The change in handgrip strength, after physical exercise, is moderated by digit ratio (2D:4D): A study among the young adults in Poland.

BACKGROUND: The digit ratio (2D:4D), the ratio of the lengths of second (2D) to the fourth (4D) fingers, is a proxy indicator of prenatal androgen exposure. On average, males display lower 2D:4D than females. Previous studies have shown that lower 2D:4D ratios were associated with better sports and physical abilities. AIM: To assess whether a challenge condition, imposed by intense exercise, could increase handgrip strength (HGS) associated with 2D:4D. METHODS: This cross-sectional experimental study included 90 healthy young Polish adults (40 males, 50 females). They underwent intense physical exercise, before (7 days) and after which they were measured for HGS and 2D:4D. Height and weight were also measured. Analyses of Covariance were employed to delineate associations. RESULTS: 2D:4D had significant predictive effects on the differences in HGS (DHGS) measured in two occasions, without and after, physical exercises. The lower was the 2D:4D, the higher the DHGS, particularly, for the left hand. CONCLUSION: The results reconfirmed that the link between prenatal testosterone exposure (indicated by 2D:4D) and physical strength depends on the context, such as a challenged condition.

Redox-signalling and Redox Biomarkers in Cardiovascular Health and Disease.

Overproduction of reactive nitrogen and oxygen species (RNS and ROS) has been linked to the pathogenesis of diabetes, hypertension, hyperlipidemia, stroke, angina, and other cardiovascular diseases. These species are produced in part by the mitochondrial respiratory chain, NADPH oxidase, and xanthine oxidase. RNS and ROS both contribute to oxidative stress, which is necessary for the development of cardiovascular disorders. In addition to ROS species like hydroxyl ion, hydrogen peroxide, and superoxide anion, RNS species like nitric oxide, peroxynitrous acid, peroxynitrite, and nitrogen dioxide radicals have also been linked to a number of cardiovascular conditions. They promote endothelial dysfunction, vascular inflammation, lipid peroxidation, and oxidative damage, all of which contribute to the development of cardiovascular pathologies. It's crucial to understand the mechanisms that result in the production of RNS and ROS in order to identify potential therapeutic targets. Redox biomarkers serve as indicators of oxidative stress, making them crucial tools for diagnosing and predicting cardiovascular states. The advancements in proteomics, metabolomics, genomics, and transcriptomics have made the identification and detection of these small molecules possible. The following redox biomarkers are notable examples: 3-nitrotyrosine, 4-hydroxy-2-nonenal, 8- iso-prostaglandin F2, 8-hydroxy-2-deoxyguanosine, malondialdehyde, Diacron reactive oxygen metabolites, total thiol, and specific microRNAs (e.g. miRNA199, miRNA21, miRNA1254, miRNA1306-5p, miRNA26b-5p, and miRNA660-5p) are examples. Although redox biomarkers have great potential, their clinical applicability faces challenges. Redox biomarkers frequently have a short half-life and exist in small quantities in the blood, making them challenging to identify and measure. The interpretation of biomarker data may also be influenced by confounding factors and the complex interplay of various oxidative stress pathways. Therefore, in-depth validation studies and the development of sensitive and precise detection methods are needed to address these problems. In the search for redox biomarkers, cutting-edge techniques like mass spectrometry, immunoassays, and molecular diagnostics are applied. New platforms and technologies have made it possible to accurately detect and monitor redox biomarkers, which facilitates their use in clinical settings. Our expanding knowledge of RNS and ROS involvement in cardiovascular disorders has made it possible to develop redox biomarkers as diagnostic and prognostic tools. Overcoming the challenges associated with their utility and utilizing advanced detection techniques, which will improve their clinical applicability, will ultimately benefit the management and treatment of cardiovascular conditions.

VEGF counteracts shear stress-determined arterial fate specification during capillary remodeling.

A key feature of arteriogenesis is capillary-to-arterial endothelial cell fate transition. Although a number of studies in the past two decades suggested this process is driven by VEGF activation of Notch signaling, how arteriogenesis is regulated remains poorly understood. Here we report that arterial specification is mediated by fluid shear stress (FSS) independent of VEGFR2 signaling and that a decline in VEGFR2 signaling is required for arteriogenesis to fully take place. VEGF does not induce arterial fate in capillary ECs and, instead, counteracts FSS-driven capillary-to-arterial cell fate transition. Mechanistically, FSS-driven arterial program involves both Notch-dependent and Notch-independent events. Sox17 is the key mediator of the FSS-induced arterial specification and a target of VEGF-FSS competition. These findings suggest a new paradigm of VEGF-FSS crosstalk coordinating angiogenesis, arteriogenesis and capillary maintenance.

Gamma protocadherins in vascular endothelial cells inhibit Klf2/4 to promote atherosclerosis.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide1. Laminar shear stress (LSS) from blood flow in straight regions of arteries protects against ASCVD by upregulating the Klf2/4 anti-inflammatory program in endothelial cells (ECs)2-8. Conversely, disturbed shear stress (DSS) at curves or branches predisposes these regions to plaque formation9,10. We previously reported a whole genome CRISPR knockout screen11 that identified novel inducers of Klf2/4. Here we report suppressors of Klf2/4 and characterize one candidate, protocadherin gamma A9 (Pcdhga9), a member of the clustered protocadherin gene family12. Pcdhg deletion increases Klf2/4 levels in vitro and in vivo and suppresses inflammatory activation of ECs. Pcdhg suppresses Klf2/4 by inhibiting the Notch pathway via physical interaction of cleaved Notch1 intracellular domain (NICD Val1744) with nuclear Pcdhg C-terminal constant domain (CCD). Pcdhg inhibition by EC knockout (KO) or blocking antibody protects from atherosclerosis. Pcdhg is elevated in the arteries of human atherosclerosis. This study identifies a novel fundamental mechanism of EC resilience and therapeutic target for treating inflammatory vascular disease.

Pyro-Phototronic Effect in All-Inorganic Two-Dimensional Ruddlesden-Popper Ferroelectric Perovskite Thin-films and Photodetection.

Ferroelectric perovskites, where ferroelectricity is embedded in the structure, are being considered for different device applications. In this study, we introduce Cs2PbI2Cl2, an all-inorganic 2D Ruddlesden-Popper (RP) halide perovskite, as a ferroelectric material suitable for pyro-phototronic applications. Thin-films of the all-inorganic perovskite are successfully cast, and they demonstrate ferroelectric properties. Unlike hybrid materials, the ferroelectricity in Cs2PbI2Cl2 does not rely on the organic moiety possessing an electric dipole moment. Instead, the 2D-layer-forming octahedra are twisted and tilted due to a distortion in the bond lengths, leading to the emergence of spontaneous electric polarization. Based on the properties, we fabricate p-i-n heterojunctions by integrating the perovskite with carrier-transport layers. To determine the band-energies of the materials, scanning tunneling spectroscopy and Kelvin probe force microscopy are employed. The band-edges evidence a type-II band-alignment at both interfaces, enabling the material to exhibit both photovoltaic and pyroelectric behaviors when subjected to pulsed illumination. The devices based on the all-inorganic RP perovskite developed in this study exhibit pyro-phototronic effects and serve as self-powered photodetectors without any need for an external bias.

TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes.

The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure of endothelial cells (EC) to proinflammatory stimuli leads to an increase in mitochondrial metabolism; however, the function and regulation of elevated mitochondrial metabolism in EC in response to proinflammatory cytokines remain unclear. Studies using high-resolution metabolomics and 13C-glucose and 13C-glutamine labeling flux techniques showed that pyruvate dehydrogenase activity (PDH) and oxidative tricarboxylic acid cycle (TCA) flux are elevated in human umbilical vein ECs in response to overnight (16 h) treatment with TNFα (10 ng/mL). Mechanistic studies indicated that TNFα mediated these metabolic changes via mitochondrial-specific protein degradation of pyruvate dehydrogenase kinase 4 (PDK4, inhibitor of PDH) by the Lon protease via an NF-κB-dependent mechanism. Using RNA sequencing following siRNA-mediated knockdown of the catalytically active subunit of PDH, PDHE1α (PDHA1 gene), we show that PDH flux controls the transcription of approximately one-third of the genes that are up-regulated by TNFα stimulation. Notably, TNFα-induced PDH flux regulates a unique signature of proinflammatory mediators (cytokines and chemokines) but not inducible adhesion molecules. Metabolomics and ChIP sequencing for acetylated modification on lysine 27 of histone 3 (H3K27ac) showed that TNFα-induced PDH flux promotes histone acetylation of specific gene loci via citrate accumulation and ATP-citrate lyase-mediated generation of acetyl CoA. Together, these results uncover a mechanism by which TNFα signaling increases oxidative TCA flux of glucose to support TNFα-induced gene transcription through extramitochondrial acetyl CoA generation and histone acetylation.

Is 2D:4D digit ratio related to avowed religion? A study among Mongolian young males from Ulaanbaatar.

BACKGROUND: The ratio of the second- (2D) to fourth (4D) digit lengths of hand (2D:4D) is a proxy marker of the relative testosterone and estrogen concentration during a relatively narrow period of fetal development that might affect behavioral and personality characteristics. AIM: To estimate the differences in 2D:4D between different religious groups among a sample of young adult males in Mongolia. METHODS: Two hundred and sixty-five Mongolian male students with mean age of 20.5 (SD = 1.7) years from different universities in Ulan Bator, were included in the study. Information on age, religious affiliation, marital status and parental education were obtained directly from each study participant. Digit lengths were measured from scanned images by using the ImageJ software 1.53 K. One-way analysis of variance was employed to evaluate whether they were significant differences in 2D:4D ratio between groups, along with Scheffe's post hoc comparison. RESULTS: Study participants significantly differed in 2D:4D across religion. Left 2D:4D, but not the right, showed a significant difference between religions, with Muslims exhibiting the highest 2D:4D mean and the lowest DR-L . CONCLUSION: Our study suggests that the 2D:4D ratio is related to the participants' religion. However, the distinctiveness of the Muslim students from study participants belonging to other religious groups in this study could also be related to ethnic differences, given that the students were Kazakhs. This is, to our knowledge, the only study looking at the relationship between the 2D:4D ratio and religious affiliation and, thus, further research is needed to confirm its results.

Profiling of Polyphenolic Compounds, Antioxidant, Antidyslipidemic and Cardiac Risk Preventive Effect of Keteki Joha and Kola Joha Rice Cultivars Grown in Assam, India: A Comparative Study.

BACKGROUND: Food grains' ability to promote health is widely recognized as a result of their rich nutritional profile and presence of antioxidants. AIM: The present study aimed to investigate the antioxidant, antidyslipidemic, and cardiac risk preventive effects of unpolished whole rice extracts of Keteki and Kola Joha of Assam, India, and to profile the polyphenolic compounds present. METHODS: Whole unpolished rice samples were extracted with ethanol and the efficacy of the extract of both rice cultivars was evaluated against high-fat and high-sugar induced hyperlipidemia in rats. The effects of extracts on lipid profile, hepatic enzyme, endogenous antioxidants, lipid peroxidation, creatine kinase-NAC, lactate dehydrogenase, C-reactive protein and lipoprotein(s) were evaluated. Atherogenic indices were calculated to find the effect of the extract on cardiac risk. HPLC analysis of whole unpolished rice samples was also carried out to profile the polyphenolics present. RESULTS: HPLC analysis revealed the presence of gallic acid, vanillic acid, caffeic acid, sinapic acid, o-coumaric acid, t-coumaric acid, rosamarinic acid, chlorogenic acid, phytic acid in both rice samples. Protocatechuic acid, syringic acid, and p-coumaric acid were detected in keteki joha, and ferulic acid was detected in kola joha only. Ethanol extracts (200 and 400 mg/kg) of both rice varieties for 30 days significantly averted dyslipidemia, preserved the level of endogenous antioxidants, and prevented lipid peroxidation. Levels of creatine kinase-NAC, lactate dehydrogenase, Creactive protein, and lipoprotein (a) were significantly (P < 0.01) less in the extract-treated group compared to the disease-control group. Extract treatment enhanced ApoA1 level while the reduced level of ApoB. ApoB/ApoA1 ratio was found more in the disease control group, which was significantly reduced in the extract-treated group. The atherogenic index, atherogenic coefficient, and cardiac risk ratio were reduced, while the cardioprotective index was enhanced in treatment groups. CONCLUSION: This paper profiled polyphenolic compounds for the first time. Keteki joha exhibited better results than Kola joha. Observations offer novel insights into the hypothesis for the first time that unpolished Keteki and Kola Joha rice can be beneficial in averting hyperlipidemia and its associated coronary events.

Fine and gross motor skills in 7-10 years old Indian children exposed to a natural disaster during early development.

Fetal life and infancy are extremely sensitive to adverse environmental conditions. This study aimed to assess the effect of exposure to a natural disaster (cyclone Aila) in utero or during infancy on fine and gross motor functions in preadolescent Indian children. The study was conducted in West Bengal, India, and included approximately 700 children (7-10 years old) who were prenatally or postnatally exposed to cyclone Aila and a nonaffected group. Anthropometric measures included height, weight, and birthweight. Socioeconomic status was based on parental education, family size, and income. Motor functions were assessed using the short form of Bruininks-Oseretsky Test of Motor Proficiency (BOT-2). Statistical analyses included, for example, generalized linear models. There were no differences in motor functions relative to the timing of the exposure (trimester) during pregnancy. Compared to the controls, prenatal Aila exposure resulted in poorer performance in all BOT-2 subtests, except for fine motor precision, strength, and balance (the last in boys), while postnatal Aila exposure, compared to the controls, resulted in poorer performance in manual dexterity, bilateral coordination, balance (girls only), and speed and agility. Early life exposure to a natural disaster has long-term adverse effect on motor proficiency in children. By inference, the welfare of pregnant women and infants should be of particular concern for emergency and health services during an environmental cataclysm.

Serum Response Factor Reduces Gene Expression Noise and Confers Cell State Stability.

The role of serum response factor (Srf), a central mediator of actin dynamics and mechanical signaling, in cell identity regulation is debated to be either a stabilizer or a destabilizer. We investigated the role of Srf in cell fate stability using mouse pluripotent stem cells. Despite the fact that serum-containing cultures yield heterogeneous gene expression, deletion of Srf in mouse pluripotent stem cells leads to further exacerbated cell state heterogeneity. The exaggerated heterogeneity is detectible not only as increased lineage priming but also as the developmentally earlier 2C-like cell state. Thus, pluripotent cells explore more variety of cellular states in both directions of development surrounding naïve pluripotency, a behavior that is constrained by Srf. These results support that Srf functions as a cell state stabilizer, providing rationale for its functional modulation in cell fate intervention and engineering.

Implications of metabolic dysfunction associated fatty liver disease in COVID-19.

Metabolic associated fatty liver disorder (MAFLD) characterizes the contributing etiologies (i.e., type 2 diabetes mellitus, metabolic syndrome, overweight) of individuals with fatty liver disease that affects 1/3rd of the world population. In 2020, the coronavirus disease 2019 (COVID-19) crisis was unprecedented, and people with different comorbidities became more susceptible to the infection caused by severe acute respiratory syndrome coronavirus 2. MAFLD patients are frequently obese with added metabolic menace like diabetes, hypertension, and dyslipidemia leading to greater jeopardy of COVID-19. MAFLD patients are 4 to 6-fold more prone towards infections. COVID-19 induces liver injury with elevated levels of aspartate aminotransferase and alanine aminotransferase and insignificantly elevated bilirubin. Hence, MAFLD in COVID-19 patients worsens the condition significantly. The evidence highlighting the interaction between MAFLD and altered liver functioning in COVID-19 suggested that COVID-19 patients with pre-existing MAFLD are at greater risk of morbidity or intensive care unit admission. Direct hepatic injury, enhanced levels of inflammatory cytokines, declined hepatic mitochondrial activity, and compromised immunity are considered as some underlying mechanisms. The main focus of this review is to discuss the implications of metabolic dysfunction associated with fatty liver disease in COVID-19 patients. The review systematically analyzes the effect of striking two worldwide pandemics (MAFLD and COVID-19) together in the present era.

The age of bone marrow dictates the clonality of smooth muscle-derived cells in atherosclerotic plaques.

Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cell (SMC) progenitors clonally expand giving rise to up to ~70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aged bone marrow (BM)-derived cells non-cell autonomously induce SMC polyclonality and worsen atherosclerosis. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin ß3 resulting in increased tumor necrosis factor [TNF]-α signaling. TNFα signals through TNF receptor 1 on SMCs to promote proliferation and induces recruitment and expansion of multiple SMC progenitors into the atherosclerotic plaque. Notably, integrin ß3 overexpression in aged BM preserves dominance of the lineage of a single SMC progenitor and attenuates plaque burden. Our results demonstrate a molecular mechanism of aged macrophage-induced SMC polyclonality and atherogenesis and suggest novel therapeutic strategies.

Citric acid esterified Glutinous Assam bora rice starch enhances disintegration and dissolution efficiency of model drug.

The current work was designed to study the starch's physicochemical attributes, tablet disintegration and dissolution efficiency and its derivatives obtained from the glutinous Assam bora rice (G-ABR) variety of Assam, Northeast India. Starch was isolated by a simple protein denaturation method, and a starch derivative was prepared through citric acid modification. G-ABRS and citrated G-ABRS were characterized through FTIR, DSC, XRD and SEM. The rate of consolidation, consolidation index, angle of internal friction, packing rearrangement and cohesive properties were determined to investigate their applications as functional excipients in pharmaceutical industries. G-ABRS and citrated G-ABRS exhibited better packing rearrangement and cohesive properties than standard corn starch. Furthermore, immediate release of API from the tablet compact was observed when the starch concentration increased from 1 to 5 %, indicating facilitation of the tablet compact disintegration. Therefore, G-ABRS and citrated G-ABRS are potentially functional and sustainable materials for pharmaceutical industries.

Evolving spectrum of diabetic wound: Mechanistic insights and therapeutic targets.

Diabetes mellitus is a chronic metabolic disorder resulting in an increased blood glucose level and prolonged hyperglycemia, causes long term health conse-quences. Chronic wound is frequently occurring in diabetes patients due to compromised wound healing capability. Management of wounds in diabetic patients remains a clinical challenge despite many advancements in the field of science and technology. Increasing evidence indicates that alteration of the biochemical milieu resulting from alteration in inflammatory cytokines and matrix metalloproteinase, decrease in fibroblast and keratinocyte functioning, neuropathy, altered leukocyte functioning, infection, etc., plays a significant role in impaired wound healing in diabetic people. Apart from the current pharmacotherapy, different other approaches like the use of conventional drugs, antidiabetic medication, antibiotics, debridement, offloading, platelet-rich plasma, growth factor, oxygen therapy, negative pressure wound therapy, low-level laser, extracorporeal shock wave bioengineered substitute can be considered in the management of diabetic wounds. Drugs/therapeutic strategy that induce angiogenesis and collagen synthesis, inhibition of MMPs, reduction of oxidative stress, controlling hyperglycemia, increase growth factors, regulate inflammatory cytokines, cause NO induction, induce fibroblast and keratinocyte proliferation, control microbial infections are considered important in controlling diabetic wound. Further, medicinal plants and/or phytoconstituents also offer a viable alternative in the treatment of diabetic wound. The focus of the present review is to highlight the molecular and cellular mechanisms, and discuss the drug targets and treatment strategies involved in the diabetic wound.

Prenatal and early postnatal exposure to a natural disaster and Attention-Deficit/Hyperactivity Disorder symptoms in Indian children.

The aim of this study was to assess the relation between early exposure to stressful events and symptoms of the Attention-Deficit/Hyperactivity Disorder (ADHD) in children, based on the outcomes from a natural experiment. It was hypothesized that children pre- and postnatally exposed to cyclone Aila have increased ADHD symptoms compared to the control group, and the effect depends on the timing of the exposure. Indian children (8-11 years) prenatally (N = 336) and early postnatally (N = 216) exposed to cyclone Aila were compared to a non-exposed control peer group (N = 285). ADHD symptoms were assessed using the Conner's Teacher Rating Scale Revised. The main effect of exposure to the cyclone on the total ADHD symptoms' score, ADHD index, Hyperactivity and Oppositional symptoms was significant and independent to covariates: age and sex of children, gestational age and birth weight, maternal stress during the year before the study and the socioeconomic status of a family. The timing of exposure and sex of the children were found to be a significant moderator of the relation between early exposure to the natural disaster and ADHD symptoms. The prenatal, but also early postnatal exposure to stressful experiences such as a natural disaster, may disturb the development of cognitive functions and behavioural control, thus increasing the risk of ADHD in children.

Relative Body Fat Distribution in Preadolescent Indian Children Exposed to a Natural Disaster during Early Development.

Fetal life and infancy are critical periods when adverse environmental conditions, such as natural disasters, may alter a developing organism, leading to life-lasting unfavorable health outcomes, such as central body fat distribution. Therefore, the aim of this study was to assess the effect of the exposure to cyclone Aila in utero or during infancy on the relative subcutaneous adiposity distribution in preadolescent Indian children. The study included children prenatally (N = 336) or postnatally (during infancy, N = 212) exposed to Aila and a non-affected group (N = 284). Anthropometric indices involved, i.e., subscapular, suprailiac, triceps, and biceps skinfolds. The relative adiposity distribution (PC1) and socioeconomic status (SES) were assessed using principal component analysis. An analysis of covariance and Tukey's post hoc test for unequal samples were performed to assess the effect of exposure to a natural disaster on the PC1, controlling for age, sex, Z-BMI, and SES. Prenatally and postnatally Aila-exposed children revealed a significantly more central-oriented pattern of relative subcutaneous fat distribution compared to the controls (p < 0.05). Early-life exposure to a natural disaster was related to an adverse pattern of relative adipose tissue distribution in preadolescent children.

Differential BMP Signaling Mediates the Interplay Between Genetics and Leaflet Numbers in Aortic Valve Calcification.

Expression of a neuropilin-like protein, DCBLD2, is reduced in human calcific aortic valve disease (CAVD). DCBLD2-deficient mice develop bicuspid aortic valve (BAV) and CAVD, which is more severe in BAV mice compared with tricuspid littermates. In vivo and in vitro studies link this observation to up-regulated bone morphogenic protein (BMP)2 expression in the presence of DCBLD2 down-regulation, and enhanced BMP2 signaling in BAV, indicating that a combination of genetics and BAV promotes aortic valve calcification and stenosis. This pathway may be a therapeutic target to prevent CAVD progression in BAV.

Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle Plasticity.

BACKGROUND: Vascular smooth muscle cell (VSMC) phenotypic switching contributes to cardiovascular diseases. Epigenetic regulation is emerging as a key regulatory mechanism, with the methylcytosine dioxygenase TET2 acting as a master regulator of smooth muscle cell phenotype. The histone acetyl-transferases p300 and CREB-binding protein (CBP) are highly homologous and often considered to be interchangeable, and their roles in smooth muscle cell phenotypic regulation are not known. METHODS: We assessed the roles of p300 and CBP in human VSMC with knockdown, in inducible smooth muscle-specific knockout mice (inducible knockout [iKO]; p300iKO or CBPiKO), and in samples of human intimal hyperplasia. RESULTS: P300, CBP, and histone acetylation were differently regulated in VSMCs undergoing phenotypic switching and in vessel remodeling after vascular injury. Medial p300 expression and activity were repressed by injury, but CBP and histone acetylation were induced in neointima. Knockdown experiments revealed opposing effects of p300 and CBP in the VSMC phenotype: p300 promoted contractile protein expression and inhibited migration, but CBP inhibited contractile genes and enhanced migration. p300iKO mice exhibited severe intimal hyperplasia after arterial injury compared with controls, whereas CBPiKO mice were entirely protected. In normal aorta, p300iKO reduced, but CBPiKO enhanced, contractile protein expression and contractility compared with controls. Mechanistically, we found that these histone acetyl-transferases oppositely regulate histone acetylation, DNA hydroxymethylation, and PolII (RNA polymerase II) binding to promoters of differentiation-specific contractile genes. Our data indicate that p300 and TET2 function together, because p300 was required for TET2-dependent hydroxymethylation of contractile promoters, and TET2 was required for p300-dependent acetylation of these loci. TET2 coimmunoprecipitated with p300, and this interaction was enhanced by rapamycin but repressed by platelet-derived growth factor (PDGF) treatment, with p300 promoting TET2 protein stability. CBP did not associate with TET2, but instead facilitated recruitment of histone deacetylases (HDAC2, HDAC5) to contractile protein promoters. Furthermore, CBP inhibited TET2 mRNA levels. Immunostaining of cardiac allograft vasculopathy samples revealed that p300 expression is repressed but CBP is induced in human intimal hyperplasia. CONCLUSIONS: This work reveals that p300 and CBP serve nonredundant and opposing functions in VSMC phenotypic switching and coordinately regulate chromatin modifications through distinct functional interactions with TET2 or HDACs. Targeting specific histone acetyl-transferases may hold therapeutic promise for cardiovascular diseases.

A comprehensive review on polysaccharides with hypolipidemic activity: Occurrence, chemistry and molecular mechanism.

Currently, research on natural products is facing challenging future in various aspects. A large group of natural polysaccharides such as ß-glucan, cellulose, hemicellulose, chitin, pectin, agaropectin, heteroglycans, lignins, hydrocolloids, homopolysaccharides, heteropolysaccharides were studied extensively for their various therapeutical potential. Several research works have already demonstrated those polysaccharides has tremendous health benefits, and found to exhibit anticancer, antiviral, immunomodulatory, antimicrobial, anticoagulant, anti-inflammatory, antidiabetic, antioxidant and antitumor activities. Different mushroom, plant, fungus, algae, vegetables, microalgae etc. are some important source of several polysaccharide macromolecules such as glucans, ulvan A, ulvan B, fucoidan, rhamnan sulfate, laminarin sulfate, agar, alginate, heteroglycans. Earlier research work demonstrated that natural polysaccharides have the highest ability to carry biological properties along with some biopolymers like as proteins and nucleic acids due to their structural variability. The preventive effect of these biomacromolecules was extensively studied, especially their beneficial effect on chronic metabolic conditions like dyslipidemia and related disorders. Dyslipidemia is a serious metabolic disorder associated with coronary heart disease, coronary artery diseases, hypercholesterolemia, atherosclerosis, etc. Dietary natural polysaccharides could play an important role in the management and prevention of dyslipidemia. Polysaccharides from natural sources mainly sulfated polysaccharides exhibited predominant lipid-lowering and cholesterol-lowering activities through different mechanisms. Polysaccharides isolated from different edible plants, vegetables, plant, algae, mushroom with higher biological activities, particularly hypolipidemic activity were highlighted in this paper, in a way for their futuristic therapeutic application. This review aims to comprehensively discuss overall advances in hypolipidemic activity of polysaccharides, including their sources, structural characteristic and chemistry, biological activity and their probable mode of action.

JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency.

Obstructive arterial diseases, including supravalvular aortic stenosis (SVAS), atherosclerosis, and restenosis, share 2 important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic, or deletion mutations in the elastin gene (ELN), and SVAS patients and elastin-mutant mice display increased arterial wall cellularity and luminal obstructions. Pharmacological treatments for SVAS are lacking, as the underlying pathobiology is inadequately defined. Herein, using human aortic vascular cells, mouse models, and aortic samples and SMCs derived from induced pluripotent stem cells of ELN-deficient patients, we demonstrated that elastin insufficiency induced epigenetic changes, upregulating the NOTCH pathway in SMCs. Specifically, reduced elastin increased levels of γ-secretase, activated NOTCH3 intracellular domain, and downstream genes. Notch3 deletion or pharmacological inhibition of γ-secretase attenuated aortic hypermuscularization and stenosis in Eln-/- mutants. Eln-/- mice expressed higher levels of NOTCH ligand JAGGED1 (JAG1) in aortic SMCs and endothelial cells (ECs). Finally, Jag1 deletion in SMCs, but not ECs, mitigated the hypermuscular and stenotic phenotype in the aorta of Eln-/- mice. Our findings reveal that NOTCH3 pathway upregulation induced pathological aortic SMC accumulation during elastin insufficiency and provide potential therapeutic targets for SVAS.