Protective Effect Research Articles

Preclinical Evidence of Mulberry Leaf Polysaccharides on Diabetic Kidney Disease: a Systematic Review and Meta-Analysis.

Mulberry leaf polysaccharides (MLPs) have a variety of biological activities. Preliminary scattered evidence of preclinical studies have reported their potenzial effects on diabetic kidney disease (DKD). Here, we intended to assess the preclinical evidence of MLPs and explore their potenzial mechanisms on DKD, offering a scientific reference for the therapeutic use of MLPs. The study has been registered under the CRD42022309117 registration number at PROSPERO. Comprehensive search was conducted across eight databases from their establishment till January 2024, and eight studies with 270 animals were included in the meta-analysis. The primary outcome measurements in the MLP group, including serum creatinine (Scr) (P = 0.0005), blood urea nitrogen (BUN) (P = 0.02), 24-hour urinary protein (UP) (P = 0.001), and urinary microalbumin (UAlb) (P < 0.0001), were significantly reduced compared to the control group. Additionally, MLP treatment was significantly correlated with fasting blood glucose (FBG), total cholesterol (TC), protein expression of TGF-β1, CTGF mRNA, and the kidney index (all P values < 0.05) and delayed the progression of local pathological changes in the kidney. Subgroup analysis revealed significant species differences in the efficacy of MLPs. Also, it showed that the dosage of streptozotocin potenzially affected the Scr and UAlb results, while the duration of MLP treatment influenced UAlb results. MLPs may exert potenzial renal protection by delaying renal fibrosis, inhibiting inflammatory reactions, suppressing the growth hormone-insulin-like growth factor-insulin-like growth factor binding protein axis, and regulating the insulin receptor pathway. In summary, MLPs have multifaceted renal protective effects, suggesting their potenzial for treating DKD.

Disparities in diabetes-related outcomes in prostate cancer patients - role of social determinants of health and race

Abstract Background Prostate cancer (PC) patients on androgen deprivation therapy (ADT) with diabetes mellitus (DM) are at increased risk of cardiovascular events (CVE) and all-cause mortality (ACM), with metformin use linked to lower ACM. Purpose To analyze the impact of low socioeconomic status (SES), low educational levels, and Non-Hispanic Black (NHB) race on the relationship between DM, and its treatments, and CVE, cardiovascular mortality (CVm), prostate cancer-specific mortality (PCsm), and ACM within 2 years of PC diagnosis in patients ± ADT. Methods We utilized SEER-Medicare (national database for individuals 65 or older covered under US federal health insurance program merged with multiple state cancer registries with ~50% US cancers covered) to study a cohort of PC patients diagnosed from 2009 to 2017, identifying PC cases with ICD-10 - C61 and DM via the Medicare chronic condition file. CVE included Afib, AMI, peripheral artery disease, ischemic stroke, and heart failure. Two patient cohorts were analyzed: those enrolled in Medicare Parts A and B with PC (cohort 1), and those exclusively on ADT (± diabetic medications) and enrolled in Medicare Part D (cohort 2). Outcomes were evaluated using Fine-Gray and Cox models, with further analysis by subgroups: NHB, SES, and education. Results We analyzed 74,052 PC patients, with 6,682 having comprehensive Part D data. Of these, 35% in cohort 1 and 16% in cohort 2 had DM, with median ages of 73 and 72, respectively. Diabetes was more prevalent among NHB men than Non-Hispanic White (NHW), 49% vs 33% in cohort 1 and 25% vs 15% in cohort 2. In cohort 1, 9% and 8.5% of overall and DM individuals were on ADT. Risk factor details are in Table 1, and CVE, CVm, PCsm, and ACM are included in Table 2, showing higher risks of various cardiovascular outcomes for DM patients, particularly for those with low-education levels. In cohort 1, we demonstrated a higher risk of all outcomes across all subgroups with DM (p&amp;lt;0.001). No significant interaction with race was present except in those with lower education levels, where NHW men with lower education showed an increased risk of CVE (sHR 1.15, 95%CI 1.10-1.21, P&amp;lt;0.001). In cohort 2, compared to metformin, the use of all other DM medications was associated with higher ACM. Additionally, those on other DM medications with lower education levels had higher CVE rates. Non-DM individuals with low SES had lower CVE rates, while NHB non-DM individuals had higher PCsm. Conclusion Our study highlights disparities in PC patients with DM in relation to cardiovascular and ACM, with NHB men and those with lower SES and educational status having worse outcomes. Metformin use in patients with low education levels was associated with reduced ACM and CVE risk, indicating its potential protective effect. These findings emphasize the need for further research on the disparities in PC and effects of diabetes medications across different subpopulations.

Conditional over-expression of heme-oxygenase 1 in myelomonocytic cells reduces AngII-induced hypertension and vascular inflammation in mice

Abstract Background Systemic arterial Hypertension is one of the most important risk factor responsible for morbidity and mortality world-wide. Angiotensin II (Ang II), a potent vasoconstrictor and key player in the renin-angiotensin-aldosterone system (RAAS) is responsible for vascular dysfunction, inflammation, and tissue damage. Heme oxygenase-1 (HO-1) overexpression may confer antioxidant and anti-inflammatory properties in Ang II-induced hypertension through its action on heme catabolism, generating carbon monoxide (CO), ferritin and biliverdin/bilirubin by the action of biliverdin reductase A (BLVRA). Methods and results Male 9–12-weeks-old HO-1indxLySMCre/wt and LySMCre/wt mice were infused with AngII (1mgAngII/Day/Kg) for 7 days to induce hypertension and compared to sham treatment. Blood pressure monitoring by tail-cuff method, and endothelium-dependent vasodilator studies via organ chamber system using acetylcholine (ACh) in isolated aortic segments (~4 mm), revealed that overexpression of HO-1 in myeloid cells resulted in decreased systolic blood pressure and improved endothelial function in AngII-infused HO-1indxLySMCre/wt mice compared to controls. Concurrently, increased BLVRA expression in liver tissue and elevated plasma bilirubin levels were detected by transcriptome analysis and high-performance liquid chromatography, respectively. These results were supported by a reduction in the expression of inducible cytokines and cell adhesion molecules (CAMs) in the aorta, assessed using qPCR. Bone marrow transplant experiments demonstrated that bone marrow from LysMcre mice in HO-1indxLySMCre/wt mice abrogated the protective effect of HO-1, resulting in endothelial damage and increased blood pressure, potentially due to decreased liver BLVRA expression and the accumulation of bone marrow-derived cells in the vessel wall in response to AngII. Additionally, adeno-associated viral vector (AAV) transfection targeting specifically BLVRA activity in liver lead to an increase in blood pressure values and worse endothelium relaxation, in parallel with higher oxidative stress and the blood neutrophils concentration, as assessed in whole blood by using oxidative burst method and blood count system respectively. Conclusion The overexpression of HO-1 in myeloid cells confers anti-inflammatory protection in AngII-induced arterial hypertension in mice. Myeloid cells bone marrow-derived overexpressing HO-1 regulate the differentiation and infiltration of pro-inflammatory immune cells in the vasculature. BLVRA expression and bilirubin levels downstream of HO-1 play a critical role in protecting against vascular damage by reducing leukocyte infiltration.

Mineralocorticoid receptor antagonist therapy in patients with ischemic heart failure and ventricular tachycardia: a comparative analysis of spironolactone vs. eplerenone

Abstract Background Mineralocorticoid receptor antagonists (MRAs) are a cornerstone of heart failure therapy and have been shown to reduce the incidence of sudden cardiac death. However, a direct comparison between spironolactone and eplerenone in patients who present ventricular tachycardia (VT) is lacking. Purpose This study aimed to compare the effect of spironolactone and eplerenone on VT recurrence in patients with ischemic heart disease (IHD) hospitalized for VT episodes. Methods Our data utilized a registry of 405 patients with IHD and HF, who were hospitalized for an episode of sustained VT and received MRA therapy. We performed propensity score matching based on age, hypertension, diabetes, history of acute myocardial infarction, left ventricular ejection fraction (LVEF) and presentation with incessant VT. The matched population included 200 patients, stratified into two equivalent groups. Cox regression analysis was performed to identify predictors of VT recurrence, with Kaplan-Meier curves facilitating time-to-event analyses. Results The median age was 69 years and the majority (91%) were male. One-third had an ICD, and 41 patients (20%) had CRT. The median LVEF was 30%, 23 patients (12%) presented with an electrical storm, while 18 (9%) had incessant VT. VT led to hemodynamic instability in 91 cases (46%). Ablation was performed in 47 patients (24%), while 1 required mechanical circulatory support. Ablation was performed in 47 patients (24%), while 1 required mechanical circulatory support. Patients were followed for at least a year and median follow-up time was 414 days. A total of 78 patients had VT recurrence and 117 patients died. Eplerenone use significantly reduced the risk of VT recurrence compared to spironolactone (HR: 0.59 [0.37-0.93], p=0.023). This effect was consistent in the multivariate model as well (p=0.007). Conclusions Eplerenone use may confer a greater protective effect against VT recurrence in patients with IHD and sustained VT. Further studies are required to confirm these preliminary findings.

GSK3179106 ameliorates lipopolysaccharide-induced inflammation and acute lung injury by targeting P38 MAPK

Acute lung injury (ALI) is a serious acute respiratory disease that can cause alveolar-capillary barrier disruption and pulmonary edema, respiratory failure and multiple organ dysfunction syndrome. However, there is no effective drugs in clinic until now. GSK3179106 has been reported can alleviate intestinal stress syndrome, but the protective effect of GSK3179106 on ALI has not been elucidated. The present study will evaluate the pharmacological activity of GSK3179106 on lipopolysaccharide (LPS)-induced inflammation and lung injury and clarify its underlying mechanism. We found that GSK3179106 significantly attenuated LPS-induced lung injury in vivo, accompanied by inhibited infiltration of inflammatory cells and reduced expression of inflammatory cytokines. Meanwhile, GSK3179106 dose-dependently reduced the LPS-induced IL-6 expression both in protein and gene levels in macrophages. Mechanistically, GSK3179106 could inhibited the phosphorylation of P38 MAPK induced by LPS. Importantly, results showed that there is a direct combination between GSK3179106 and P38 MAPK. Together, our findings not only clarified the anti-inflammatory activity of GSK3179106 but also discovered its new clinical indications. Therefore, compound GSK3179106 may be a potential candidate for the treatment of acute inflammatory diseases.

Restoration of autophagy reduces diabetes-induced endothelial dysfunction

Abstract Introduction Diabetes leads to endothelial dysfunction, a main determinant of several cardiovascular diseases. The molecular mechanisms underlying the effects of hyperglycemia in endothelial cells are not fully characterized. Autophagy, the intracellular process by which the cell digests and recycles senescent or damaged cytoplasmic elements, exerts cardiovascular protective effects, limiting cardiac and vascular injury in the presence of stress. However, it is unclear how hyperglycemia modulates autophagy in endothelial cells. Purpose In this study, we elucidated the role of autophagy in vascular damage induced by diabetes. We also tested whether the restoration autophagy attenuates diabetes-induced endothelial damage. Methods We evaluated the effects of high-glucose (HG, 30 mM for 6 and 24 hours) on markers of endothelial function, autophagy, autophagic flux, and mitophagy in human umbilical endothelial cells (HUVEC) in vitro and in mesenteric arteries from wild-type mice (WT) ex vivo. We tested the effects of autophagy reactivation using the natural polyamine spermidine or ATG7 overexpression (ATG7ov) on apoptosis and angiogenesis in HUVEC treated with HG. Vascular reactivity experiments in the presence of autophagy activation were performed in HG-treated mouse mesenteric arteries and human saphenous veins from patients with peripheral artery disease. Finally, we evaluated the level of autophagy in the mammary arteries of newly discovered diabetic patients undergoing coronary artery bypass graft surgery. Results We found that HG reduces autophagy (0.6 fold p&amp;lt;0.05) and mitophagy (1.5 fold p&amp;lt;0.001) in HUVECs. We also demonstrated that endothelial cells undergoing hyperglycemia fail to activate autophagy under hypoxic conditions (0.6 fold p&amp;lt;0.05). Reactivation of autophagy by ATG7ov rescues apoptosis (0.52 fold p&amp;lt;0.05) and angiogenesis (2.3 fold p&amp;lt;0.05) in HUVEC treated with HG. We further observed that HG exacerbates endothelial dysfunction in a mouse model of genetic inhibition (Beclin 1 +/- mice), compared to WT mice (-19.16 % +-4.97 SEM vs -48.39 % +-2.18 SEM p&amp;lt;0.001). Mechanistically, HG increases cellular acetylation status (0.7 fold p&amp;lt;0.05) and activates p300 (1 fold p&amp;lt;0.05), an autophagy inhibitor. ATG7ov or spermidine, a p300 inhibitor, rescue endothelial-dependent relaxation in mesenteric arteries of WT mice treated with HG (ATG7ov -62.48 % +-5.16 SEM; SP -63.01 +-3.22 SEM; HG -40.67 % +-3.82 p&amp;lt;0.001). Finally, we observed reduced levels of autophagy in mammary arteries from diabetic patients and demonstrated that SP improves vascular function in human saphenous veins (-37.6 % +-12.76 SEM vs -12.52 % +-5.6 SEM p&amp;lt;0.001). Conclusion Our results suggest that the impairment of autophagy is a strong contributor of diabetes induced-endothelial dysfunction. Targeting autophagy may represent a valid therapeutic strategy to counteract the cardiovascular consequences of metabolic stress.

Mechanosensitive Ion Channel Piezo1 regulates tight junctions between endothelium and mediates the occurrence of aortic dissection

Abstract Aims Exploring whether changes in endothelial Piezo1 mechanically sensitive ion channels can lead to thoracic aortic dissection（TAD） and its specific mechanisms of action. Methods and results IF showed aberrant Piezo1 expressions in the CD31+ endothelial cells in thoracic aortas of patients with TAD. In a β-aminopropionitrile (BAPN)-induced TAD mouse model, knockout of Piezo1 in endothelial cells shows a protective effect on aortic dissection, while the crucial tight junction (TJ) components ZO-1 was significantly increased by En Face staining. For identified how the Piezo1 ion channel influences the ZO-1 between endothelium, we used mass spectrometry analysis and RNA sequencing to identify a key factor Trib1 mediating the ubiquitination degradation of ZO-1. Also, we found the low expression of Trib1 in endothelial cell of Piezo1 ECKO mouse with BAPN feeding. Finally, we rescued the expression of TRIB1 by targeting endothelial cells with AAV9-TIE2-TRIB1, demonstrating that Piezo1 indeed promotes the occurrence of aortic dissection through degrading the TRIB1-COP1-ZO-1 complex. Conclusion The activation of Piezo1 promotes the occurrence of （TAD） through Trib1 mediated degradation of endothelial tight junctions. Inhibiting endothelial Piezo has the potential to become a specific therapeutic and preventive target for（TAD）.

Cardioprotective potential of oleuropein, hydroxytyrosol, oleocanthal and their combination: unravelling complementary effects on acute myocardial infarction and metabolic syndrome

Abstract Background/Introduction Clinical studies have established the role of olive products in primary and secondary prevention of cardiovascular (CV) disease, but the single compounds or compound combinations responsible for the protective effects are still under investigation. Purpose We sought to explore and compare the cardioprotective potential of Oleuropein (OL), Hydroxytyrosol (HT), Oleocanthal (OC) and Oleanolic Acid (OA) and three combinational treatments after chronic oral administration in mice subjected to Ischemia/Reperfusion Injury (IRI) in the presence of metabolic syndrome (MS) and verify the effect of combination in a proof-of-concept clinical study in Chronic Coronary Artery Syndrome (CCAS) patients. Methods First, we explored the IRI-limiting potential of 6-weeks daily oral treatment with OL (20.6 mg/kg), HT (5.9 mg/kg), OC (11.6 mg/kg), OA (17.4 mg/kg) or vehicle (DMSO 5%) in healthy C57Bl6 mice. At week 6, myocardial ischemia/reperfusion (30 minutes/2 hours) was induced and infarct size was measured. Next, MS was established by 14 weeks of Western diet and the isolated compounds were administered for the last 6 weeks. At week 14, IRI was surgically induced, and infarct size was determined. Basic MS parameters (fasting blood glucose, plasma cholesterol, body weight and blood pressure) were recorded at baseline, weeks 8 and 14. According to the exerted benefits, three combinational treatments were designed and tested on the MS model of IRI. The underlying cardioprotective mechanism was investigated on the mixture with preponderant CV benefits (OL-HT-OC, Combo 2). ApoE-/- mice fed with Western diet for 12 weeks were treated with Combo 2 orally for the last 4 weeks and aortic atherosclerotic lesion extent was determined to detect possible antiatherosclerotic effects. After multi-organ toxicity evaluation, a Combo 2-based supplement was administered in CCAS patients for evaluation of cardiac function, inflammation and oxidative stress biomarkers. Results OL, OC and OA, but not HT, significantly reduced infarct size in vivo both in healthy and MS mice. OL was the only compound to reduce hyperglycemia, while OA significantly reduced plasma cholesterol. All mixtures (Combo 1: OL-HT-OA, Combo 2: OL-HT-OC, Combo 3: OL-HT-OC-OA) were cardioprotective, but only Combo 2 prevented MS progression by limiting hyperglycemia. Combo 2 protection against IRI was attributed to apoptosis suppression (reduced Bax/BcL-xL ratio) and increased expression of the antioxidant enzymes Superoxide Dismutase and Catalase in the ischemic myocardium. Combo 2 treatment also reduced atherosclerotic lesion extent. In our proof-of-concept clinical study, Combo 2 treatment ameliorated cardiac, vascular and endothelial function in CCAS patients. Conclusions Combinational treatment with OL-HT-OC exerts potent cardioprotective, antihyperglycemic and antiatherosclerotic properties in vivo, with remarkable and clinically translatable CV benefits in high-risk patients.

Vaccination status and long COVID symptoms among patients hospitalized with COVID-19: the WHF COVID-19 Long-term Study

Abstract Background COVID-19 vaccinations have been found to be effective in reducing the severity of COVID-19 infection and in-hospital deaths; however, insufficient evidence exists about the effect of vaccination on long term morbidity and mortality after hospitalization in patients from low- and middle-income countries. Methods The global WHF COVID-19 Long-Term Follow-up Study recruited 2,504 COVID-19 hospitalized patients from 26 collaborating sites in 16 countries between January 2022 - June 2023. Patients were followed up , at 1, 3, 6, and 9-12 months post-discharge to examine short- and long-term physical and psycho-social outcomes. A standardised questionnaire was used to collect data on demographics, pre-existing comorbidities, COVID-19 symptoms on admission, vaccination status, and outcomes at discharge, including persisting symptoms, new onset hypertension or diabetes, major adverse cardiovascular events (MACE), and mortality. We compared persistent long COVID symptoms, MACE, and mortality outcomes up to one year by COVID-19 vaccination status. Results The majority of study participants were Asians (78%), males (56%) with a mean (SD) age of 59.2 (19.9) years and from low- and middle-income (65%), upper middle-income (20%) and high-income (15%) countries. The most commonly reported comorbidities were hypertension: 54% and diabetes: 38%. Approximately two-thirds of the patients had received at least one dose of COVID-19 vaccination prior to hospitalization. Unvaccinated patients were more likely to present with dyspnea (60% vs 53%, p-value&amp;lt;0.001) and acute respiratory infection (15% vs 9%, p-value&amp;lt;0.001) during hospitalization. Unvaccinated patients also had twice the in-hospital mortality rate, compared with vaccinated patients (6% vs 3%, p-value&amp;lt;0.001). Unvaccinated patients had a greater incidence of MACE (23% vs 18%, p-value=0.016) during hospitalization and across all follow-up visits. Unvaccinated patients also had a higher mortality rate across all follow-up visits (mortality at one year post-discharge 14% vs 10%, p&amp;lt;0.001). At the 9-12 month follow-up, about a quarter of the patients had at least one long COVID symptom, but unvaccinated patients had a higher rate of long COVID symptoms, including fatigue (23% vs 14%, p&amp;lt;0.001), palpitations (17% to 7%, p-value&amp;lt;0.001), and anxiety (13% to 7%, p=0.002). Conclusions Our data highlight the long-term protective effect of COVID-19 vaccination on reducing morbidity and mortality among COVID-19 patients after hospital discharge. However, a substantial proportion of COVID-19 vaccinated patients still showed persistent long COVID symptoms (22%) and mortality (10%). Future research is needed to investigate individual- and health system-level factors contributing to poor health outcomes post-COVID-19 infection.

Chronic psychosocial stress affects insulin-like growth factor 1 and its receptors in mouse ovaries.

Context Chronic psychosocial stress negatively affects folliculogenesis and oogenesis. Intraovarian mechanisms mediating these effects are poorly understood. Aims This work aimed to find out how chronic psychosocial stress affects ovarian IGF1 and its receptor (IGF1R), as well as Igf1 and Igf1r gene expression in cumulus-oocyte complexes (COCs). It also aimed to address possible protective effects of gonadotropin stimulation on IGF1 ovarian signalling. Methods Female CD1 mice experienced chronic psychosocial stress of 11-day isolation followed by overcrowding for 10days. To verify the model, blood corticosterone levels and the quality of oocytes were evaluated in stressed females. The levels of IGF1/IGF1R, blood IGF1 concentration, and expression of Igf1 /Igf1r in the ovaries were compared in stressed and unstressed females. Key results Psychosocial stress caused an elevation of corticosterone level, which was alleviated by gonadotropin treatment. The stressed mice showed a decreased IGF1 level in the ovaries and a decreased expression of Igf1 and Igf1r in COCs. In the unstressed females, gonadotropin injection decreased the expression of Igf1 and Igf1r ; in the stressed females, the same treatment increased Igf1r expression. Neither stress nor ovarian stimulation with gonadotropins affected the serum IGF1 level. Conclusions Psychosocial stress suppresses IGF1 signalling in the ovaries. Gonadotropin treatment modulates these effects differently in stressed and unstressed animals. Implications The results may have translational value for human reproduction. Ovarian IGF1 can be considered a candidate for further improvement of IVF results in women under conditions of chronic stress.

The effect of oral anticoagulants on the incidence of dementia in patients with atrial fibrillation: a systematic review and meta-analysis

Abstract Background Atrial fibrillation (AF) is a common cardiac arrhythmia, with dementia being an increasingly recognised complication of this. Treatment with oral anticoagulant (OAC) therapy may be protective in developing this complication. Purpose This meta-analysis aims to investigate the validity of this hypothesis, whilst additionally exploring the effect of specific OAC medication subtypes on the incidence of dementia. Methods A comprehensive search of MEDLINE and Embase for relevant studies reporting the efficacy of OAC therapy for the incidence of dementia in patients with AF was conducted from its inception until March 2023. This included observational studies that reported odds ratio, risk ratio and hazard ratio for adult AF patients. Studies including patients with prior OAC use or prior history of dementia were excluded. Statistical analysis was performed using a random-effects model to calculate the pooled hazard ratio and their corresponding 95% confidence interval for all outcomes. Subgroup analyses were also performed according to the study design, presence of observational window, and prior history of stroke in patients. Results A total of 13 studies were included in the study. Although the heterogeneity was high in all comparisons, we demonstrated that OAC usage lowered the risk of developing dementia in AF patients when compared to the non-OAC cohort. Looking more specifically at medication subtypes, direct oral anticoagulants (DOACs) and vitamin K agonists (VKA) were both effective in reducing the likelihood of AF patients developing dementia when compared to non-OAC treatments. Conclusion Our meta-analysis confirms that administration of OAC and its subtypes (VKA and DOAC) are effective pharmacotherapies in managing dementia in patients with AF. These findings have important clinical implications for the management of AF patients and highlight the need for further investigation of the protective effects of OAC therapy on cognitive decline. Future research should explore the long-term effects of OAC therapy on cognitive function in AF patients.

Mediterranean-type diet trajectories and 20-year cardiovascular disease incidence: the ATTICA study (2002-2022)

Abstract Background/Introduction The protective effects of the Mediterranean-type diet (MTD) against cardiovascular disease (CVD) are well-known. However, based on a recent systematic review of 57 studies with 1,125,560 participants, MTD adherence has declined worldwide, even in the Mediterranean region, compared to the past, especially in the last decade. Moreover, studies evaluating changes in diet and CVD risk are scarce. Purpose The aim of this study was to longitudinally evaluate MTD adherence and changes in MTD adherence during 20-years of follow-up and its relation to 20-year CVD incidence. Methods Participants initially free-of-CVD from the ATTICA study were used (n=1,986). At 2002 and 2022, CVD events were assessed according to WHO-ICD-10 and MTD adherence was assessed via MedDietScore (range: 0-55). Hence, MTD trajectories were defined according to MTD adherence in 2002 and in 2022 as: low-low, low-high, high-low, high-high (i.e., high: MedDietScore &amp;gt;27/55). Results During the 20-year follow-up, 30.2% (n=600) of the participants were always away (i.e., low-low), 30.0% (n=596) went away (high-low), 21.4% (n=424) were always close (high-high) and 22% got closer (low-high) to the MTD. The 20-year CVD incidence was: 38.8% (n=233), 87.7% (n=321), 10.2% (n=61) and 24.3% (n=103) in those in the low-low, low-high, high-low and high-high trajectory, respectively (p-value&amp;lt;0.001). In multi-adjusted models, adjusted for socio-economic, clinical and lifestyle parameters, it was found that compared to those who were always away from the MTD, those who were always close had 68% lower CVD risk [Hazard Ratio-HR: 0.32, 95%Confidence Interval-CI: 0.14, 0.72], while those who went away during the 20-year follow-up had 47% lower CVD risk [HR: 0.53, 95%CI: 0.32, 0.86]. Conclusion Our study findings highlight the long-lasting effects of the MTD adherence early in the life-course. Public health measures to prevent CVD should focus on facilitating MTD adherence, as early in life as possible.

What works to reduce regional health inequalities? A case of East vs West Germany post reunification

Abstract Regional inequalities in mortality are rising across the globe. The case of German reunification offers a unique opportunity to explore how such inequalities can be reduced, or even eliminated: following reunification, a long-standing life expectancy gap between East and West Germany was closed for women and markedly reduced for men in a period of less than 15 years. Drawing from theory on health inequalities, we investigate the contribution of material, behavioural and psychosocial factors likely related to the narrowing of the life expectancy gap between East and West Germany following reunification. We used regional data from official national statistics covering the period 1994-2020 for 15 regions in East and West Germany. Using fixed-effects models with an interaction term for regions in the East, we investigated whether within-region changes in key hypothesised factors (social security expenditure, healthcare improvements, changes in alcohol consumption, and life satisfaction), have had differential impacts on life expectancy at birth and at 65 years. We find that increases in social security benefits in the East following reunification has been the most important factor for lowering inequalities between the two parts of Germany: for every standard deviation increase in social security benefits, life expectancy at birth increased by an additional 0.20 [0.07,0.33] years for males and by 0.15 [-0.01,0.31] years for females in East relative to West Germany. We find the protective effect of social security benefits also for women at 65 years (additional 0.14 years [0.006,0.268]) but not for men. Overall, our findings suggest that increasing social security expenditure could be an effective policy-based tool for reducing health disparities across regions with different levels of economic development. This provides additional support for the relevance of the materialist hypothesis and the political economy of root causes of health inequalities. Key messages • Our findings suggest that increasing social security expenditure could be an effective policy-based tool for reducing regional health disparities. • We find support for the materialist and political economy approaches to explaining health inequalities.

Antioxidant Capacity of Thyme (Thymus vulgaris) Essential Oil and Its Effect on In Vivo Fertility of Rams Subjected to Testicle Heat Stress.

The detrimental effects of hyperthermia on the testes and the protective effect of thyme essential oil against testicular damage induced by this stress in rams were studied. Twenty-four rams of the Barbarine breed with an average weight of 62.5 ± 0.3 kg and an average age of 24 ± 0.6 months. The experiment consisted of inducing localized heat stress on the first group of rams by applying heat bags to both testicles of six rams (G s). The second group underwent the same heat stress on the testes but received orally 100 µL/day/animal of thyme essential oil (G s-he). A positive control did not undergo stress but received thyme essential oil (G he) with the same doses as the (G s-he) group, and the negative control did not undergo either stress or receive the essential oil of thyme (G c). One hundred twenty-eight adult ewes of the same breed divided into four groups of 32 ewes were used to study the effect of different treatments on the in vivo ram's fertility. Ewes are synchronized and we have applied natural mating with oestrus control, the reproduction balance sheet is calculated after lambing. The results showed that tests of heat stress (HS) negatively affect semen quality but did not cause infertility. However, neither tests for heat stress nor treatment with thyme EO significantly affected the haematological profile. The study of the effect of heat stress on the testes on fertility in vivo showed a drop in the number of females who were fertilized at the first oestrus and consequently a drop in fertility. However, the rams that suffered the same stress but were treated with EO thymus recorded an improvement in these parameters.

A 3-year retrospective exploration of predictors for cardiac arrest in atrial fibrillation

Abstract Background An increasing correlation between atrial fibrillation (AF) and a heightened risk of cardiac arrest is emerging. Yet, the specific predictors of cardiac arrest in hospitalized patients with AF remain unclear. Purpose This study aims to identify these predictors, providing essential insights for refined risk assessment and targeted clinical interventions. Methods Adult patients hospitalized between 2018 and 2020 with a primary diagnosis of AF with or without cardiac arrest were identified using the International Classification of Diseases, Tenth Revision (ICD-10) code. Demographics and comorbidities were recorded. Logistic regression was employed to identify predictors of increased cardiac arrest. Results In a study of 272,028 hospitalizations with AF, 2,352 patients suffered cardiac arrest, and 523 died during hospitalization. Factors associated with increased odds of cardiac arrest include heart failure (OR = 1.79, 95% CI: 1.60–2.00), cardiogenic shock (OR = 2.95, 95% CI: 2.35–3.71), history of coronary angioplasty or bypass (OR = 1.79, 95% CI: 1.59–2.02), chronic kidney disease (OR = 1.26, 95% CI: 1.12–1.42), end-stage kidney disease (OR = 2.34, 95% CI: 1.98–2.77), and septic shock (OR = 6.50, 95% CI: 4.80–8.80). Chronic obstructive pulmonary disease (COPD) and infection were associated with a 13% (OR = 1.13, 95% CI: 1.02–1.26) and 45% (OR = 1.45, 95% CI: 1.25–1.68) increase in odds for cardiac arrest, respectively. Increased age (OR = 0.99, 95% CI: 0.98–0.99) and female sex (OR = 0.83, 95% CI: 0.76–0.91) showed an inverse relation with cardiac arrest. Hypertension and obesity exhibited protective effects against cardiac arrest, with odds ratios of 0.85 (95% CI: 0.74–0.97) and 0.83 (95% CI: 0.75–0.93), respectively. Conclusion Our study underscores the intricate web of factors influencing cardiac arrest risk in AF patients. A personalized approach to risk assessment in the context of AF might be needed.

Investigating the role of WT1 in Brugada syndrome pathophysiology

Abstract Background Brugada syndrome (BrS) is a heritable arrhythmic disorder presumably caused by conduction slowing in the right ventricular (RV) outflow tract (RVOT). A recent genome-wide association study found an association between common variants on chromosome 11 near WT1, tagged by the SNP rs72905083, and BrS susceptibility. Purpose To study whether WT1 affects cardiac conduction and could therefore represents the underlying association of the chr11 locus with BrS susceptibility. Methods We conducted in silico analyses of omics datasets to identify the likely causal gene at the chr11 BrS locus. Next, we conducted electrophysiological studies in heterozygous young adult (4 months old) Wt1-deficient (Wt1+/-) mice and wild-type littermates to explore the effect of Wt1 on cardiac conduction. To study the potential role of Wt1 in the setting of reduced conduction reserve, we compared aged Scn5a haploinsufficient mice (Scn5a+/-;Wt1+/+, 17 months) with littermates haploinsufficient for both Wt1 and Scn5a (Scn5a+/-;Wt1+/-). Optical mapping was performed in Langendorff-perfused hearts, where conduction was further challenged by acute ajmaline administration or by pacing at the effective refractory period (ERP). Transcriptomic analyses were conducted in Wt1+/- and wild-type mice by RNAseq of PCM1-sorted cardiomyocytes. Results Analysis of omics datasets uncovered WT1 as the likely causal gene since WT1 was the closest gene to, and in fact overlapped, the BrS-associated region; promoter capture Hi-C data in human tissue showed chromatin contact between the promoter of WT1 and the associated region; and H3K27ac ChIP-seq signals (i.e. enhancer activity) of putative cardiac enhancers located within the associated region were correlated with WT1 transcript abundance across multiple tissues (Z-score = 4.32, p=1.57e-05). No differences were observed in ECG parameters or optically mapped epicardial conduction between Wt1+/- mice and wild-type littermates. However, comparison of aged Scn5a+/-;Wt1+/- and Scn5a+/-; Wt1+/+ hearts, in the setting of acute ajmaline challenge or pacing at the ERP, showed faster conduction in RV/RVOT in the presence of Wt1 haploinsufficiency (genotype effect: p=0.057 and p=0.041 for RV and RVOT epicardial conduction, respectively, during ajmaline challenge; p=0.034 for RV epicardial conduction during pacing at ERP). RNAseq of RV/RVOT cardiomyocytes revealed higher Scn5a expression in Wt1+/- vs wild-type (p=0.006). Conclusion We identified WT1 as the gene that most likely underlies the effect of the chr11 BrS susceptibility locus. Functional data revealed protective effects of reduced Wt1 expression in the setting of reduced conduction reserve. Transcriptomic data suggest that this occurs through a transcriptional effect on Scn5a expression.

Protective effect of TCR-mediated MAIT cell activation during experimental autoimmune encephalomyelitis

Mucosal-associated invariant T (MAIT) cells express semi-invariant T cell receptors (TCR) for recognizing bacterial and yeast antigens derived from riboflavin metabolites presented on the non-polymorphic MHC class I-related protein 1 (MR1). Neuroinflammation in multiple sclerosis (MS) is likely initiated by autoreactive T cells and perpetuated by infiltration of additional immune cells, but the precise role of MAIT cells in MS pathogenesis remains unknown. Here, we use experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and find an accumulation of MAIT cells in the inflamed central nervous system (CNS) enriched for MAIT17 (RORγt+) and MAIT1/17 (T-bet+RORγt+) subsets with inflammatory and protective features. Results from transcriptome profiling and Nur77GFP reporter mice show that these CNS MAIT cells are activated via cytokines and TCR. Blocking TCR activation with an anti-MR1 antibody exacerbates EAE, whereas enhancing TCR activation with the cognate antigen, 5-(2-oxopropylideneamino)−6-D-ribitylaminouracil, ameliorates EAE severity, potentially via the induction of amphiregulin (AREG). In summary, our findings suggest that TCR-mediated MAIT cell activation is protective in CNS inflammation, likely involving an induction of AREG.

Socio-economic gradients in urban green space access and respiratory health

Abstract Background This study investigates social disparities as one of the drivers influencing the access to green spaces and exposure to natural environments, potentially exacerbating disparities in respiratory health in children. Methods Longitudinal ELSPAC birth cohort study data included 4384 complete case participants born in cities of Brno and Znojmo, examined throughout the years 1990-2010. Estimates on socio-economic status (SES) scores of children’s parents and their education were used as socio-economical predictors. Tree cover density (TCD) calculated as mean canopy closure percentage in the individual walking distance neighbourhoods and the ownership and accessibility of a garden were used as indicators of green space accessibility. Multiple logistic regression models were employed to estimate odds ratios for predictors of respiratory health outcomes, controlling for several confounders. Results Parents’ SES was found to be positively associated with neighbourhood TCD, and this effect was even more pronounced for garden owners. Higher tree cover was then significantly negatively associated with development of acute bronchitis (OR 0.88, CI 95 % 0.84-0.94 for 1 SD of tree cover), while not having a garden (OR 1.81, CI 95 % 1.42-2.33) and living in area with lower tree cover (OR continuously decreasing from 1.88 to 1.68 for lowest and highest quartile respectively) was significantly associated with progression of acute bronchitis into chronic bronchitis in a fully adjusted model. Vice versa, higher tree cover was statistically significantly positively associated with development of allergic rhinitis (OR 1.09, CI 95 % 1.03-1.15), suggesting viability of the novel method of estimation of individual neighbourhood greenness. Conclusions The results suggest protective effect of access to urban green spaces against adverse respiratory outcomes in children. The socially uneven distribution of access emphasizes the importance of urban policies in promoting urban health. #NGEU Key messages • There is a significant protective effect of access to green spaces against respiratory diseases and their progression. • There’s an unequal, but varied distribution of access to green spaces, and social gradient in health, highlighting the importance of urban green space distributive politics.

Roasted Astragalus membranaceus Inhibits Aβ25–35-Induced Oxidative Stress in Neuronal Cells by Activating the Nrf2/HO-1 and AKT/CREB/BDNF Pathways

(1) Background: Astragalus membranaceus (AM) has antioxidant and anti-inflammatory effects, but its specific mechanism of action in the brain is still unclear. In this study, we developed a roasting process to maximize the cognitive improvement impact of AM. We focused on enhancing physiological activity to enhance the brain neuron protection effect and alleviate neuronal damage caused by neurodegenerative diseases. (2) Methods: AM was roasted at 260 °C for 20, 30, or 40 min, and the hot water extracts were tested on HT22 cells for ROS levels, apoptosis, and antioxidant protein expression. The effect on the BDNF-AKT-CREB pathway under stress was also analyzed. (3) Results: Roasted AM decreased ROS production and the expression of apoptosis-related factors while activating the expression of antioxidant proteins in HT22 cells treated with Aβ25–35. In particular, 30 min roasting (R-AM2) significantly reduced ROS production, inhibited cell death, and increased antioxidant protein expression. The Nrf2 pathway was activated Bax, and cleaved caspase-3 levels were reduced. BDNF and p-CREB expression were increased by 20% and 50–70%, respectively. In the MAPK pathway, p-ERK levels were increased by 30%, and p-P38 levels were increased by approximately 20%. (4) Conclusions: These findings suggest that roasted AM upregulates brain-derived neurotrophic factor (BDNF) in HT22 cells, providing neuroprotective effects by activating the AKT/CREB/BDNF pathway and inhibiting neuronal apoptosis. Therefore, roasted AM shows potential as a neuroprotective agent for preventing or treating neurodegenerative diseases, such as Alzheimer’s, linked to BDNF deficiency.

Unsupervised machine learning identifies distinct phenotypes in cardiac complications of pediatric patients treated with anthracyclines

BackgroundAnthracyclines are essential in pediatric cancer treatment, but patients are at risk cancer therapy-related cardiac dysfunction (CTRCD). Standardized definitions by the International Cardio-Oncology Society (IC-OS) aim to enhance precision in risk assessment.ObjectivesCategorize distinct phenotypes among pediatric patients undergoing anthracycline chemotherapy using unsupervised machine learning.MethodsPediatric cancer patients undergoing anthracycline chemotherapy at our institution were retrospectively included. Clinical and echocardiographic data at baseline, along with follow-up data, were collected from patient records. Unsupervised machine learning was performed, involving dimensionality reduction using principal component analysis and K-means clustering to identify different phenotypic clusters. Identified phenogroups were analyzed for associations with CTRCD, defined following contemporary IC-OS definitions, and hypertensive response.ResultsA total of 187 patients (63.1% male, median age 15.5 years [10.4–18.7]) were included and received anthracycline chemotherapy with a median treatment duration of 0.66 years [0.35–1.92]. Median follow-up duration was 2.78 years [1.31–4.21]. Four phenogroups were identified with following distribution: Cluster 0 (32.6%, n = 61), Cluster 1 (13.9%, n = 26), Cluster 2 (24.6%, n = 46), and Cluster 3 (28.9%, n = 54). Cluster 0 showed the highest risk of moderate CTRCD (HR: 3.10 [95% CI: 1.18–8.16], P = 0.022) compared to other clusters. Cluster 3 demonstrated a protective effect against hypertensive response (HR: 0.30 [95% CI: 0.13– 0.67], P = 0.003) after excluding baseline hypertensive patients. Longitudinal assessments revealed differences in global longitudinal strain and systolic blood pressure among phenogroups.ConclusionsUnsupervised machine learning identified distinct phenogroups among pediatric cancer patients undergoing anthracycline chemotherapy, offering potential for personalized risk assessment.