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Liraglutide has been shown to alleviate heart failure in patients with type 2 diabetes. High-intensity interval training (HIIT) has also been proven to improve cardiac function in diabetes. The present study explored the effects and underlying mechanisms of liraglutide and HIIT combination therapy in alleviating diabetic cardiomyopathy (DCM). A high-fat diet and low-dose streptozotocin (STZ) were utilized to induce the DCM model. Eight weeks of liraglutide injection and HIIT were used to treat DCM. Subsequently, cardiac function, serum metabolic biomarkers, serum glucagon-like peptide-1 (GLP-1), histology examination, cardiac alpha-myosin heavy chain (α-MHC), and β-MHC messenger RNA (mRNA) expression, forkhead box protein O1 (FOXO1) and muscle-specific RING finger protein 1 (MURF1) mRNA expression and colocalization, and expression of GLP-1 and GLP-1 receptor (GLP-1R) proteins were detected after the intervention. Results showed that DCM rats developed hyperglycemia with eccentric hypertrophy, fibrosis, and reduced systolic and diastolic function. All interventions significantly reversed the development of heart failure by alleviating the disruption of contractile apparatus, reversed the adult α-MHC transformed to fetal β-MHC, and reduced FOXO1 and MURF1 mRNA expression. Combination therapy had a better effect in alleviating cardiac fibrosis, reducing cardiovascular risk biomarkers, controlling eccentric hypertrophy, and improving systolic function. Combination therapy significantly reduced FOXO1 and MURF1 colocalization and improved the GLP-1R sensitivity in diabetic hearts. Overall, these findings demonstrate that combination therapy can reverse cardiac failure in diabetic rats by controlling the degradation of contractile apparatus by downregulating the cardiac atrophy gene expression and interrupting their colocalization, as well as upregulating GLP-1 signaling. [ABSTRACT FROM AUTHOR]

Bacteriophage Sf14 infects the human pathogen Shigella flexneri. A previous low-resolution structure suggested the presence of a decoration protein on its T = 9 icosahedral capsid. Here, we determined high-resolution structures of the Sf14 capsid and neck, along with a moderate-resolution structure of the whole Sf14 tail and baseplate. These structures indicate the capsid has not one, but two different types of decoration proteins: a trimeric β-tulip lattice that covers the entire capsid and a set of Hoc-like proteins that bind preferentially to hexamers at the quasi-3-fold axes of symmetry. The neck also contains two sets of whiskers oriented in opposite directions, and the tail has two types of long tail fibers which may bind different receptors. Based on homology and phylogenetic analysis, Sf14 may be the product of multiple horizontal gene transfer events. The structures presented here can be used to investigate further hypotheses of phage structure-function relationships and structural diversity. Structures of Shigella bacteriophage Sf14 show similarity with several features from diverse bacteriophages that, when combined, produce a T = 9 icosahedral capsid coated in decoration proteins and a contractile tail with two tail fibers. [ABSTRACT FROM AUTHOR]

\nIntroduction: The pathogenic role of nitric oxide (NO) signaling during development of thoracic aortic aneurysm (TAA) in Marfan syndrome (MFS) is currently unclear. We characterized vasomotor function and its relationship to the activity of the NO-generating enzymes in mice with early onset progressively severe MFS. Methods: Wire myography, immunoblotting, measurements of aortic NO, and superoxide levels were used to compare vasomotor function, contractile protein levels, and the activity of endothelial and inducible NO synthase (eNOS and iNOS, respectively) in ascending thoracic aortas of Fbn1mgR/mgR mice relative to wild-type littermates. Results: Isometric force measurements of aortic rings from 16-day-old male Fbn1mgR/mgR mice revealed a significant reduction in acetylcholine-induced relaxation and increased phenylephrine (PE)-promoted contractility, associated with abnormally low eNOSSer1177 phosphorylation, decreased NO production, and augmented superoxide levels. Greater aortic contractility was associated with α1-adrenoceptor upregulation and normal levels of contractile proteins. While iNOS inhibition had no effect on vasomotor functions, mutant aortic rings preincubated with a nonspecific NOS inhibitor yielded a greater PE response, implying a significant contribution of endothelial dysfunction to aortic hypercontractility. Conclusion: Impaired eNOS signaling disrupts aortic cholinergic relaxation and adrenergic contraction in MFS mice with dissecting TAA. A thoracic aortic aneurysm is a bulge or weakening in the main artery of the chest, which can be life-threatening if it ruptures. Nitric oxide (NO) is a small gaseous compound produced in the lining of our blood vessels (directly exposed to the bloodstream), which plays a crucial role in keeping our blood vessels relaxed and open, ensuring proper flow throughout the body. When the production of NO is impaired, our blood vessels can become less flexible and may not dilate properly, leading to cardiovascular diseases. In our study, we looked at how NO affects the development of thoracic aortic aneurysm in people with Marfan syndrome (MFS), who develop a severe form of aneurysm that can result in its rupture and the death of patients. We used mice that have a severe form of MFS to see how their blood vessels responded compared to normal healthy mice. We found that MFS mice had difficulty relaxing their blood vessels, crucial for proper blood flow, and their vessels were producing excessive force when stimulated with substances that trigger vasoconstriction. This was due to low levels of NO and increased levels of a harmful molecule called superoxide in the MFS mice. Our findings shed light on how NO imbalance contributes to thoracic aortic aneurysm in MFS, which could lead to new treatment options in the future. [ABSTRACT FROM AUTHOR]

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Hypertrophic Cardiomyopathy (HCM) is often caused by heterozygous mutations in β-myosin heavy chain (MYH7 , β-MyHC). In addition to hyper- or hypocontractile effects of HCM-mutations, heterogeneity in contractile function (contractile imbalance) among individual cardiomyocytes was observed in end-stage HCM-myocardium. Contractile imbalance might be induced by burst-like transcription, leading to unequal fractions of mutant versus wildtype mRNA and protein in individual cardiomyocytes (allelic imbalance). Until now it is not known if allelic and contractile imbalance are present early in HCM-development or rather occur in response to disease-associated remodeling. To address this question, we used patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with heterozygous MYH7 -mutations R723G and G741R as models of early-stage HCM without secondary adaptions upon disease progression. R723G-hiPSC-CMs showed typical HCM-markers like hypertrophy and myofibrillar disarray. Using RNA-FISH and allele-specific single-cell-PCR, we show for both cell lines that MYH7 is transcribed in bursts. Highly variable mutant vs. wildtype MYH7 -mRNA fractions in individual HCM-hiPSC-CMs indicated allelic imbalance. HCM-hiPSC-CM-lines showed functional alterations like slowed twitch contraction kinetics and reduced calcium sensitivity of myofibrillar force generation. A significantly larger variability in force generation or twitch parameters of individual HCM-hiPSC-CMs compared to WT-hiPSC-CMs indicated contractile imbalance. Our results with early-stage hiPSC-CMs strongly suggest that burst-like transcription and allelic imbalance are general features of CMs, which together with mutation-induced changes of sarcomere contraction could induce contractile imbalance in heterozygous CMs, presumably aggravating development of HCM. Genetic or epigenetic approaches targeting functional heterogeneity in HCM could lead to promising future therapies, in addition to myosin modulation. [Display omitted] • hiPSC-CMs represent an early-stage HCM model. • hiPSC-CMs show burst-like transcription and allelic and contractile imbalance. • CM transcriptional and functional heterogeneity likely are present early in HCM. • In HCM heterogeneity among CMs is not a response to disease associated remodeling. • CM contractile imbalance could aggravate mutation induced HCM-progression. [ABSTRACT FROM AUTHOR]

EpCAM and its close relative Trop2 are well-known cell surface markers of carcinoma, but their potential role in cancer metastasis remains unclear. They are known, however, to downregulate myosin-dependent contractility, a key parameter involved in adhesion and migration. We investigate here the morphogenetic impact of the high EpCAM and Trop2 levels typically found in epithelial breast cancer cells, using spheroids of MCF7 cells as an in vitro model. Intriguingly, EpCAM depletion stimulated spheroid cohesive spreading, while Trop2 depletion had the opposite effect. Combining cell biological and biophysical approaches, we demonstrate that while EpCAM and Trop2 both contribute to moderate cell contractility, their depletions differentially impact on the process of "wetting" a substrate, here both matrix and neighboring cells, by affecting the balance of cortical tension at cell and tissue interfaces. These distinct phenotypes can be explained by partial enrichment at specific interfaces. Our data are consistent with the EpCAM-Trop2 pair acting as a mechanostat that tunes adhesive and migratory behaviours. Synopsis: Cell adhesion and cell cortex contractility are important determinants of the morphogenetic properties of solid tissues, including tumours. This study shows that EpCAM and Trop2, two closely related surface markers of carcinoma, play antagonistic roles, respectively opposing or favouring cohesion and collective migration of breast cancer cells. Both EpCAM or Trop2 repress myosin activity and cortical contractility. EpCAM tends to act preferentially on the cell cortex at free edges, Trop2 on matrix and cell adhesive contacts, subtly controlling the balance of tensions at interfaces. Consistently, the two molecules show differential enrichments at the corresponding cell cortices. MCF7 spheroids depleted of EpCAM extensively spread while remaining compact, while those depleted of Trop2 show lower cohesion and spreading than wild type spheroids. Effects of EpCAM and Trop2 can be accurately modelled based on the biophysical analogy with the phenomenon of wetting-dewetting. Two closely related cell surface proteins affect cortical tension in different domains and differentially regulate cell cluster cohesion and spreading. [ABSTRACT FROM AUTHOR]

The article discusses the time-dependent effect of FKBP12 loss in the development of dilated cardiomyopathy. It explores the role of FKBP12 and FKBP12.6 in regulating RyR2-mediated Ca2+ release in cardiomyocytes. The study highlights the impact of FKBP12 deficiency on cardiac structure, Ca2+ handling, and contractile function, emphasizing the importance of FKBP12 expression during early embryonic development. The research provides insights into the mechanisms underlying dilated cardiomyopathy associated with FKBP12 deficiency, suggesting further investigation is needed to understand the pathogenesis of the condition. [Extracted from the article]

Collagenase digestion (d) and cellular outgrowth (og) are the current modalities of meniscus fibrochondrocytes (MFC) isolation for bioengineering and mechanobiology‐related studies. However, the impact of these modalities on study outcomes is unknown. Here, we show that og‐ and d‐isolated MFC have distinct proliferative capacities, transcriptomic profiles via RNA sequencing (RNAseq), extracellular matrix (ECM)‐forming, and migratory capacities. Our data indicate that microtissue pellet models developed from og‐isolated MFC display a contractile phenotype with higher expressions of alpha‐smooth muscle actin (ACTA2) and transgelin (TAGLN) and are mechanically stiffer than their counterparts from d‐MFC. Moreover, we introduce a novel method of MFC isolation designated digestion‐after‐outgrowth (dog). The transcriptomic profile of dog‐MFC is distinct from d‐ and og‐MFC, including a higher expression of mechanosensing caveolae‐associated caveolin‐1 (CAV1). Additionally, dog‐MFC were superior chondrogenically and generated larger‐size microtissue pellet models containing a higher frequency of smaller collagen fibre diameters. Thus, we demonstrate that the modalities of MFC isolation influence the downstream outcomes of bioengineering and mechanobiology‐related studies. [ABSTRACT FROM AUTHOR]

The orientation and function of smooth muscle in the cervix may contribute to the important biomechanical properties that change during pregnancy. Thus, this study examined the three-dimensional structure, smooth muscle phenotype, and mechanical and contractile functions of the upper and lower cervix of nongravid (not pregnant) and gravid (pregnant) mice. In gravid cervix, we uncovered region-specific changes in the structure and organization of fiber tracts. We also detected a greater proportion of contractile smooth muscle cells (SMCs), but an equal proportion of synthetic SMCs, in the upper versus lower cervix. Furthermore, we revealed that the lower cervix had infrequent spontaneous contractions, distension had a minimal effect on contractility, and the upper cervix had forceful contractions in response to labor-inducing agents (oxytocin and prostaglandin E2). These findings identify regional differences in cervix contractility related to contractile SMC content and fiber organization, which could be targeted with diagnostic technologies and for therapeutic intervention. [ABSTRACT FROM AUTHOR]

The left and right ventricles of the human heart are functionally and developmentally distinct such that genetic or acquired insults can cause dysfunction in one or both ventricles resulting in heart failure. To better understand ventricle-specific molecular changes influencing heart failure development, we first performed unbiased quantitative mass spectrometry on pre-mortem non-diseased human myocardium to compare the metabolome and proteome between the normal left and right ventricles. Constituents of gluconeogenesis, glycolysis, lipogenesis, lipolysis, fatty acid catabolism, the citrate cycle and oxidative phosphorylation were down-regulated in the left ventricle, while glycogenesis, pyruvate and ketone metabolism were up-regulated. Inter-ventricular significance of these metabolic pathways was then found to be diminished within end-stage dilated cardiomyopathy and ischaemic cardiomyopathy, while heart failure-associated pathways were increased in the left ventricle relative to the right within ischaemic cardiomyopathy, such as fluid sheer-stress, increased glutamine-glutamate ratio, and down-regulation of contractile proteins, indicating a left ventricular pathological bias. Human myocardial proteomic and metabolomic analyses reveal ventricle-specific metabolic remodelling from normal hearts to heart failure, showing differential regulation in glucose and lipid metabolism, with a left ventricular pathological bias. [ABSTRACT FROM AUTHOR]

Congenital ocular malformations originate from defective morphogenesis during early eye development and cause 25% of childhood blindness. Formation of the eye is a multi-step, dynamic process; it involves evagination of the optic vesicle, followed by distal and ventral invagination, leading to the formation of a two-layered optic cup with a transient optic fissure. These tissue folding events require extensive changes in cell shape and tissue growth mediated by cytoskeleton mechanics and intercellular adhesion. We hypothesized that the Rho GTPase Cdc42 may be an essential, convergent effector downstream of key regulatory factors required for ocular morphogenesis. CDC42 controls actin remodeling, apicobasal polarity, and junction assembly. Here we identify a novel essential function for Cdc42 during eye morphogenesis in mouse; in Cdc42 mutant eyes expansion of the ventral optic cup is arrested, resulting in microphthalmia and a wide coloboma. Our analyses show that Cdc42 is required for expression of the polarity effector proteins PRKCZ and PARD6, intercellular junction protein tight junction protein 1, β -catenin, actin cytoskeleton F-actin, and contractile protein phospho myosin light chain 2. Expression of RPE fate determinants OTX2 and MITF, and formation of the RPE layer are severely affected in the temporal domain of the proximal optic cup. EdU incorporation is significantly downregulated. In addition, mitotic retinal progenitor cells mislocalize deeper, basal regions, likely contributing to decreased proliferation. We propose that morphogenesis of the ventral optic cup requires Cdc42 function for coordinated optic cup expansion and establishment of subretinal space, tissue tension, and differentiation of the ventral RPE layer. [ABSTRACT FROM AUTHOR]

Emerging evidence suggests the potential of rapamycin, an antibiotic from Streptomyces hygroscopicus that functions as a mechanistic target of rapamycin (mTOR) inhibitor, as a mimetic of caloric restriction (CR) for maintaining skeletal muscle health. Several studies showed that rapamycin administration (RAP) reduced appetite and energy intake. However, the physiological and molecular differences between RAP and CR in skeletal muscle are not fully understood. Here we observed the effects of 4 weeks of RAP administration and CR corresponding to the reduction in energy intake produced by RAP administration (PF, paired feeding) on fast glycolytic and slow oxidative muscle in young adult rats. We found that 4 weeks of RAP demonstrated low fast-glycolytic muscle mass with smaller type I and IIb/x myofiber size independent of the energy intake. In addition, PF improved the contractile function of the plantar flexor muscle, whereas RAP did not improve its function. The suppressing response of mTORC1 signaling to RAP is greater in slow-oxidative muscles than in fast-glycolytic muscles. In addition, systemic glucose tolerance was exacerbated by RAP, with reduced expression of Rictor and hexokinase in skeletal muscle. These observations imply that RAP may have a slight but significant negative impact and it obviously different to CR in young adult skeletal muscle. [ABSTRACT FROM AUTHOR]

Cyclic ADP‐ribose (cADPR) has emerged as a calcium‐regulating second messenger in smooth muscle cells. CD38 protein possesses ADP‐ribosyl cyclase and cADPR hydrolase activities and mediates cADPR synthesis and degradation. We have previously shown that CD38 expression is regulated by estrogen and progesterone in the myometrium. Considering hormonal regulation in gestation, the objective of the present study was to determine the role of CD38/cADPR signaling in the regulation of intracellular calcium upon contractile agonist stimulation using immortalized pregnant human myometrial (PHM1) cells. Western blot, immunofluorescence, and biochemical studies confirmed CD38 expression and the presence of ADP‐ribosyl cyclase (2.6 ± 0.1 pmol/mg) and cADPR hydrolase (26.8 ± 6.8 nmoles/mg/h) activities on the PHM1 cell membrane. Oxytocin, PGF2α, and ET‐1 elicited [Ca2+]i responses, and 8‐Br‐cADPR, a cADPR antagonist significantly attenuated agonist‐induced [Ca2+]i responses between 20% and 46% in average. The findings suggest that uterine contractile agonists mediate their effects in part through CD38/cADPR signaling to increase [Ca2+]i and presumably uterine contraction. As studies in humans are limited by the availability of myometrium from healthy donors, PHM1 cells form an in vitro model to study human myometrium. [ABSTRACT FROM AUTHOR]

During skeletal muscle adaptation to physiological or pathophysiological signals, contractile apparatus and mitochondrial function are coordinated to alter muscle fiber type. Although recent studies have identified various factors involved in modifying contractile proteins and mitochondrial function, the molecular mechanisms coordinating contractile and metabolic functions during muscle fiber transition are not fully understood. Using a gene‐deficient mouse approach, our previous studies uncovered that vestigial‐like family member 2 (Vgll2), a skeletal muscle‐specific transcription cofactor activated by exercise, is essential for fast‐to‐slow adaptation of skeletal muscle. The current study provides evidence that Vgll2 plays a role in increasing muscle mitochondrial mass and oxidative capacity. Transgenic Vgll2 overexpression in mice altered muscle fiber composition toward the slow type and enhanced exercise endurance, which contradicted the outcomes observed with Vgll2 deficiency. Vgll2 expression was positively correlated with the expression of genes related to mitochondrial function in skeletal muscle, mitochondrial DNA content, and protein abundance of oxidative phosphorylation complexes. Additionally, Vgll2 overexpression significantly increased the maximal respiration of isolated muscle fibers and enhanced the suppressive effects of endurance training on weight gain. Notably, no additional alteration in expression of myosin heavy chain genes was observed after exercise, suggesting that Vgll2 plays a direct role in regulating mitochondrial function, independent of its effect on contractile components. The observed increase in exercise endurance and metabolic efficiency may be attributed to the acute upregulation of genes promoting fatty acid utilization as a direct consequence of Vgll2 activation facilitated by endurance exercise. Thus, the current study establishes that Vgll2 is an integrative regulator of mitochondrial function and contractility in skeletal muscle. [ABSTRACT FROM AUTHOR]

Background and Aims: Sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, has been shown to have beneficial effects on the diabetic heart. Beta-adrenoceptor (β-AR)-mediated responses are impaired in diabetes. Our aim was to investigate the impact of sitagliptin on the diabetic rat heart in terms of β-AR-mediated responsiveness. In addition, we examined the expression of proteins associated with diastolic dysfunction and endoplasmic reticulum (ER) stress, as well as proteins involved in the β-AR signalling pathway. Methods: Eight-week-old Sprague-Dawley rats were divided into control, diabetic, and sitagliptin-treated (10 mg/kg/day for 4 weeks) diabetic groups. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin (STZ). Throughout the treatment period, the rats received sitagliptin orally. Cardiac β-AR responsiveness was assessed using in vitro papillary muscle experiments with a nonselective β-AR agonist, isoprenaline, and in vitro Langendorff heart preparation experiments with a β3-AR selective agonist CL 316,243. Western blot experiments were conducted to assess the protein expression of SERCA2a, GRP78, β3-AR, eNOS, and p-eNOS. Results: Sitagliptin did not reduce blood glucose levels or reverse weight loss in diabetic rats. However, it improved the heart weight to body weight ratio, indicating a reduction in cardiac hypertrophy. Sitagliptin did not correct the isoprenaline-induced contractile response in the diabetic group, nor did it alter the β3-AR mediated relaxation. Sitagliptin treatment also did not improve the downregulation of SERCA2a or the upregulation of GRP78. However, it reduced the upregulation of β3-AR. The protein expression of eNOS and the ratio of p-eNOS to eNOS were similar among the groups. Conclusion: This study indicates that sitagliptin treatment did not improve isoprenaline-mediated contractile responses or affect β3-AR-mediated relaxation in the diabetic heart. However, the observed increase in β3-AR protein expression in the diabetic heart treated with sitagliptin indicated a potential differential effect of the drug on this pathway compared to the β1-AR signalling pathway. Further studies are needed to elucidate the precise mechanisms by which sitagliptin influences β3-AR-mediated pathways. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) predisposes to cardiac remodeling and coronary microvascular dysfunction. Studies in swine identified changes in microvascular structure and function, as well as changes in mitochondrial structure and oxidative stress. However, CKD was combined with metabolic derangement, thereby obscuring the contribution of CKD alone. Therefore, we studied the impact of CKD on the heart and combined proteome studies with measurement of cardiac function and perfusion to identify processes involved in cardiac remodeling in CKD. CKD was induced in swine at 10–12 weeks of age while sham-operated swine served as controls. 5–6 months later, left ventricular (LV) function and coronary flow reserve were measured. LC–MS–MS-based proteomic analysis of LV tissue was performed. LV myocardium and kidneys were histologically examined for interstitial fibrosis and oxidative stress. Renal embolization resulted in mild chronic kidney injury (increased fibrosis and urinary NGAL). PV loops showed LV dilation and increased wall stress, while preload recruitable stroke work was impaired in CKD. Quantitative proteomic analysis of LV myocardium and STRING pre-ranked functional analysis showed enrichments in pathways related to contractile function, reactive oxygen species, and extracellular matrix (ECM) remodeling, which were confirmed histologically and associated with impaired total anti-oxidant capacity. H2O2 exposure of myocardial slices from CKD, but not normal swine, impaired contractile function. Furthermore, in CKD, mitochondrial proteins were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow. Thus, mild CKD induces alterations in mitochondrial proteins along with contractile proteins, oxidative stress and ECM remodeling, that were associated with changes in cardiac function and perfusion. [ABSTRACT FROM AUTHOR]

Smooth muscle cell (SMC) phenotypic switching is a hallmark of many vascular diseases. Although prior work has established that chemical and mechanical cues contribute to SMC phenotypic switching, the impact of three-dimensional (3D) confinement on this process remains elusive. Yet, in vivo, arterial SMCs reside within confined environments. In this study, we designed a microfluidic assay to investigate the interplay between 3D confinement and different environmental stimuli in SMC function. Our results show that tightly, but not moderately, confined SMCs acquire a contractile phenotype when exposed to collagen I. Elevated compressive forces induced by hydrostatic pressure abolish this upregulation of the contractile phenotype and compromise SMC survival, particularly in tightly confined spaces. Transforming growth factor beta 1, which promotes the contractile state in moderate confinement, fails to enhance the contractility of tightly confined cells. Fibronectin and engagement of cadherin 2 suppress the contractile phenotype of SMCs regardless of the degree of confinement. In contrast, homophilic engagement of cadherin 11 upregulates SMC-specific genes and enhances contractility in both moderately and tightly confined cells. Overall, our work introduces 3D confinement as a regulator of SMC phenotypic responses to chemical and mechanical signals. [ABSTRACT FROM AUTHOR]

Psychological stress contributes to cardiovascular disease (CVD) and sudden cardiac death, yet its molecular basis remains obscure. RNA binding protein RBM24 plays a critical role in cardiac development, rhythm regulation, and cellular stress. Here, we show that psychological stress activates RBM24 S181 phosphorylation through eIF4E2-GSK3β signaling, which causally links psychological stress to CVD by promoting APOE translation (apolipoprotein E). Using an Rbm24 S181A KI mouse model, we show that impaired S181 phosphorylation leads to cardiac contractile dysfunction, atrial fibrillation, dyslipidemia, reduced muscle strength, behavioral abnormalities, and sudden death under acute and chronic psychological stressors. The impaired S181 phosphorylation of RBM24 inhibits cardiac translation, including APOE translation. Notably, cardiomyocyte-specific expression of APOE rescues cardiac electrophysiological abnormalities and contractile dysfunction, through preventing ROS stress and mitochondrial dysfunction. Moreover, RBM24-S181 phosphorylation acts as a serum marker for chronic stress in human. These results provide a functional link between RBM24 phosphorylation, eIF4E-regulated APOE translation, and psychological-stress-induced CVD. Mental stress is well known to cause cardiovascular disease. Here, the authors show that an imbalance in RBM24-S181 phosphorylation impairs cardiac translation of APOE, leading to cardiac contractile dysfunction, atrial fibrillation, fibrosis, and sudden death under psychological stress. [ABSTRACT FROM AUTHOR]

Sepsis evokes compromised myocardial function prompting heart failure albeit target therapy remains dismal. Our study examined the possible role of mitophagy receptor FUNDC1 in septic cardiomyopathy. A sepsis model was established using cecal ligation and puncture (CLP) in FUNDC1 knockout (FUNDC1−/−) and WT mice prior to the evaluation of cardiac morphology, echocardiographic and cardiomyocyte contractile, oxidative stress, apoptosis, necroptosis, and ferroptosis. RNAseq analysis depicted discrepant patterns in mitophagy, oxidative stress and ferroptosis between CLP-challenged and control murine hearts. Septic patients displayed cardiac injury alongside low plasma FUNDC1 and iron levels. CLP evoked interstitial fibrosis, cardiac dysfunction (lowered ejection fraction, fractional shortening, shortening/relengthening velocity, peak shortening and electrically-stimulated intracellular Ca2+ rise, alongside increased LV end systolic diameter and relengthening duration), O 2 − buildup, apoptosis, necroptosis, and ferroptosis (downregulated GPX4 and SLC7A11), the responses of which were accentuated by FUNDC1 ablation. In particular, levels of lipid peroxidation enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) were upregulated following CLP procedure, with a more pronounced response in FUNDC1−/− mice. Co-immunoprecipitation and interaction interface revealed an evident interaction between FUNDC1 and ACSL4. In vitro studies revealed that the endotoxin lipopolysaccharide provoked cardiomyocyte contractile and lipid peroxidation anomalies, the responses were reversed by the mitophagy inducer oleanolic acid, inhibition of ACSL4 and ferroptosis. These findings favor a role for FUNDC1-ACSL4-ferroptosis cascade in septic cardiomyopathy. [Display omitted] • Sepsis is associated with dampened mitophagy and overwhelmed ferroptosis in the heart. • Upregulation in ACSL4 plays an important role in ferroptosis in septic hearts. • Deficiency in mitophagy receptor FUNDC1 accentuates CLP-evoked cardiac remodeling and contractile dysfunction. • FUNDC1-ACSL4-ferroptosis cascade may be a target for the management of septic cardiomyopathy. [ABSTRACT FROM AUTHOR]

G protein alpha q subunit (Gαq) can binds to the G protein-coupled receptor (GPCR) for signaling and is closely related to lipid metabolism. Endurance exercise is an effective means of combating acquired obesity and its complications, but the mechanisms by which endurance exercise modulates hereditary obesity and its complications are unknown. In this study, we achieved knockdown of Gαq in drosophila adipose tissue and skeletal muscle by constructing the Gαq-UAS-RNAi/Ppl-Gal4 and Gαq-UAS-RNAi/Mef2-GAl4 systems. Drosophila were subjected a three-week endurance exercise intervention, and changes in relevant indicators were detected and observed by RT-PCR, ELISA, oil red staining, immunofluorescence staining, and transmission electron microscopy. The results showed that knockdown of Gαq in both adipose tissue and skeletal muscle induced a significant increase in triglycerides accompanied by a decrease in rapid climbing ability, a decrease in Superoxide Dismutase (SOD) activity level, and a decrease in Mitochondrial respiratory chain complexI (MRCC I) content in Drosophila whole body and skeletal muscle, and down-regulated the expression of the G protein alpha q subunit (Gαq), the skeletal muscle myosin heavy chain expression gene (Mhc), mitochondrial biogenesis gene Spargal(the PGC-1alpha homologue in Drosophila). Endurance exercise significantly improved the triglyceride levels in the whole body and skeletal muscle of drosophila with Gαq knockdown in adipose tissue and skeletal muscle, as well as their ability to climb, increased SOD activity level and MRCCI content level, and up-regulated the expression of Gαq, Mhc, and Spargal(Srl). Thus, the present findings suggest that genetic defects in the Gαq gene in adipose and skeletal muscle tissues induce hereditary obesity and skeletal muscle dysfunction, and that endurance exercise attenuates this hereditary obesity and concomitant skeletal muscle dysfunction in drosophila by improving skeletal muscle fiber contractile proteins, mitochondrial function and function, and antioxidant capacity via mediating the Gαq/Mhc, Gαq/Srl/MRCC-I, and Gαq/SOD pathways. [ABSTRACT FROM AUTHOR]

Aims Differentiated vascular smooth muscle cells (VSMCs) express a unique network of mRNA isoforms via smooth muscle–specific alternative pre-mRNA splicing (SM-AS) in functionally critical genes, including those comprising the contractile machinery. We previously described RNA Binding Protein with Multiple Splicing (RBPMS) as a potent driver of differentiated SM-AS in the rat PAC1 VSMC cell line. What is unknown is how RBPMS affects VSMC phenotype and behaviour. Here, we aimed to dissect the role of RBPMS in SM-AS in human cells and determine the impact on VSMC phenotypic properties. Methods and results We used human embryonic stem cell–derived VSMCs (hESC-VSMCs) as our platform. hESC-VSMCs are inherently immature, and we found that they display only partially differentiated SM-AS patterns while RBPMS protein levels are low. We found that RBPMS over-expression induces SM-AS patterns in hESC-VSMCs akin to the contractile tissue VSMC splicing patterns. We present in silico and experimental findings that support RBPMS' splicing activity as mediated through direct binding and via functional cooperativity with splicing factor RBFOX2 on a significant subset of targets. We also demonstrate that RBPMS can alter the motility and the proliferative properties of hESC-VSMCs to mimic a more differentiated state. Conclusion Overall, this study emphasizes a critical role for RBPMS in establishing the contractile phenotype splicing programme of human VSMCs. [ABSTRACT FROM AUTHOR]

The methyltransferase enhancer of zeste homolog 2 (EZH2) regulates gene expression, and aberrant EZH2 expression and signaling can drive fibrosis and cancer. However, it is not clear how chemical and mechanical signals are integrated to regulate EZH2 and gene expression. We show that culture of cells on stiff matrices in concert with transforming growth factor (TGF)-β1 promotes nuclear localization of EZH2 and an increase in the levels of the corresponding histone modification, H3K27me3, thereby regulating gene expression. EZH2 activity and expression are required for TGFβ1-and stiffness-induced increases in H3K27me3 levels as well as for morphological and gene expression changes associated with epithelial-mesenchymal transition (EMT). Inhibition of Rho associated kinase (ROCK) proteins or myosin II signaling attenuates TGFβ1- induced nuclear localization of EZH2 and decreases H3K27me3 levels in cells cultured on stiff substrata, suggesting that cellular contractility, in concert with a major cancer signaling regulator TGFβ1, modulates EZH2 subcellular localization. These findings provide a contractilitydependent mechanism by which matrix stiffness and TGFβ1 together mediate EZH2 signaling to promote EMT. [ABSTRACT FROM AUTHOR]

The article discusses the prevalence of heart failure (HF) as a major disease burden in Europe, exacerbated by comorbidities such as chronic kidney disease, anaemia, obesity, and diabetes. It highlights the systemic nature of HF, requiring an interdisciplinary approach for prevention and treatment. The new COST Action EU-METAHEART aims to address metabolic alterations in HF through research areas focusing on cardiomyocyte metabolism, coronary vascular dysfunction, immunometabolism, and mitochondrial redox alterations. The Action seeks to improve understanding, identify treatment targets, and train the next generation of scientists in this field. [Extracted from the article]

The document is a contents list for the journal "Lab on a Chip," which focuses on devices and applications at the micro- and nanoscale. It includes a range of articles on various topics, such as microfluidic technologies, CRISPR diagnostics, drug delivery, and 3D printing. The journal aims to connect the world with the chemical sciences and is published by The Royal Society of Chemistry. The document also mentions approved training courses offered by the society. [Extracted from the article]

Severe asthma is characterized by increased cell volume (hypertrophy) and enhanced contractile function (hyperresponsiveness) of the airway smooth muscle cells (ASMCs). The causative relationship and underlying regulatory mechanisms between them, however, have remained unclear. Here, we manipulated the single-cell volume of in vitro cultured human ASMCs to increase from 2.7 to 5.2 and 8.2 × 103 μm3 as a simulated ASMC hypertrophy by culturing the cells on micropatterned rectangular substrates with a width of 25 μm and length from 50 to 100 and 200 μm, respectively. We found that as the cell volume increased, ASMCs exhibited a pro-contractile function with increased mRNA expression of contractile proteins, increased cell stiffness and traction force, and enhanced response to contractile stimulation. We also uncovered a concomitant increase in membrane tension and Piezo1 mRNA expression with increasing cell volume. Perhaps more importantly, we found that the enhanced contractile function due to cell volume increase was largely attenuated when membrane tension and Piezo1 mRNA expression were downregulated, and an auto-regulatory loop between Piezo1 and YAP mRNA expression was also involved in perpetuating the contractile function. These findings, thus, provide convincing evidence of a direct link between hypertrophy and enhanced contractile function of ASMCs that was mediated via Piezo1 mRNA expression, which may be specifically targeted as a novel therapeutic strategy to treat pulmonary diseases associated with ASMC hypertrophy such as severe asthma. [ABSTRACT FROM AUTHOR]

Platelets are critical mediators of hemostasis and thrombosis. Platelets circulate as discs in their resting form but change shape rapidly upon activation by vascular damage and/or soluble agonists such as thrombin. Platelet shape change is driven by a dynamic remodeling of the actin cytoskeleton. Actin filaments interact with the protein myosin, which is phosphorylated on the myosin light chain (MLC) upon platelet activation. Actin-myosin interactions trigger contraction of the actin cytoskeleton, which drives platelet spreading and contractile force generation. Filamin A (FLNA) is an actin cross-linking protein that stabilizes the attachment between subcortical actin filaments and the cell membrane. In addition, FLNA binds multiple proteins and serves as a critical intracellular signaling scaffold. Here, we used platelets from mice with a megakaryocyte/platelet-specific deletion of FLNA to investigate the role of FLNA in regulating platelet shape change. Relative to controls, FLNA-null platelets exhibited defects in stress fiber formation, contractile force generation, and MLC phosphorylation in response to thrombin stimulation. Blockade of Rho kinase (ROCK) and protein kinase C (PKC) with the inhibitors Y27632 and bisindolylmaleimide (BIM), respectively, also attenuated MLC phosphorylation; our data further indicate that ROCK and PKC promote MLC phosphorylation through independent pathways. Notably, the activity of both ROCK and PKC was diminished in the FLNA-deficient platelets. We conclude that FLNA regulates thrombin-induced MLC phosphorylation and platelet contraction, in a ROCK- and PKC-dependent manner. [ABSTRACT FROM AUTHOR]

Reduced muscle contractility and mitochondrial bioenergetics are the hallmarks of systolic heart failure. There is currently no therapy targeting both. Here, we show that gene delivery of Perm1 via adeno-associated virus (AAV) simultaneously enhances cardiac contractility and mitochondrial biogenesis in C57BL6 mice. Moreover, we found that PERM1 interacts with troponin C (TnC), a key contractile protein in striated muscle, and that AAV-Perm1 led to the upregulation of TnC. This study suggests that gene delivery of Perm1 may be a novel therapeutic approach to treat systolic heart failure by simultaneously restoring cardiac contractility and mitochondrial bioenergetics. NEW & NOTEWORTHY:Perm1 gene delivered with AAV9 enhances cardiac contractility in mice, and it is concomitant with the increase of mitochondrial bioenergetics and upregulation of TnC. This is the first study showing that PERM1, previously known as a striated muscle-specific mitochondrial regulator, also positively regulates cardiac contractility. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is composed of a series of peptides, receptors, and enzymes that play a pivotal role in maintaining cardiovascular homeostasis. Among the most important players in this system are the angiotensin-II and angiotensin-(1-7) peptides. Our group has recently demonstrated that alamandine (ALA), a peptide with structural and functional similarities to angiotensin-(1-7), interacts with cardiomyocytes, enhancing contractility via the Mas-related G protein-coupled receptor member D (MrgD). It is currently unknown whether this modulation varies along the distinct phases of the day. To address this issue, we assessed the ALA-induced contractility response of cardiomyocytes from mice at four Zeitgeber times (ZTs). At ZT2 (light phase), ALA enhanced cardiomyocyte shortening in an MrgD receptor-dependent manner, which was associated with nitric oxide (NO) production. At ZT14 (dark phase), ALA induced a negative modulation on the cardiomyocyte contraction. β-Alanine, an MrgD agonist, reproduced the time-of-day effects of ALA on myocyte shortening. NG-nitro-L-arginine methyl ester, an NO synthase inhibitor, blocked the increase in fractional shortening induced by ALA at ZT2. No effect of ALA on myocyte shortening was observed at ZT8 and ZT20. Our results show that ALA/MrgD signaling in cardiomyocytes is subject to temporal modulation. This finding has significant implications for pharmacological approaches that combine chronotherapy for cardiac conditions triggered by disruption of circadian rhythms and hormonal signaling. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that leads to respiratory decline caused by scarring and thickening of lung tissues. Multiple pathways contribute to the fibrotic process in this disease, such as inflammation, epithelial-to-mesenchymal transition, and oxidative stress. The Rho-associated coiled-coil forming protein kinase (ROCK) signaling pathway is a key regulator of profibrotic signaling, as it affects the organization of actin-myosin and the remodeling of the extracellular matrix. ROCK1/2, a downstream effector of RhoA, is overexpressed in patients with IPF and is a promising target for IPF therapy. However, because of the hypotensive side effects of ROCK1/2 inhibitors, selective ROCK2 compounds are being explored. In this study, we report the discovery of GNS-3595, a potent and selective ROCK2 inhibitor that has ∼80-fold selectivity over ROCK1 at physiological concentrations of ATP. GNS-3595 effectively inhibited ROCK2-mediated phosphorylation of myosin light chain and reduced the expression of fibrosis-related proteins (e.g., collagen, fibronectin, and α-smooth muscle actin) in various in vitro cellular models. GNS-3595 also prevented transforming growth factor β–induced fibroblast-to-myofibroblast transition. In addition, in a bleomycin-induced mouse model of pulmonary fibrosis, therapeutic exposure to GNS-3595, suppressed lung fibrosis, stabilized body weight loss, and prevented fibrosis-induced lung weight gain. Transcriptome and protein expression analysis from lung tissues showed that GNS-3595 can revert the fibrosis-related gene expression induced by bleomycin. These results indicate that GNS-3595 is a highly potent, selective, and orally active ROCK2 inhibitor with promising therapeutic efficacy against pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Objective: Atomoxetine (ATX), a selective noradrenaline re-uptake inhibitor, is a preferred drug with sufficient efficacy and favorable safety profile for the treatment of attention-deficit hyperactivity disorder. Ejaculatory dysfunctions have been reported in the patients receiving ATX as sexual side effects, of which underlying mechanisms are largely unknown. The present study aimed to investigate the effect of ATX on mouse isolated vas deferens (VD) contractility as a potential mechanism of ATX-induced ejaculatory dysfunction. Material and Methods: Isolated organ bath studies were performed on prostatic parts of VD obtained from adult male Balb/c mice. The effect of ATX (10-6, 10-5, 3x10-5 and 10-4 M) on KCl (80 mM)-, phenylephrine (PhE, 3x10-4 M)-, adenosine 5'-triphosphate (ATP, 10-2 M)- and electrical field stimulation (EFS; 100 V, 64 Hz)-induced contractions of VD strips were evaluated in concentration dependent manner. Results: ATX at 10-6 and 10-5 did not alter the contractile responses (p > 0.05), however, higher concentrations of ATX (3x10-5 or 10-4 M) significantly inhibited the KCl-, PhE-, ATP- and EFSinduced contractions of VD strips (p < 0.05). Conclusion: The present study demonstrated for the first time that ATX decreased the contractile responses of mouse isolated VD concentration-dependently. Our results suggest that ejaculatory dysfunction might be related to the inhibitory effect of ATX on VD. [ABSTRACT FROM AUTHOR]

Aging leads to a progressive decline in cardiac function, increasing the risk of heart failure with preserved ejection fraction (HFpEF). This study elucidates the impact of α-Klotho, an anti-aging hormone, on cardiac diastolic dysfunction and explore its downstream mechanisms. Aged wild-type and heterozygous Klotho-deficient mice received daily injection of soluble α-Klotho (sKL) for 10 weeks, followed by a comprehensive assessment of heart function by echocardiography, intracardiac pressure catheter, exercise tolerance, and cardiac pathology. Our findings show that klotho deficiency accentuated cardiac hypertrophy, diastolic dysfunction, and exercise intolerance, while sKL treatment ameliorates these abnormalities and improves cardiac capillary densities. Downstream of klotho, we focused on the Sirtuin1 (Sirt1) signaling pathway to elucidate the potential underlying mechanism by which Klotho improves diastolic function. We found that decreased Klotho levels were linked with Sirt1 deficiency, whereas sKL treatment restored Sirt1 expression in aged hearts and mitigated the DNA damage response pathway activation. Through tandem mass tag proteomics and unbiased acetylomics analysis, we identified 220 significantly hyperacetylated lysine sites in critical cardiac proteins of aged hearts. We found that sKL supplementation attenuated age-dependent DNA damage and cardiac diastolic dysfunction. In contrast, Klotho deficiency significantly increased hyperacetylation of several crucial cardiac contractile proteins, potentially impairing ventricular relaxation and diastolic function, thus predisposing to HFpEF. These results suggest the potential benefit of sKL supplementation as a promising therapeutic strategy for combating HFpEF in aging. [ABSTRACT FROM AUTHOR]

The document "Chemical Analyses and Therapeutic Properties of Plant Extracts" published in the journal Molecules explores the efficacy, quality, and safety of herbal medicines, focusing on bioactive properties of plant extracts. Studies in the Special Issue investigate extracts from plants worldwide, identifying properties like anti-inflammatory, antioxidant, and neuroprotective activities. Different extraction methods impact constituent composition and biological activity, shedding light on the therapeutic potential of plant extracts for developing new therapies. Animal and cell-based models are used to understand the mechanisms of action and therapeutic potential of plant extracts, contributing to insights on how bioactive properties are conferred by constituents. [Extracted from the article]

The letter published in Neurology India discusses the correlation between hemodynamics and the growth of fusiform intracranial aneurysms. The study focuses on a 40-year-old male patient with multiple intracranial aneurysms, specifically analyzing the hemodynamic properties of a growing left middle cerebral artery aneurysm. The research findings suggest that the growth of the aneurysm occurred in a low wall shear stress (WSS) area, supporting the hypothesis that WSS plays a role in the morphological growth of aneurysms. [Extracted from the article]

People with a spinal cord injury are at an increased risk of metabolic dysfunction due to skeletal muscle atrophy and the transition of paralyzed muscle to a glycolytic, insulin-resistant phenotype. Providing doses of exercise through electrical muscle stimulation may provide a therapeutic intervention to help restore metabolic function for people with a spinal cord injury, but high-frequency and high-force electrically induced muscle contractions increase fracture risk for the underlying osteoporotic skeletal system. Therefore, we investigated the acute molecular responses after a session of either a 3 Hz or 1 Hz electrically induced exercise program. Ten people with a complete spinal cord injury completed a 1 h (3 Hz) or 3 h (1 Hz) unilateral electrically induced exercise session prior to a skeletal muscle biopsy of the vastus lateralis. The number of pulses was held constant. Tissue samples were analyzed for genomic and epigenomic expression profiles. There was a strong acute response after the 3 Hz exercise leading to the upregulation of early response genes (NR4A3, PGC-1α, ABRA, IRS2, EGR1, ANKRD1, and MYC), which have prominent roles in regulating molecular pathways that control mitochondrial biogenesis, contractile protein synthesis, and metabolism. Additionally, these genes, and others, contributed to the enrichment of pathways associated with signal transduction, cellular response to stimuli, gene expression, and metabolism. While there were similar trends observed after the 1 Hz exercise, the magnitude of gene expression changes did not reach our significance thresholds, despite a constant number of stimuli delivered. There were also no robust acute changes in muscle methylation after either form of exercise. Taken together, this study supports that a dose of low-force electrically induced exercise for 1 h using a 3 Hz stimulation frequency is suitable to trigger an acute genomic response in people with chronic paralysis, consistent with an expression signature thought to improve the metabolic and contractile phenotype of paralyzed muscle, if performed on a regular basis. [ABSTRACT FROM AUTHOR]

This research letter published in the journal Circulation discusses the potential cardioprotective activity of a retro-enantiomer peptide called Angiotensin-(1-9) [Ang-(1-9) RE]. The authors synthesized this peptide and found that it interacts with the angiotensin receptor type 2 (AT2R) and displays increased stability in serum compared to the original peptide Ang-(1-9). The study conducted on spontaneously hypertensive rats (SHRs) showed that Ang-(1-9) RE reduced systolic blood pressure and was more effective than Ang-(1-9) in reducing cardiac hypertrophy and collagen content in the hearts of SHRs. The study suggests that Ang-(1-9) RE has promising therapeutic applications for cardiovascular diseases. The text also briefly mentions the Iran Pasteur Institute, which has played a significant role in controlling infectious diseases in Iran and is considered a major component of Iran's healthcare and research infrastructure. [Extracted from the article]

Vascular smooth muscle cell (VSMC) phenotype switch and dysfunctions have been reported to participate in aortic dissection (AD) progression. This study was aimed to investigate the role of angiopoietin-like 4 (ANGPTL4) in regulating VSMCs phenotype switch. Key genes were analyzed in AD using public datasets, and it was found that the central differential gene ANGPTL4 was up-regulated in AD. The KEGG signaling pathway annotation was performed to validate the associated pathways, and the expression of ANGPTL4 was verified using multiple datasets and clinical samples. Furthermore, the specific functions of ANGPTL4 on platelet-derived growth factor-BB (PDGF-BB)-treated human aortic smooth muscle cell (HASMC) phenotypes were investigated. The dynamic effects of ANGPTL4 and core signaling antagonists on HASMC phenotypes were examined. Hub gene ANGPTL4 was significantly up-regulated in AD. ANGPTL4 was linked to the PI3K/Akt signaling, angiogenesis, and neovascularization and remodeling. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotypes, including promoted cell viability and migration, decreased contractile VSMC markers α-SMA and SM22α, elevated ECM degradation markers MMP-2 and MMP-9, and promoted phosphorylation of PI3K and Akt. ANGPTL4 knockdown partially abolished PDGF-BB-induced contractile/synthetic VSMCs imbalance and HASMC dysfunctions. Furthermore, in ANGPTL4 -overexpressing HASMCs pre-treated with PDGF-BB, the PI3K/Akt signaling inhibitor LY294002 also partially eliminated the effects caused by the PDGF-BB treatment and ANGPTL4 overexpression. ANGPTL4 is significantly up-regulated in AD. ANGPTL4 overexpression further enhanced PDGF-BB effects on HASMC phenotype switch and dysfunctions, which might be involved in the PI3K/Akt signaling. [ABSTRACT FROM AUTHOR]

Overactive bladder (OAB) is a condition characterized by an urgency to urinate, which is associated with the urodynamic observation of detrusor overexcitation. Although the etiology of OAB is currently unclear, it has been suggested that in patients with OAB, disruption of bladder epithelial barrier integrity can disturb the normal contractile function of the detrusor. Additionally, dietary preferences have been suggested to influence the severity of OAB. Therefore, the aim of the present study was to investigate the effect of a high salt diet (HSD) on the development of OAB in a murine model. Mice were fed either a HSD or standard diet for 8 weeks, following which voiding characteristics and bladder barrier function were assessed. The present study demonstrated that a HSD in mice was associated with OAB-like symptoms such as increased urinary frequency and non-voiding bladder contractions. The HSD group demonstrated a thinner bladder mucus layer and decreased expression of bladder barrier markers, tight junction protein-1 and claudin-1, which may be potentially indicative of induced bladder damage. A HSD for 8 weeks in mice and a high salt treatment at the uroepithelium cellular (SV-HUC-1s) level resulted in increased uroepithelial oxidative stress and inflammatory cell infiltration, as indicated by increased expression levels of TNF-α and IL-1β, as well as activation of the nucleotide-binding domain leucine-rich-containing family pyrin domain-containing 3 (NLRP3) and NF-κB signaling pathways in vivo and in vitro. Therefore, the present study indicated that a HSD could be a potentially important risk factor for the development of OAB, as it may be associated with overactivation of contractile function of the bladder by impairing the integrity of the bladder epithelial barrier and activation of the NLRP3 and NF-κB signaling pathways. Remodeling of the bladder barrier and reduction of the inflammatory response may be potential targets for the treatment of OAB in the future. [ABSTRACT FROM AUTHOR]

The prevalence of skeletal muscle atrophy, caused by disease and aging, is rising as life expectancy increases. Exercise is the most effective treatment option; however, it is often impractical for individuals suffering from disease or bedridden. The formulation of non-exercise-based interventions is necessary. This study assessed the impact of acupuncture (AC), electro-acupuncture (EA), and electrical stimulation (ES) on muscle mass and contractile properties in a model of casting-induced muscle atrophy. Sprague-Dawley rats (n = 40) were assigned to five groups: control (CON), cast (CT), cast receiving AC (CT-AC), cast receiving EA (CT-EA), and cast receiving ES (CT-ES) (n = 8 each). Treatments were 15 min and three times/week for 14 days. Contractile properties and protein markers of atrophy and inflammation were measured. Casting decreased muscle mass and fiber cross-sectional area, but AC, EA, and ES attenuated cast-induced muscle atrophy. All treatments increased peak twitch tension compared to CT. CT increased the protein levels of MAFbx and MuRF1, while AC, EA, and ES mitigated the elevation of these proteins. Our results indicate that acupuncture, electro-acupuncture, and electrical stimulation show promise as therapeutic strategies to counteract skeletal muscle loss and dysfunction resulting from disuse atrophy caused by injury, disease, and aging. [ABSTRACT FROM AUTHOR]

Severe aortic stenosis (AS) is not a disease of the valve only, but one involving the myocardium. Left ventricular systolic dysfunction in severe AS is associated with worse outcomes, despite aortic valve replacement (AVR). This case-based narrative review aims to highlight both the macro- and microscopic structural features of the myocardium in severe classic AS, with a particular focus on differentiating the afterload mismatch group from those with true contractile dysfunction. Left ventricular systolic dysfunction is associated with maladaptive patterns of left ventricular hypertrophy, mid-wall interstitial fibrosis, subendocardial replacement fibrosis secondary to ischaemia and possibly, low-grade chronic inflammation, and myocardial oedema. The underlying molecular signals appear to establish an ongoing cycle of maladaptive remodelling, but the initiating triggers remain poorly understood. Furthermore, features that differentiate those with afterload mismatch from those with true contractile dysfunction have been poorly investigated and further prospective research would provide important insight that could translate to earlier detection of those who may benefit from AVR before irreversible myocardial damage ensues, improved decision-making around management of these patients and the development of novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction (IUGR) is one of the most common pathologies of pregnancy. Due to this pathology, the functioning of many systems, including the cardiovascular, is impaired. In adult animals, who have suffered IUGR, the contribution of procontractile mechanisms of vascular tone regulation (e.g., Rho-kinase signaling pathway) increases, while that of anticontractile mechanisms (e.g., endothelial NO), on the contrary, decreases, which can lead to vasospasm and impaired blood supply to the organs. Since NO and Rho-kinase play a pronounced vasomotor role in early postnatal ontogenesis, this work was aimed to assess the effect of IUGR on the contribution of these mechanisms to the regulation of arterial contractile responses during the early postnatal period in rats. IUGR was modeled by restricting the amount of food calories consumed by females (by 50%) since day 11 of pregnancy until parturition. In rat offspring aged 11–12 days, we studied the responses of the isolated saphenous artery in isometric mode and evaluated the content of mRNA and proteins of interest in this artery. IUGR did not alter the offspring arterial reactivity to the α1-adrenergic receptor agonist methoxamine. The increase in vasocontractile responses to methoxamine in the presence of the endothelial nitric oxide synthase (eNOS) inhibitor L-NNA, as well as the expression levels of eNOS (mRNA and protein) and arginase-2 (mRNA), did not change in the arteries of IUGR rat pups, whereas the arterial sensitivity to the exogenous NO donor DEA/NO was higher in IUGR vs. Control rat pups. Despite relatively low levels of RhoA and Rho-kinase II proteins in the arterial tissue of IUGR rat pups, the decrease in contractile responses, elicited by the Rho-kinase inhibitor Y27632, was equally pronounced in the arteries of rat pups from both IUGR and Control groups. Thus, IUGR, caused by maternal nutritional restriction during pregnancy, causes no pronounced changes in the regulation of systemic vascular tone during the early postnatal period. [ABSTRACT FROM AUTHOR]

Aging is associated with cardiac contractile abnormalities, but the etiology of these contractile deficits is unclear. We hypothesized that cardiac contractile and regulatory protein expression is altered during aging. To investigate this possibility, left ventricular (LV) lysates were prepared from young (6 months) and old (24 months) Fischer344 rats. There are no age‐related changes in SERCA2 expression or phospholamban phosphorylation. Additionally, neither titin isoform expression nor phosphorylation differed. However, there is a significant increase in β‐isoform of the myosin heavy chain (MyHC) expression and phosphorylation of TnI and MyBP‐C during aging. In permeabilized strips of papillary muscle, force and Ca2+ sensitivity are reduced during aging, consistent with the increase in β‐MyHC expression and TnI phosphorylation. However, the increase in MyBP‐C phosphorylation during aging may represent a mechanism to compensate for age‐related contractile deficits. In isolated cardiomyocytes loaded with Fura‐2, the peak of the Ca2+ transient is reduced, but the kinetics of the Ca2+ transient are not altered. Furthermore, the extent of shortening and the rates of both sarcomere shortening and re‐lengthening are reduced. These results demonstrate that aging is associated with changes in contractile and regulatory protein expression and phosphorylation, which affect the mechanical properties of cardiac muscle. [ABSTRACT FROM AUTHOR]

Diabetes mediates endothelial dysfunction and increases the risk of Alzheimer's disease and related dementias. Diabetes also dysregulates the ET system. ET-1-mediated constriction of brain microvascular pericytes (BMVPCs) has been shown to contribute to brain hypoperfusion. Cellular senescence, a process that arrests the proliferation of harmful cells and instigates phenotypical changes and proinflammatory responses in endothelial cells that impact their survival and function. Thus, we hypothesized that ET-1 mediates BMVPC senescence and phenotypical changes in diabetes-like conditions. Human BMVPCs were incubated in diabetes-like conditions with or without ET-1 (1 µmol/L) for 3 and 7 days. Hydrogen peroxide (100 µmol/L H2O2) was used as a positive control for senescence and to mimic ischemic conditions. Cells were stained for senescence-associated β-galactosidase or processed for immunoblotting and quantitative real-time PCR analyses. In additional experiments, cells were stimulated with ET-1 in the presence or absence of ETA receptor antagonist BQ-123 (20 μmol/L) or ETB receptor antagonist BQ-788 (20 μmol/L). ET-1 stimulation increased β-galactosidase accumulation which was prevented by BQ-123. ET-1 also increased traditional senescence marker p16 protein and pericyte-specific senescence markers, TGFB1i1, PP1CA, and IGFBP7. Furthermore, ET-1 stimulated contractile protein α-SMA and microglial marker ostepontin in high glucose suggesting a shift toward an ensheathing or microglia-like phenotype. In conclusion, ET-1 triggers senescence, alters ETA and ETB receptors, and causes phenotypical changes in BMVPCs under diabetes-like conditions. These in vitro findings need to be further studied in vivo to establish the role of ETA receptors in the progression of pericyte senescence and phenotypical changes in VCID. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AFib) is the most common cardiac rhythm disturbance, often treated via electrical cardioversion. Following rhythm restoration, a period of depressed mechanical function known as atrial stunning occurs, suggesting that defects in contractility occur in AFib and are revealed upon restoration of rhythm. This project aims to define the contractile remodeling that occurs in AFib. To assess contractile function, we used a canine atrial tachypacing model of induced AFib. Mass spectrometry analysis showed dysregulation of contractile proteins in samples from AFib compared with sinus rhythm atria. Atrial cardiomyocytes show reduced force of contraction, decreased resting tension, and increased calcium sensitivity in skinned single cardiomyocyte studies. These alterations correlated with degradation of myofilament proteins including myosin heavy chain altering force of contraction, titin altering resting tension, and troponin I altering calcium sensitivity. We measured degradation of other myofilament proteins, including cardiac myosin binding protein C and actinin, that show degradation products in the AFib samples that are absent in the sinus rhythm atria. Many of the degradation products appeared as discrete cleavage products that are generated by calpain proteolysis. We assessed calpain activity and found it to be significantly increased. These results provide an understanding of the contractile remodeling that occurs in AFib and provide insight into the molecular explanation for atrial stunning and the increased risk of atrial thrombus and stroke in AFib. NEW & NOTEWORTHY: Atrial fibrillation is the most common cardiac rhythm disorder, and remodeling during atrial fibrillation is highly variable between patients. This study has defined the biophysical changes in contractility that occur in atrial fibrillation along with identifying potential molecular mechanisms that may drive this remodeling. This includes proteolysis of several myofilament proteins including titin, troponin I, myosin heavy chain, myosin binding protein C, and actinin, which is consistent with the observed contractile deficits. [ABSTRACT FROM AUTHOR]

Macropinocytosis is a broadly conserved endocytic process discovered nearly 100 years ago, yet still poorly understood. It is prominent in cancer cell feeding, immune surveillance, uptake of RNA vaccines and as an invasion route for pathogens. Macropinocytic cells extend large cups or flaps from their plasma membrane to engulf droplets of medium and trap them in micron-sized vesicles. Here they are digested and the products absorbed. A major problem -- discussed here -- is to understand how cups are shaped and closed. Recently, lattice light-sheet microscopy has given a detailed description of this process in Dictyostelium amoebae, leading to the 'stalled-wave' model for cup formation and closure. This is based on membrane domains of PIP3 and active Ras and Rac that occupy the inner face of macropinocytic cups and are readily visible with suitable reporters. These domains attract activators of dendritic actin polymerization to their periphery, creating a ring of protrusive F-actin around themselves, thus shaping the walls of the cup. As domains grow, they drive a wave of actin polymerization across the plasma membrane that expands the cup. When domains stall, continued actin polymerization under the membrane, combined with increasing membrane tension in the cup, drives closure at lip or base. Modelling supports the feasibility of this scheme. No specialist coat proteins or contractile activities are required to shape and close cups: rings of actin polymerization formed around PIP3 domains that expand and stall seem sufficient. This scheme may be widely applicable and begs many biochemical questions. [ABSTRACT FROM AUTHOR]

Chronic lipid overconsumption, associated with the Western diet, causes excessive cardiac lipid accumulation, insulin resistance, and contractile dysfunction, altogether termed lipotoxic cardiomyopathy (LCM). Existing treatments for LCM are limited. Traditional Chinese Medicine (TCM) has been shown as beneficial in diabetes and its complications. The following compounds—Resveratrol, Quercetin, Berberine, Baicalein, and Isorhamnetin—derived from TCM and often used to treat type 2 diabetes. However, virtually nothing is known about their effects in the lipid-overexposed heart. Lipid-induced insulin resistance was generated in HL-1 cardiomyocytes and adult rat cardiomyocytes by 24 h exposure to high palmitate. Upon simultaneous treatment with each of the TCM compounds, we measured myocellular lipid accumulation, insulin-stimulated fatty acid and glucose uptake, phosphorylation levels of AKT and ERK1/2, plasma membrane appearance of GLUT4 and CD36, and expression of oxidative stress-/inflammation-related genes and contractility. In lipid-overloaded cardiomyocytes, all the selected TCM compounds prevented lipid accumulation. These compounds also preserved insulin-stimulated CD36 and GLUT4 translocation and insulin-stimulated glucose uptake in an Akt-independent manner. Moreover, all the TCM compounds prevented and restored lipid-induced contractile dysfunction. Finally, some (not all) of the TCM compounds inhibited oxidative stress-related SIRT3 expression, and others reduced inflammatory TNFα expression. Their ability to restore CD36 trafficking makes all these TCM compounds attractive natural supplements for LCM treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose: An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function. Experimental Approach: We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility. Key Results: IP2015 inhibited the uptake of 5‐HT, noradrenaline and dopamine by human monoamine transporters expressed in cells and in rat brain synaptosomes. Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose‐dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D2‐like receptor antagonists, clozapine and (−)‐sulpiride, or cutting the cavernosal nerve inhibited IP2015‐induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015‐mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db/db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration‐dependent relaxations. These relaxations were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, NG‐nitro‐l‐arginine and a D1‐like receptor antagonist, SCH23390. Quantitative polymerase chain reaction (qPCR) showed the expression of the dopamine transporter in the rat corpus cavernosum. Conclusion and Implications: Our findings suggest that IP2015 stimulates erectile function by a central mechanism involving dopamine reuptake inhibition and direct NO‐mediated relaxation of the erectile tissue. This novel multi‐modal mechanism of action could offer a new treatment approach to erectile dysfunction. [ABSTRACT FROM AUTHOR]

Background: Rho kinase (ROCK) pathway plays a critical role in post‐COVID‐19 pulmonary fibrosis (PCPF) and its intervention with angiotensin‐converting enzyme 2 (ACE2) and vascular endothelial growth factor (VEGF) will be a potential therapeutic target. Objectives: The present study was conducted to investigate the efficacy of zoledronate (ZA) on carbon tetrachloride (CCl4) induced pulmonary fibrosis (PF) in rats through targeting ACE2, ROCK, and VEGF signaling pathways. Methods: Fifty male Wistar rats were divided into five groups: control, vehicle‐treated, PF, PF‐ZA 50, and PF‐ZA 100 groups. ZA was given in two different doses 100 and 50 μg/kg/week intraperitoneally. After anesthesia, mean arterial blood pressure (MBP) was measured. After scarification, lung coefficient was calculated. Lung levels of ACE 2, interleukin‐1β (IL‐1β), transforming growth factor‐β (TGF‐β), VEGF, glutathione (GSH), and superoxide dismutase (SOD) were measured. Expression of ROCK, phosphorylated myosin phosphatase target subunit 1 (P‐MYPT1), and matrix metalloproteinase (MMP‐1), along with histopathological changes and immune‐histochemical staining for lung α‐smooth muscle actin (α‐SMA), tumor necrosis factor‐alpha (TNFα), and caspase‐3, were evaluated. Results: ZA significantly prevented the decrease in MBP. ZA significantly increased ACE2, GSH, and SOD and significantly decreased IL‐1β, TGF‐β, and VEGF in lung in comparison to PF group. ZA prevented the histopathological changes induced by CCl4. ZA inhibited lung expression of ROCK, P‐MYPT1, MMP‐1, α‐SMA, TNFα, and caspase‐3 with significant differences favoring the high dose intervention. Conclusion: ZA in a dose‐dependent manner prevented the pathological effect of CCl4 in the lung by targeting mevalonate pathway. It could be promising therapy against PCPF. [ABSTRACT FROM AUTHOR]

The transcription factors (TFs) MyoCD (myocardin) and Elk-1 (ETS Like-1 protein) competitively bind to SRF (serum response factor) and control myogenic- and mitogenic-related gene expression in smooth muscle, respectively. Their functions are therefore mutually inhibitory, which results in a contractile-versus-proliferative phenotype dichotomy. Airway smooth muscle cell (ASMC) phenotype alterations occur in various inflammatory airway diseases, promoting pathological remodeling and contributing to airflow obstruction. We characterized MyoCD and Elk-1 interactions and their roles in phenotype determination in human ASMCs. MyoCD overexpression in ASMCs increased smooth muscle gene expression, force generation, and partially restored the loss of smooth muscle protein associated with prolonged culturing while inhibiting Elk-1 transcriptional activities and proliferation induced by EGF (epidermal growth factor). However, MyoCD overexpression failed to suppress these responses induced by FBS, as FBS also upregulated SRF expression to a degree that allowed unopposed function of both TFs. Inhibition of the RhoA pathway reversed said SRF changes, allowing inhibition of Elk-1 by MyoCD overexpression and suppressing FBS-mediated contractile protein gene upregulation. Our study confirmed that MyoCD in increased abundance can competitively inhibit Elk-1 function. However, SRF upregulation permits a dual contractile–proliferative ASMC phenotype that is anticipated to exacerbate pathological alterations, whereas therapies targeting SRF may inhibit pathological ASMC proliferation and contractile protein gene expression. [ABSTRACT FROM AUTHOR]

Background: Bacterial genomes often encode structures similar to phage capsids (encapsulins) and phage tails which can be induced spontaneously or using genotoxic compounds such as mitomycin C. These high molecular-weight (HMW) putative antibacterial proteins (ABPs) are used against the competitive strains under natural environment. Previously, it was unknown whether these HMW putative ABPs originating from the insect pathogenic Gram-positive, spore-forming bacterium Brevibacillus laterosporus (Bl) isolates (1821L, 1951) are spontaneously induced during the growth and pose a detrimental effect on their own survival. Furthermore, no prior work has been undertaken to determine their biochemical characteristics. Results: Using a soft agar overlay method with polyethylene glycol precipitation, a narrow spectrum of bioactivity was found from the precipitated lysate of Bl 1951. Electron micrographs of mitomycin C- induced filtrates showed structures similar to phage capsids and contractile tails. Bioactivity assays of cell free supernatants (CFS) extracted during the growth of Bl 1821L and Bl 1951 suggested spontaneous induction of these HMW putative ABPs with an autocidal activity. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis of spontaneously induced putative ABPs showed appearance of ~ 30 kDa and ~ 48 kDa bands of varying intensity across all the time intervals during the bacterial growth except in the initial hours. Statistically, spontaneously induced HMW putative ABPs of Bl 1951 exhibited a significant decrease in the number of viable cells of its producer strain after 18 h of growth in liquid. In addition, a significant change in pH and prominent bioactivity of the CFS of this particular time period was noted. Biochemically, the filtered supernatant derived from either Bl 1821L or Bl 1951 maintained bioactivity over a wide range of pH and temperature. Conclusion: This study reports the spontaneous induction of HMW putative ABPs (bacteriocins) of Bl 1821L and Bl 1951 isolates during the course of growth with potential autocidal activity which is critically important during production as a potential biopesticide. A narrow spectrum of putative antibacterial activity of Bl 1951 precipitate was found. The stability of HMW putative ABPs of Bl 1821L and Bl 1951 over a wide range of pH and temperature can be useful in expanding the potential of this useful bacterium beyond the insecticidal value. [ABSTRACT FROM AUTHOR]