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GLP-1 receptor agonists, which were initially intended to treat type 2 diabetes patients, have demonstrated promise as an adjuvant therapy for type 1 diabetes (T1D). These medications can manage T1D by improving ß-cell function, reducing glucose fluctuation, and providing cardioprotective effects. Recent research suggests that boosting cell proliferation and lowering apoptosis can help maintain the bulk of ß-cells. Furthermore, GLP-1 receptor agonists have potent anti-inflammatory characteristics, improving immunological control and lowering systemic inflammation, both of which are critical for reducing autoimmune damage in T1D. Beyond glucose control, these agonists have neuroprotective qualities and aid in weight management. Combining these medications with insulin could significantly change how T1D is managed. The clinical data and biological mechanisms discussed in this review support the potential use of GLP-1 receptor agonists in T1D.

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This study aimed to prepare, characterize and assess the antioxidant activity of yellow bedstraw extracts (YBEs), focusing on identifying extracts with high antioxidant capacity. The selected extract was loaded into an oral liquid formulation and further investigated for its therapeutic potential in reducing blood pressure and associated complications in spontaneously hypertensive Wistar kyoto rats (SHR). Rats were divided into untreated SHR and SHR treated with a YBE-based oral formulation over four weeks. After treatment, blood pressure was measured, and cardiac function was assessed using the Langendorff technique to simulate ex vivo ischemic conditions. Prooxidant levels were assessed in plasma while antioxidant activity was evaluated in red blood cells. Histological analyses of heart, kidney, and liver samples were conducted to assess pathological changes induced by hypertension. Our results showed that the oral formulation loaded with ethanol YBE effectively reduced blood pressure, preserved myocardial function under ischemic stress, and decreased oxidative stress markers in blood. Importantly, our formulation with YBE demonstrated potential in attenuating structural kidney damage associated with hypertension. Overall, these findings suggest a cardioprotective effect of orally administered YBE formulation, highlighting its potential as an herbal supplement. However, clinical studies are warranted to validate these findings and explore the extract's suitability for clinical use.

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Cardiovascular diseases (CVDs) contribute to major public health issues. Some studies have found that caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) may effectively prevent or treat CVDs. However, there is a major need to sum up our current understanding of the possible beneficial or detrimental effects of CA and CAPE on CVDs and related mechanisms. Therefore, this study aimed to summarize the data on this topic. A methodical search was carried out on key databases, including Pubmed, Google Scholar, Scopus, and Web of Science, from the beginning to June 2024. Studies were then assessed for eligibility based on inclusion and exclusion criteria. Treatment with CA and CAPE significantly and positively affected cardiovascular health in various aspects, including atherosclerotic diseases, myocardial infarction, hypertension, cardiac arrhythmias, and hypercoagulation state. Several mechanisms were proposed to mediate these effects, including transcription factors and signaling pathways associated with antioxidant, cytostatic, and anti-inflammatory processes. CA and CAPE were found to have several beneficial effects via multiple mechanisms during the prevention and treatment of various CVDs. However, these promising effects were only reported through in vitro and animal studies, which reinforces the need for further evaluation of these effects via human clinical investigations.

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Metformin is an orally effective anti-hyperglycemic drug that despite being introduced over 60 years ago is still utilized by an estimated 120 to 150 million people worldwide for the treatment of type 2 diabetes (T2D). Metformin is used off-label for the treatment of polycystic ovary syndrome (PCOS) and for pre-diabetes and weight loss. Metformin is a safe, inexpensive drug with side effects mostly limited to gastrointestinal issues. Prospective clinical data from the United Kingdom Prospective Diabetes Study (UKPDS), completed in 1998, demonstrated that metformin not only has excellent therapeutic efficacy as an anti-diabetes drug but also that good glycemic control reduced the risk of micro- and macro-vascular complications, especially in obese patients and thereby reduced the risk of diabetes-associated cardiovascular disease (CVD). Based on a long history of clinical use and an excellent safety record metformin has been investigated to be repurposed for numerous other diseases including as an anti-aging agent, Alzheimer's disease and other dementias, cancer, COVID-19 and also atrial fibrillation (AF). AF is the most frequently diagnosed cardiac arrythmia and its prevalence is increasing globally as the population ages. The argument for repurposing metformin for AF is based on a combination of retrospective clinical data and in vivo and in vitro pre-clinical laboratory studies. In this review, we critically evaluate the evidence that metformin has cardioprotective actions and assess whether the clinical and pre-clinical evidence support the use of metformin to reduce the risk and treat AF.

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As the world's aging population increases, cardiovascular diseases (CVDs) associated with aging deserve increasing attention. CVD in association with age is considered a major cause of morbidity and mortality worldwide. In this review, we provide an overview of the key molecular pathways, cellular processes such as autophagy, oxidative stress, inflammatory responses, myocardial remodeling and ischemia-refocused injury that accompany CVD as well as the natural products of targeting these mechanisms and some of the dietary habits that have been studied in cardiovascular-related diseases. The potential preventive and therapeutic avenues resulting from these dietary habits and natural products related to animal models and clinical studies can help us to better understand the processes involved in cardiovascular diseases and provide recommendations to reduce the cardiovascular burden associated with aging heart.

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Hypercholesterolemia, especially LDL-C («Low-Density-Lipoprotein - Cholesterol¼), is a major cardiovascular risk factor, especially for coronary artery disease. Patients at high or very high cardiovascular risk should reach LDL concentrations as low as possible («the lower, the better¼), with a reduction of at least 50 % from baseline levels according to the most recent guidelines, especially those in secondary prevention. An ezetimibe-statin combination most often allows to reach this goal thanks to a complementary action. The objectives of this article are to remind the dual actions of these two medications, to summarize the clinical evidence showing not only a remarkable cholesterol-lowering effect but also a reduction in cardiovascular events in both controlled trials and observational real-life studies, to specify the positioning of this combined oral therapy in the last international guidelines and to mention pharmaceutical specialties that combine ezetimibe with a statin available for the practitioner.

L'hypercholestérolémie, en particulier le LDL-C («Low-Density-Lipoprotein - Cholesterol¼), est un facteur de risque cardiovasculaire, notamment coronarien, majeur. Les patients à haut ou très haut risque cardiovasculaire doivent atteindre des concentrations de LDL les plus basses possibles (concept du «the lower, the better¼), avec une diminution d'au moins 50 % des valeurs de base selon les dernières recommandations, tout particulièrement ceux en prévention secondaire. Une combinaison ézétimibe-statine permet souvent d'atteindre cet objectif grâce à une action complémentaire. Le but de cet article est de rappeler la dualité des mécanismes d'action de ces deux approches, de résumer les évidences cliniques montrant non seulement un remarquable effet hypocholestérolémiant mais aussi une réduction des événements cardiovasculaires dans les essais cliniques et dans les études observationnelles de vraie vie, de préciser la position de cette combinaison thérapeutique orale dans les dernières recommandations internationales et de mentionner les spécialités pharmaceutiques associant l'ézétimibe à une statine mises à la disposition du praticien.

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The potential role of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in the management of COVID-19 and other medical conditions has emerged as an intriguing area of research. PCSK9 is primarily known for its impact on cholesterol metabolism, but recent studies have unveiled its involvement in various physiological processes, including inflammation, immune regulation, and thrombosis. In this abstract, the authors review the rationale and potential implications of PCSK9 inhibition during the inflammatory stage of SARS-CoV-2 infection. Severe cases of COVID-19 are characterized by an uncontrolled inflammatory response, often referred to as the cytokine storm, which can lead to widespread tissue damage and organ failure. Preclinical studies suggest that PCSK9 inhibition could dampen this inflammatory cascade by reducing the production of pro-inflammatory cytokines. Additionally, PCSK9 inhibition may protect against acute respiratory distress syndrome (ARDS) through its effects on lung injury and inflammation. COVID-19 has been linked to an increased risk of cardiovascular complications, especially in patients with pre-existing cardiovascular conditions or dyslipidemia. PCSK9 inhibitors are known for their ability to lower low-density lipoprotein (LDL) cholesterol levels by enhancing the recycling of LDL receptors in the liver. By reducing LDL cholesterol, PCSK9 inhibition might protect blood vessels from further damage and lower the risk of atherosclerotic plaque formation. Moreover, PCSK9 inhibitors have shown potential antithrombotic effects in preclinical studies, making them a potential avenue to mitigate the increased risk of coagulation disorders and thrombotic events observed in COVID-19. While the potential implications of PCSK9 inhibition are promising, safety considerations and possible risks need careful evaluation. Hypocholesterolemia, drug interactions, and long-term safety are some of the key concerns that should be addressed. Clinical trials are needed to establish the efficacy and safety of PCSK9 inhibitors in COVID-19 patients and to determine the optimal timing and dosing for treatment. Future research opportunities encompass investigating the immune response, evaluating long-term safety, exploring combination therapy possibilities, and advancing personalized medicine approaches. Collaborative efforts from researchers, clinicians, and policymakers are essential to fully harness the therapeutic potential of PCSK9 inhibition and translate these findings into meaningful clinical outcomes.

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Both spironolactone and finerenone treatments significantly reduced SBP and there was no statistical difference in their antihypertensive effects. The differences in body weight (at the end of 1/2/3/4 week) to pre-dose body weight ratio and heart rate (at the end of 1/2/3/4 week) to pre-dose heart rate ratio were not statistically significant in the vehicle, spironolactone, finerenone, and control groups.There was no statistically significant difference in mortality among the vehicle, spironolactone, and finerenone groups. The relative heart mass, ANP, BNP, CVF, Col I, TGF-ß, and Casp-3 were gradually decreased in vehicle group, spironolactone group, and finerenone group. Among them, BNP, CVF, TGF-ß, and Casp-3 were significantly decreased in the finerenone group compared with the vehicle group. HE and Masson staining showed that the cardiomyocytes of rats in the vehicle group and spironolactone group were disorganized, with cell hypertrophy, significantly enlarged cell gaps and a large amount of collagen deposition, whereas the cardiomyocytes of rats in the finerenone group and the control group were more neatly arranged, with smaller cell gaps and a small amount of collagen tissue deposition. RNA sequencing (RNA-seq) showed that there was a total of 119 differentially expressed genes (DEGs) between finerenone treatment and vehicle treatment. Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis showed that the signaling pathways involved were mainly in drug metabolism-cytochrome P450, chemical carcinogenesis, IL-17 signaling pathway, axon guidance, and hematopoietic cell lineage. Protein-protein interaction (PPI) analysis showed that the core genes were Oaslf, Nos2, LOC687780, Rhobtb1, Ephb3, and Rps27a.

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BACKGROUND: Elevated high-density lipoprotein-cholesterol (HDL-cholesterol) levels have been linked to unfavorable outcomes in various clinical settings, but the association with thyroid nodules remains unclear. We aimed to analyze the correlation between elevated HDL-cholesterol and the presence of thyroid nodules along with certain demographic and clinical findings. METHODS: In this retrospective study, the patients were divided into three groups based on their body mass index (BMI): <25, 25-29, and >30 and evaluated. Data of 677 patients aged between 15 and 95 years (52.6 ± 15.6) were evaluated. The entire study population comprised 516 females (76.2%). RESULTS: Thyroid nodules (67.1%) and left ventricle diastolic dysfunction (LVDD) (58.1%) were the two most frequent findings in the overall cohort. In the multivariate regression model, BMI, heart rate, and HDL-cholesterol values were significant and independent predictors (p = 0.000 for all) of the presence of thyroid nodules. The presence of thyroid nodules is higher in females, particularly within the higher BMI groups [odds ratio (OR) = 1.048 (CI = 1.02-1.08) for BMI < 25, p = 0.003; OR = 1.094 (CI = 1.05-1.14) for BMI 25-29, p = 0.000; OR = 1.115 (CI = 1.05-1.19) for BMI ≥ 30]. This higher incidence is not observed in males. CONCLUSION: While the precise mechanisms underlying this association are yet to be fully elucidated, elevated HDL-cholesterol may serve as an indicator of thyroid nodules rather than a marker of cardiovascular protection.

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BACKGROUND: Metformin is among the most frequently prescribed antidiabetic drugs worldwide and remains the first-line therapy for type 2 diabetes due to its well-established glucose-lowering efficacy and favorable safety profile. SUMMARY: Studies over the past decades show that metformin also exerts many other beneficial effects independent of its glucose-lowering effect both in experimental models and human subjects. Among them, the most notable is its cardiovascular protective effect. In this review, we discuss the latest cutting-edge research findings on metformin's cardiovascular protection from both preclinical studies and randomized clinical trials. We focus on describing novel basic research discoveries reported in influential journals and discussing their implications in the context of latest clinical trial findings related to common cardiovascular and metabolic disorders, including atherosclerosis and dyslipidemia, myocardial injury, and heart failure. KEY MESSAGES: While substantial preclinical and clinical evidence suggests metformin as a potential cardiovascular protectant, large-scale randomized controlled trials are warranted to establish its clinical efficacy in treating patients with atherosclerotic cardiovascular disease and heart failure.

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PURPOSE: This is to evaluate aspirin's cardiovascular (CV) protective effect in chronic kidney disease (CKD) patients. METHODS: We searched PubMed, Embase, Cochrane Library, and Web of Science (up to December 2022) for randomized controlled trials (RCTs) and observational studies comparing aspirin with placebo in CKD patients for the prevention of CV disease (CVD). Efficacy outcomes included CVD, heart failure, myocardial infarction, stroke, CV and all-cause mortality; safety outcomes included major bleeding, minor bleeding, and renal events. RESULTS: Six RCTs and 6 observational studies, including 35,640 participants, met the inclusion criteria and reported relevant CV outcomes, with a mean follow-up of 46.83 months. The pooled data showed aspirin had no significant preventive effect on CVD events (RR=1.03; 95% CI, 0.84-1.27). However, CV mortality was significantly reduced in the aspirin group (RR=0.74; 95% CI, 0.58-0.95). Furthermore, aspirin use did not increase the risk of major bleeding and renal events but significantly increased minor bleeding events (RR=2.11; 95% CI, 1.30-3.44). Renal events were significantly increased after sensitivity analysis (RR=1.10; 95% CI, 1.04-1.16). CONCLUSION: Aspirin did not prevent CV events, with a significantly increased risk of minor bleeding and renal events. Besides, aspirin use had no statistically significant reduction in the risk of all-cause mortality but had a statistically significant reduction in the risk of CV mortality.

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Four Chinese herbs from the Citrus genus, namely Aurantii Fructus Immaturus (Zhishi), Aurantii Fructus (Zhiqiao), Citri Reticulatae Pericarpium Viride (Qingpi) and Citri Reticulatae Pericarpium (Chenpi), are widely used for treating various cardiovascular and gastrointestinal diseases. Many ingredients have already been identified from these herbs, and their various bioactivities provide some interpretations for the pharmacological functions of these herbs. However, the complex functions of these herbs imply undisclosed cholinergic activity. To discover some ingredients with cholinergic activity and further clarify possible reasons for the complex pharmacological functions presented by these herbs, depending on the extended structure-activity relationships of cholinergic and anti-cholinergic agents, a simple method was established here for quickly discovering possible choline analogs using a specific TLC method, and then stachydrine and choline were first identified from these Citrus herb decoctions based on their NMR and HRMS data. After this, two TLC scanning (TLCS) methods were first established for the quantitative analyses of stachydrine and choline, and the contents of the two ingredients and synephrine in 39 samples were determined using the valid TLCS and HPLC methods, respectively. The results showed that the contents of stachydrine (3.04‱) were 2.4 times greater than those of synephrine (1.25‱) in Zhiqiao and about one-third to two-thirds of those of Zhishi, Qingpi and Chenpi. Simultaneously, the contents of stachydrine, choline and synephrine in these herbs present similar decreasing trends with the delay of harvest time; e.g., those of stachydrine decrease from 5.16‱ (Zhishi) to 3.04‱ (Zhike) and from 1.98‱ (Qingpi) to 1.68‱ (Chenpi). Differently, the contents of synephrine decrease the fastest, while those of stachydrine decrease the slowest. Based on these results, compared with the pharmacological activities and pharmacokinetics reported for stachydrine and synephrine, it is indicated that stachydrine can be considered as a bioactive equilibrist for synephrine, especially in the cardio-cerebrovascular protection from these citrus herbs. Additionally, the results confirmed that stachydrine plays an important role in the pharmacological functions of these citrus herbs, especially in dual-directionally regulating the uterus, and in various beneficial effects on the cardio-cerebrovascular system, kidneys and liver.

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OBJECTIVES: To investigate the actions of amlodipine-folic acid (amlodipine-FA) preparation on hypertension and cardiovascular in renal hypertensive rats with hyperhomocysteinemia (HHcy), so as to provide experimental basis for clinical research of amlodipine folic acid tablets. METHODS: Rats model of renal hypertension with HHcy were established. The rats were randomly divided into groups of model, amlodipine, folic acid (FA) and amlodipine-FA of various dosages. Normal rats were used as normal control group. Blood pressure, Hcy as well as plasma NO, ET-1 and hemodynamics were assayed. Histological alterations of heart and abdominal aorta were also examined. RESULTS: Compared with the normal group, blood pressure, plasma Hcy, and NO of the rats in model group were significantly increased, while the plasma ET-1 was decreased. Compared with the normal group, the animals in the model group had reduced cardiac function, thickened wall of the aorta and narrowed lumen. In FA group and amlodipine group, the rat plasma NO was increased while ET-1 was decreased, the protective effect of amlodipine-FA group on endothelial cells was further enhanced. In amlodipine group, the rat hemodynamics (LVSP, LVEDP and ±dp/dtmax, et al.) and vascular damage were significantly reduced, while in amlodipine-FA group, the heart function were further improved, and myocardial and vascular hypertrophy were significantly reduced. CONCLUSIONS: As compared to amlodipine alone, amlodipine -FA can lower both blood pressure and plasma Hcy, significantly enhancing vascular endothelial function to protect the heart and blood vessel in renal hypertensive rats with HHcy.

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Introduction: Cannabidiol (CBD) has important pharmacological activity, which includes antispasmodic, antioxidant, antithrombotic, and antianxiety properties. CBD has been applied as a health supplement to atherosclerosis. However, CBDs effect on gut microbiota and metabolic phenotype is unclear. Materials and Methods: We constructed a high production of cardiovascular risk factors, such as trimethylamine-N-oxide (TMAO) and phenylacetylglutamine (PAGln), in a mouse model using Clostridium sporogenes colonization. We used 16S ribosomal RNA (rRNA) gene sequencing and ultra-high performance liquid chromatography-quadrupole time-of flight mass spectrometry-based metabolomics to evaluate the effect of CBD on gut microbiota and plasma metabolites. Results: CBD decreased the levels of creatine kinase (CK), alanine transaminase (ALT), and low-density lipoprotein cholesterol and markedly increased high-density lipoprotein cholesterol. Furthermore, CBD treatment increased the abundance of beneficial bacteria, which include Lachnospiraceae_NK4A136 and Blautia in the gut, but it decreased the levels of TMAO and PAGln in the plasma. Conclusion: CBD might have beneficial effects for cardiovascular protection.

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Due to their cardiovascular protective effect, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) represent breakthrough therapies for type 2 diabetes mellitus (T2DM). In this review article, we discuss the mechanistic and clinical synergies that make the combined use of GLP-1RAs and SGLT2is appealing in patients with T2DM. Overall, the presented cumulative evidence supports the benefits of GLP-1RA plus SGLT2i combination therapy on metabolic-cardiovascular-renal disease in patients with T2DM, with a low hypoglycemia risk. Accordingly, we encourage the adoption of GLP-1RA plus SGLT2i combination therapy in patients with T2DM and established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD (i.e., age ≥ 55 years, overweight/obesity, dyslipidemia, hypertension, current tobacco use, left ventricular hypertrophy, and/or proteinuria). Regarding renal effects, the evidence of SGLT2is in preventing kidney failure is more abundant than for GLP-1RAs, which showed a beneficial effect on albuminuria but not on hard kidney endpoints. Hence, in case of persistent albuminuria and/or uncontrolled metabolic risks (i.e., inadequate glycemic control, hypertension, overweight/obesity) on SGLT2i therapy, GLP-1RAs should be considered as the preferential add-on therapy in T2DM patients with chronic kidney disease. Despite the potential clinical benefits of GLP-1RA plus SGLT2i combination therapy in patients with T2DM, several factors may delay this combination to become a common practice soon, such as reimbursement and costs associated with polypharmacy. Altogether, when administering GLP-1RA plus SGLT2i combination therapy, it is important to adopt an individualized approach to therapy taking into account individual preferences, costs and coverage, toxicity profile, consideration of kidney function and glucose-lowering efficacy, desire for weight loss, and comorbidities.

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PURPOSE OF REVIEW: Influenza is the cause of millions of deaths yearly in the USA and globally. It presents a significant health burden in millions of people and is associated with chronic disease exacerbations including acute cardiovascular events such as myocardial infarction and stroke. We reviewed recent studies and a meta-analysis to assess the part that influenza vaccination plays in cardiovascular system protection. RECENT FINDINGS: A sizable study measured the effect of influenza vaccination on cardiovascular health and mortality. This retrospective observational study used the 2012-2015 US National Inpatient Sample (NIS) database and included 22,634,643 hospitalizations. The patients who received the vaccine against influenza were associated with lower myocardial infarction (MI) (RR = 0.84, 95% CI: 0.82-0.87, p < 0.001), transient ischemic attack (TIA) (RR = 0.93, 95% CI: 0.9-0.96, p < 0.001), cardiac arrest (RR = 0.36, 95% CI: 0.33-0.39, p < 0.001), stroke (RR = 0.94, 95% CI: 0.91, 0.97, p < 0.001), and mortality (RR = 0.38, 95% CI: 0.36-0.4, p < 0.001). Recent studies have reported a decrease in cardiovascular risk and mortality with influenza vaccine administration. Therefore, it is recommended to obtain the influenza vaccine (if there are no contraindications), especially individuals who are at risk of chronic disease exacerbations including acute cardiovascular events.

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Background: Multiple myeloma (MM) is the second most common hematological malignancy, and the treatments markedly elevate the survival rate of the patients in recent years. However, the prevalence of cardiovascular adverse events (CVAEs) in MM had been increasing recently. CVAEs in MM patients are an important problem that we should focus on. Clinical tools for prognostication and risk-stratification are needed. Patients and methods: This is a retrospective study that included patients who were newly diagnosed with multiple myeloma (NDMM) in Shanghai Changzheng Hospital and Affiliated Jinhua Hospital, Zhejiang University School of Medicine from June 2018 to July 2020. A total of 253 patients from two medical centers were divided into training cohort and validation cohort randomly. Univariable analysis of the baseline factors was performed using CVAEs endpoints. Multivariable analysis identified three factors for a prognostic model that was validated in internal validation cohorts. Results: Factors independently associated with CVAEs in NDMM were as follows: age>61 years old, high level of baseline office blood pressure, and left ventricular hypertrophy (LVH). Age contributed 2 points, and the other two factors contributed 1 point to a prognostic model. The model distinguished the patients into three groups: 3-4 points, high risk; 2 points, intermediate risk; 0-1 point, low risk. These groups had significant difference in CVAEs during follow-up days in both training cohort (p<0.0001) and validation cohort (p=0.0018). In addition, the model had good calibration. The C-indexes for the prediction of overall survival of CVAEs in the training and validation cohorts were 0.73 (95% CI, 0.67-0.79) and 0.66 (95% CI, 0.51-0.81), respectively. The areas under the receiver operating characteristic curve (AUROCs) of the 1-year CVAEs probability in the training and validation cohorts were 0.738 and 0.673, respectively. The AUROCs of the 2-year CVAE probability in the training and validation cohorts were 0.722 and 0.742, respectively. The decision-curve analysis indicated that the prediction model provided greater net benefit than the default strategies of providing assessment or not providing assessment for all patients. Conclusion: A prognostic risk prediction model for predicting CVAEs risk of NDMM patients was developed and internally validated. Patients at increased risk of CVAEs can be identified at treatment initiation and be more focused on cardiovascular protection in the treatment plan.

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Healthy, premenopausal women have the advantage of female-specific cardiovascular protection compared to age-matched healthy men. However, pathologies such as obesity and Type 2 diabetes mellitus (T2DM) cause losing of this female-specific cardiovascular protection in young, obese and diabetic females. Molecular mechanisms underlying this loss of female-specific cardiovascular protection in young, obese and diabetic females are not clearly elucidated. This review takes a close look at the latest advances in our understanding of sex differences in adult cardiac gene expression patterns in health and disease. Based on the emerging data, this review proposes that female biased gene expression patterns in healthy adult hearts of human and pre-clinical models support the existence of active fetal gene program in healthy, premenopausal female heart compared to age-matched healthy male heart. However, the misalignment of gene expression pattern in this female-specific active cardiac fetal gene program caused by pathologies such as obesity and T2DM may contribute to the loss of female-specific cardiovascular protection in young, obese and diabetic females.

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INTRODUCTION: Cocoa flavonoids have been described to reduce the cardiovascular risk. Nevertheless, the involved mechanisms should be clarified and the dose-effect relation has never been evaluated. AIM: To investigate the dose-dependent effects of cocoa flavonoids on markers of endothelial and platelet activation and oxidative stress. METHODS: According to a randomized, double-blind, controlled, cross-over design, 20 healthy nonsmokers were assigned to receive either five treatments with daily intake of 10 g cocoa (0, 80, 200, 500 and 800 mg cocoa flavonoids/day) in five periods lasting 1 week each. RESULTS: Compared with flavonoid-free cocoa control, cocoa reduced sICAM-1 mean values [from 1190.2 to 1123.0; 906.3; 741.7 and 625.6 pg/mL (p = 0.0198 and p = 0.0016, for 500 and 800 mg respectively], sCD40L mean values [from 218.8 to 210.2; 165.5; 134.5 and 128.4 pg/mL (p = 0.023 and p = 0.013, for 500 and 800 mg respectively] and 8-isoprostanes F2 mean values [from 4703.9 to 4670.7; 2000.1; 2098.4 and 2052.3 pg/mL (p = 0.025; p = 0.034 and p = 0.029, for 200, 500 and 800 mg respectively)]. CONCLUSIONS: In our study we observed that short-term cocoa consumption improved proinflammatory mediators, lipid peroxidation and oxidative stress with a significant effect for higher dosages of flavonoids. Our findings suggest cocoa might be a valid tool for dietary intervention in prevention of atherosclerosis.

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ETHNOPHARMACOLOGICAL RELEVANCE: Crataegus pinnatifida belongs to the Rosaceae family and extensively distribute in North China, Europe, and North America. Its usage was first described in "Xinxiu Ben Cao." The dried fruits of Crataegus pinnatifida Bunge or Crataegus pinnatifida var. major N. E. Br., also known as "Shanzha," is a famous medicine and food homology herb with a long history of medicinal usage in China. C. pinnatifida has the functions for digestive promotion, cardiovascular protection, and lipid reduction. It was traditionally used to treat indigestion, cardiodynia, thoracalgia, hernia, postpartum blood stagnation, and hemafecia. In recent years, C. pinnatifida has attracted worldwide attention as an important medicinal and economical crop due to its multiple and excellent health-promoting effects on cardiovascular, nervous, digestive, endocrine systems, and morbigenous microorganisms of the human body due to its medicinal and nutritional values. AIM OF THE REVIEW: The current review aims to provide a comprehensive analysis of the geographical distribution, traditional usage, phytochemical components, pharmacological actions, clinical settings, and toxicities of C. pinnatifida. Moreover, the connection between the claimed biological activities and the traditional usage, along with the future perspectives for ongoing research on this plant, were also critically summarized. MATERIALS AND METHODS: We collected the published literature on C. pinnatifida using a variety of scientific databases, including Web of Science, ScienceDirect, PubMed, Wiley, Springer, Taylor & Francis, ACS Publications, Google Scholar, Baidu Scholar, CNKI, The Plant List Database, and other literature sources (Ph.D. and MSc dissertations) from 2012 to 2022. RESULTS: In the last decade, over 250 phytochemical compounds containing lignans, phenylpropanoids, flavonoids, triterpenoids, and their glycosides, as well as other compounds, have been isolated and characterized from different parts, including the fruit, leaves, and seeds of C. pinnatifida. Among these compounds, flavonoids and triterpenoids were major bioactive components of C. pinnatifida. They exhibited a broad spectrum of pharmacological actions with low toxicity in vitro and in vivo, such as cardiovascular protection, neuroprotection, anti-inflammatory, antioxidant, antibacterial, antiviral, anti-diabetes, anti-cancer, anti-mutagenic, anti-osteoporosis, anti-aging, anti-obesity, and hepatoprotection and other actions. CONCLUSION: A long history of traditional uses and abundant pharmacochemical and pharmacological investigations have demonstrated that C. pinnatifida is an important medicine and food homology herb, which displays outstanding therapeutic potential, especially in the digestive system and cardiovascular disease. Nevertheless, the current studies on the active ingredients or crude extracts of C. pinnatifida and the possible mechanism of action are unclear. More evidence-based scientific studies are required to verify the traditional uses of C. pinnatifida. Furthermore, more efforts must be paid to selecting index components for quality control research and toxicity and safety studies of C. pinnatifida.

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