions: A Lesson for the Future.

One of the characteristics of the SARS-CoV-2 infection in Italy is the significant regional difference in terms of lethality and mortality. These geographical variances were clear in the first wave and confirmed in the second one as well. The study aimed to analyze the correlation between regional differences in COVID-19 mortality and different regional care models, by retrospectively analyzing the association between the Italian COVID-19 deaths and the number of hospital beds, long-term care facilities, general practitioners (GPs), and the health expenditure per capita. The period considered was from 1 March 2020 to 1 March 2021. The number of hospital beds (p < 0.0001) and the number of GPs (p = 0.0094) significantly predicted the COVID-19 death rate. The Italian regions with a higher number of hospital beds and a lower number of GPs showed a higher number of deaths. Multivariate analyses confirmed the results. The Italian regions with a higher amount of centralized healthcare, as represented by the number of hospital beds, experienced a higher number of deaths, while the regions with greater community support, as exemplified by the number of the GPs, faced higher survival. These results suggest the need for a change in the current healthcare system organization.

Sex/Gender- and Age-Related Differences in ß-Adrenergic Receptor Signaling in Cardiovascular Diseases.

Sex differences in cardiovascular disease (CVD) are often recognized from experimental and clinical studies examining the prevalence, manifestations, and response to therapies. Compared to age-matched men, women tend to have reduced CV risk and a better prognosis in the premenopausal period. However, with menopause, this risk increases exponentially, surpassing that of men. Although several mechanisms have been provided, including sex hormones, an emerging role in these sex differences has been suggested for ß-adrenergic receptor (ß-AR) signaling. Importantly, ß-ARs are the most important G protein-coupled receptors (GPCRs), expressed in almost all the cell types of the CV system, and involved in physiological and pathophysiological processes. Consistent with their role, for decades, ßARs have been considered the first targets for rational drug design to fight CVDs. Of note, ß-ARs are seemingly associated with different CV outcomes in females compared with males. In addition, even if there is a critical inverse correlation between ß-AR responsiveness and aging, it has been reported that gender is crucially involved in this age-related effect. This review will discuss how ß-ARs impact the CV risk and response to anti-CVD therapies, also concerning sex and age. Further, we will explore how estrogens impact ß-AR signaling in women.