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Clinical Hypertension Jul 2024This study explores the impact of intensive blood pressure (BP) control on left ventricular hypertrophy (LVH) incidence and evaluates the prognostic implications of LVH...
BACKGROUND
This study explores the impact of intensive blood pressure (BP) control on left ventricular hypertrophy (LVH) incidence and evaluates the prognostic implications of LVH status (pre-existing/new-onset/persistent/regression) using Systolic Blood Pressure Intervention Trial (SPRINT) Electrocardiogram Data.
METHODS
Poisson regression was used to assess new-onset LVH and LVH regression rates. Multivariable-adjusted Cox proportional hazard models determined the risk of adverse cardiovascular events (ACE), a composite of myocardial infarction (MI), non-MI acute coronary syndrome, stroke, heart failure, or cardiovascular death, alongside safety adverse events.
RESULTS
In 8,016 participants, intensive BP control significantly reduced new-onset LVH (8.27 vs. 14.79 per 1000-person years; adjusted p<0.001) and increased LVH regression (14.89 vs. 11.89 per 1000-person years; adjusted p<0.001). Elevated ACE risk was notable in participants with pre-existing LVH [adjusted HR: 1.94 (95% CI: 1.25-2.99); p = 0.003], new-onset LVH [adjusted 1.74 (95% CI: 1.16-2.60); p = 0.007], and persistent LVH[adjusted HR: 1.96 (95% CI: 1.11-3.46); p = 0.020], compared to those without LVH. Intriguingly, LVH regression attenuated this risk increment [adjusted HR: 1.57 (95% CI: 0.98-2.53); p = 0.062]. Achieving a BP target of < 120/80 mmHg nullified the increased ACE risk in those with pre-existing LVH.
CONCLUSIONS
Intensive BP control is instrumental in both reducing the emergence of LVH and fostering its regression. Pre-existing, new-onset LVH and persistent LV remain a predictor of adverse cardiovascular prognosis, whereas LVH regression and achieving on-treatment BP < 120/80 mmHg in pre-existing LVH individuals may further mitigate residual cardiovascular risk.
CLINICAL TRIAL REGISTRATION
URL: ClinicalTrials.gov Unique Identifier: NCT01206062.
PubMed: 38946010
DOI: 10.1186/s40885-024-00275-8 -
Journal of Nutritional Science and... 2024Alaska pollack protein (APP), has been reported as a protein source that can enhance muscle hypertrophy more than other protein sources in animal studies. This study... (Randomized Controlled Trial)
Randomized Controlled Trial
Alaska pollack protein (APP), has been reported as a protein source that can enhance muscle hypertrophy more than other protein sources in animal studies. This study aimed to examine the effects of APP ingestion on muscle quantity and quality in young adults. Fifty-five young college students were assigned to two groups: APP and placebo (whey protein: WP) groups, and instructed to ingest 4.5 g of each protein in addition to daily meals, and to maintain their usual daily physical activities for 3 mo. Twenty-one and 23 students completed the intervention and were analyzed in APP and WP groups, respectively. The maximum knee extension torque significantly increased in both groups during the intervention. The motor unit discharge rate, which is an indicator of activation, for a given force level significantly decreased in both groups during the intervention, but its decrease in the APP group was significantly greater than in the WP group. Echo intensity of the vastus lateralis evaluated by ultrasound images significantly decreased in both groups. The muscle thickness and skeletal muscle mass did not change. Small amount of additional APP intake induces greater effects on neural activation than WP, suggesting the greater neural economy of generation of force.
Topics: Humans; Young Adult; Male; Female; Muscle, Skeletal; Dietary Proteins; Adult; Adaptation, Physiological; Gadiformes; Torque; Quadriceps Muscle; Muscle Strength; Double-Blind Method
PubMed: 38945888
DOI: 10.3177/jnsv.70.228 -
Mymensingh Medical Journal : MMJ Jul 2024Soft tissue injuries of the hand or forearm often results in exposure of tendon or bone which needs coverage with a suitable flap. This prospective observational study... (Observational Study)
Observational Study
Soft tissue injuries of the hand or forearm often results in exposure of tendon or bone which needs coverage with a suitable flap. This prospective observational study was carried out in National Institute of Traumatology and Orthopaedic Rehabilitation (NITOR), Dhaka, Bangladesh from February 2019 to January 2020, to evaluate the use of the pedicled paraumbilical perforator flaps as a reliable flap to cover such defects. Total 34 patients having soft tissue defects in the hand and forearm with exposed tendons, bones or implant were included in this study. All the defects were covered by paraumbilical perforator flap. The defects were caused by road traffic accident (n=22), machinery injury (n=10) and burn injury (n=2). Sixteen patients had defects involving the forearm, six over dorsum of hand, another two over first web space and the rest had defects over two or more areas of forearm, hand and wrist. Lateral extent of flaps was upto anterior axillary line in 41.18% cases and upto mid-axillary line in 55.88% cases. Flap division and final inset was done in second stage after 3 weeks. Donor site closed primarily in all cases, except in two cases where it was covered by skin graft. All the flaps survived with no incidence of flap necrosis, dehiscence or infection after first stage. However, after the division of the flap, two patients developed marginal necrosis of the proximal margin which healed spontaneously by conservative treatment. The mean flap surface area utilized was 108 cm2. Donor area healed well without any major complications. Three patients developing scar hypertrophy were treated with intra-lesional triamcinolone injections. The paraumbilical perforator flap is a reliable option to cover soft tissue defects of hand and forearm due to easier planning and harvesting of the flap, adequate skin paddle and minimum donor site morbidity.
Topics: Humans; Perforator Flap; Male; Soft Tissue Injuries; Female; Adult; Prospective Studies; Hand Injuries; Middle Aged; Forearm; Adolescent; Forearm Injuries; Young Adult; Plastic Surgery Procedures; Child
PubMed: 38944720
DOI: No ID Found -
Journal of Pediatric Urology Jun 2024Many pediatric urology conditions affect putatively normal tissues or appear too commonly to be based solely on specific DNA mutations. Understanding epigenetic...
INTRODUCTION
Many pediatric urology conditions affect putatively normal tissues or appear too commonly to be based solely on specific DNA mutations. Understanding epigenetic mechanisms in pediatric urology, therefore, has many implications that can impact cell and tissue responses to settings, such as environmental and hormonal influences on urethral development, uropathogenic infections, obstructive stimuli, all of which originate externally or extracellularly. Indeed, the cell's response to external stimuli is often mediated epigenetically. In this commentary, we highlight work on the critical role that epigenetic machinery, such as DNA methyltransferases (DNMTs), Enhancer of Zeste Polycomb Repressive Complex 2 Subunit (EZH2), and others play in regulating gene expression and cellular functions in three urological contexts.
DESIGN
Animal and cellular constructs were used to model clinical pediatric uropathology. The hypertrophy, trabeculation, and fibrosis of the chronically obstructed bladder was explored using smooth muscle cell models employing disorganised vs. normal extracellular matrix (ECM), as well as a new animal model of chronic obstructive bladder disease (COBD) which retains its pathologic features even after bladder de-obstruction. Cell models from human and murine hypospadias or genital tubercles (GT) were used to illustrate developmental responses and epigenetic dependency of key developmental genes. Finally, using bladder urothelial and organoid culture systems, we examined activity of epigenetic machinery in response to non uropathogenic vs. uropathogenic E.coli (UPEC). DNMT and EZH2 expression and function were interrogated in these model systems.
RESULTS
Disordered ECM exerted a principal mitogenic and epigenetic role for on bladder smooth muscle both in vitro and in CODB in vivo. Key genes, e.g., BDNF and KCNB2 were under epigenetic regulation in actively evolving obstruction and COBD, though each condition showed distinct epigenetic responses. In models of hypospadias, estrogen strongly dysregulated WNT and Hox expression, which was normalized by epigenetic inhibition. Finally, DNA methylation machinery in the urothelium showed specific activation when challenged by uropathogenic E.coli. Similarly, UPEC induces hypermethylation and downregulation of the growth suppressor p16INK4A. Moreover, host cells exposed to UPEC produced secreted factors inducing epigenetic responses transmissible from one affected cell to another without ongoing bacterial presence.
DISCUSSION
Microenvironmental influences altered epigenetic activity in the three described urologic contexts. Considering that many obstructed bladders continue to display abnormal architecture and dysfunction despite relief of obstruction similar to after resection of posterior valves or BPH, the epigenetic mechanisms described highlight novel approaches for understanding the underlying smooth muscle myopathy of this crucial clinical problem. Similarly, there is evidence for an epigenetic basis of xenoestrogen on development of hypospadias, and UTI-induced pan-urothelial alteration of epigenetic marks and propensity for subsequent (recurrent) UTI. The impact of mechanical, hormonal, infectious triggers on genitourinary epigenetic machinery activity invite novel avenues for targeting epigenetic modifications associated with these non-cancer diseases in urology. This includes the use of deactivated CRISPR-based technologies for precise epigenome targeting and editing. Overall, we underscore the importance of understanding epigenetic regulation in pediatric urology for the development of innovative therapeutic and management strategies.
PubMed: 38944627
DOI: 10.1016/j.jpurol.2024.06.008 -
Biochemical Pharmacology Jun 2024Gestational diabetes mellitus (GDM) is associated with cardiovascular disease in postnatal life. The current study tested the hypothesis that GDM caused the cardiac...
Up-regulation of BRD4 contributes to gestational diabetes mellitus-induced cardiac hypertrophy in offspring by promoting mitochondria dysfunction in sex-independent manner.
Gestational diabetes mellitus (GDM) is associated with cardiovascular disease in postnatal life. The current study tested the hypothesis that GDM caused the cardiac hypertrophy in fetal (ED18.5), postnatal day 7 (PD7), postnatal day 21 (PD21) and postnatal day 90 (PD90) offspring by upregulation of BRD4 and mitochondrial dysfunction. Pregnant mice were divided into control and GDM groups. Hearts were isolated from ED18.5, PD7, PD21 and PD90. GDM increased the body weight (BW) and heart weight (HW) in ED18.5 and PD7, but not PD21 and PD90 offspring. However, HW/BW ratio was increased in all ages of GDM offspring compared to control group. Electron microscopy showed disorganized myofibrils, mitochondrial swelling, vacuolization, and cristae disorder in GDM offspring. GDM resulted in myocardial hypertrophy in offspring, which persisted from fetus to adult in a sex-independent manner. Echocardiography analysis revealed that GDM caused diastolic dysfunction, but had no effect on systolic function. Meanwhile, myocardial BRD4 was significantly upregulated in GDM offspring and BRD4 inhibition by JQ1 alleviated GDM-induced myocardial hypertrophy in offspring. Co-immunoprecipitation showed that BRD4 interacted with DRP1 and there was an increase of BRD4 and DRP1 interaction in GDM offspring. Furthermore, GDM caused the accumulation of damaged mitochondria in hearts from all ages of offspring, including mitochondrial fusion fission imbalance (upregulation of DRP1, and downregulation of MFN1, MFN2 and OPA1) and myocardial mitochondrial ROS accumulation, which was reversed by JQ1. These results suggested that the upregulation of BRD4 is involved in GDM-induced myocardial hypertrophy in the offspring through promoting mitochondrial damage in a gender-independent manner.
PubMed: 38944397
DOI: 10.1016/j.bcp.2024.116387 -
European Journal of Pharmacology Jun 2024Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalently co-occurring, important risk factors for a broad array of neuropsychiatric diseases....
Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are prevalently co-occurring, important risk factors for a broad array of neuropsychiatric diseases. To date, how these two contrastive concomitant pairs increase the risk of neuropsychiatric states, notably exacerbating PTSD-related symptoms, remains unknown. Moreover, pharmacological interventions with agents that could reverse PTSD-AUD comorbidity, however, remained limited. Hence, we investigated the neuroprotective actions of naringin in mice comorbidly exposed to PTSD followed by repeated ethanol (EtOH)-induced AUD. Following a 7-day single-prolong-stress (SPS)-induced PTSD in mice, binge/heavy drinking, notably related to AUD was induced in the PTSD mice with every-other-day ethanol (2 g/kg, p.o.) administration, followed by daily treatments with naringin (25 and 50 mg/kg) or fluoxetine (10 mg/kg), from days 8-21. PTSD-AUD-related behavioral changes, alcohol preference, hypothalamic-pituitary-adrenal (HPA)-axis dysfunction-induced neurochemical alterations, oxidative/nitrergic stress, and inflammation were examined in the prefrontal-cortex, striatum, and hippocampus. PTSD-AUD mice showed aggravated anxiety, spatial-cognitive, social impairments and EtOH intake, which were abated by naringin, similar to fluoxetine. Our assays on the HPA-axis showed exacerbated increased corticosterone release and adrenal hypertrophy, accompanied by marked dopamine and serotonin increase, with depleted glutamic acid decarboxylase enzyme in the three brain regions, which naringin, however, reversed, respectively. PTSD-AUD mice also showed increased TNF-α, IL-6, malondialdehyde and nitrite levels, with decreased antioxidant elements in the prefrontal-cortex, striatum, and hippocampus compared to SPS-EtOH-mice; mainly exacerbating catalase and glutathione decrease in the hippocampus relative SPS-mice. These findings suggest that AUD exacerbates PTSD pathologies in different brain regions, notably comprising neurochemical dysregulations, oxidative/nitrergic and cytokine-mediated inflammation, with HPA dysfunction, which were, however, revocable by naringin.
PubMed: 38944175
DOI: 10.1016/j.ejphar.2024.176791 -
Cardiovascular Research Jun 2024
Single-nucleus transcriptomics reveals adrenergic and STAT3 signaling in paradoxical low-flow low-gradient -specific cardiomyocyte subclusters: implications for aortic stenosis pathogenesis and treatment.
PubMed: 38943668
DOI: 10.1093/cvr/cvae137 -
Journal of Diabetes Investigation Jun 2024Regulatory T cells (Tregs) have protected against many cardiovascular diseases. This study was intended to explore the effect of Tregs on diabetic cardiomyopathy (DCM)...
AIMS/INTRODUCTION
Regulatory T cells (Tregs) have protected against many cardiovascular diseases. This study was intended to explore the effect of Tregs on diabetic cardiomyopathy (DCM) using a db/db mouse model.
MATERIALS AND METHODS
Eight-week-old male db/db mice were randomly divided into four groups: the control group, administered 200 μL phosphate-buffered saline; the small-dose Treg group, administered 10 Tregs; the large-dose Treg group, administered 10 Tregs; and the PC group, administered 100 μg anti-CD25 specific antibody (PC61) and 10 Tregs. After 12 weeks, mice were euthanized. Transthoracic echocardiography was carried out at the beginning and end of the experiment. Relevant basic experiments to evaluate the effects of Tregs on DCM were carried out.
RESULTS
Echocardiography showed that the impaired diastolic and systolic functions were significantly improved in mice administered large-dose Tregs. Large-dose Tregs significantly ameliorated myocardial hypertrophy and fibrosis, and decreased hypertrophic gene expression and collagen deposition. The protective effects of Tregs on diabetic hearts were associated with decreased oxidative stress, inflammatory response and apoptosis. In addition, Tregs promoted the activation of the phosphatidylinositol 3-kinase-protein kinase B signaling pathway, whereas they inhibited extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase phosphorylation, which might be responsible for the cardioprotective role of Tregs against DCM.
CONCLUSIONS
Tregs ameliorated myocardial hypertrophy and fibrosis, improved cardiac dysfunction, and protected against DCM progression in db/db mice. The mechanisms involved a decrease of inflammatory response, oxidative stress and apoptosis, which might be mediated by phosphatidylinositol 3-kinase-protein kinase B and mitogen-activated protein kinase pathways. Hence, Tregs might serve as a promising therapeutic approach for DCM treatment.
PubMed: 38943657
DOI: 10.1111/jdi.14251 -
Scientific Reports Jun 2024Plekhm2 is a protein regulating endosomal trafficking and lysosomal distribution. We recently linked a recessive inherited mutation in PLEKHM2 to a familial form of...
Plekhm2 is a protein regulating endosomal trafficking and lysosomal distribution. We recently linked a recessive inherited mutation in PLEKHM2 to a familial form of dilated cardiomyopathy and left ventricular non-compaction. These patients' primary fibroblasts exhibited abnormal lysosomal distribution and autophagy impairment. We therefore hypothesized that loss of PLEKHM2 impairs cardiac function via autophagy derangement. Here, we characterized the roles of Plekhm2 in the heart using global Plekhm2 knockout (PLK2-KO) mice and cultured cardiac cells. Compared to littermate controls (WT), young PLK2-KO mice exhibited no difference in heart function or autophagy markers but demonstrated higher basal AKT phosphorylation. Older PLK2-KO mice had body and heart growth retardation and increased LC3II protein levels. PLK2-KO mice were more vulnerable to fasting and, interestingly, impaired autophagy was noted in vitro, in Plekhm2-deficient cardiofibroblasts but not in cardiomyocytes. PLK2-KO hearts appeared to be less sensitive to pathological hypertrophy induced by angiotensin-II compared to WT. Our findings suggest a role of Plekhm2 in murine cardiac autophagy. Plekhm2 deficiency impaired autophagy in cardiofibroblasts, but the autophagy in cardiomyocytes is not critically dependent on Plekhm2. The absence of Plekhm2 in mice appears to promote compensatory mechanism(s) enabling the heart to manage angiotensin-II-induced stress without detrimental consequences.
Topics: Animals; Mice; Autophagy; Cells, Cultured; Fibroblasts; Mice, Knockout; Myocardium; Myocytes, Cardiac; Phosphorylation; Protein Serine-Threonine Kinases
PubMed: 38942823
DOI: 10.1038/s41598-024-65670-5 -
European Journal of Pharmacology Jun 2024Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, which endothelial-to-mesenchymal transition (EndMT) being its main progressive phase....
Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, which endothelial-to-mesenchymal transition (EndMT) being its main progressive phase. Wogonin, a flavonoid extracted from the root of Scutellaria baicalensis Georgi, hinders the abnormal proliferation of cells and has been employed in the treatment of several cardiopulmonary diseases. This study was designed to investigate how wogonin affected EndMT during PH. Monocrotaline (MCT) was used to induce PH in rats. Binding capacity of TGF-β1 receptor to wogonin detected by molecular docking and molecular dynamics. EndMT model was established in pulmonary microvascular endothelial cells (PMVECs) by transforming growth factor beta-1 (TGF-β1). The result demonstrated that wogonin (20 mg/kg/day) attenuated right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular thickness in PH rats. EndMT in the pulmonary vascular was inhibited after wogonin treatment as evidenced by the restored expression of CD31 and decreased expression of α-SMA. Wogonin has strong affinity for both TGFBRI and TGFBRII, and has a better binding stability for TGFBRI. In TGF-β1-treated PMVECs, wogonin (0.3, 1, and 3 μM) exhibited significant inhibitory effects on this transformation process via down-regulating the expression of p-Smad2 and Snail, while up-regulating the expression of p-Smad1/5. Additionally, results of western blot and fluorescence shown that the expression of α-SMA were decrease with increasing level of CD31 in PMVECs. In conclusion, our research showed that wogonin suppressed EndMT via the TGF-β1/Smad pathway which may lead to its alleviated effect on PH. Wogonin may be a promising drug against PH.
PubMed: 38942264
DOI: 10.1016/j.ejphar.2024.176786