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A recent International Diabetes Federation report suggests that more than 463 million people between 20 and 79 years have diabetes. Of the 20 million women affected by hyperglycemia during pregnancy, 84% have gestational diabetes. In addition, more than 1.1 million children or adolescents are affected by type 1 diabetes. Factors contributing to the increase in diabetes prevalence are complex and include contributions from genetic, environmental, and epigenetic factors. However, molecular regulatory mechanisms influencing the progression of an individual towards increased susceptibility to metabolic diseases such as diabetes are not fully understood. Recent studies suggest that the pathogenesis of diabetes involves epigenetic changes, resulting in a persistently dysregulated metabolic phenotype. This review summarizes the role of epigenetic mechanisms, mainly DNA methylation and histone modifications, in the development of the pancreas, their contribution to the development of diabetes, and the potential employment of epigenetic modulators in diabetes treatment.

Nociceptive markers in mice have been identified in two distinct peptidergic and nonpeptidergic neurons in the dorsal root ganglion (DRG) and distributed in different laminae of the dorsal horn of the spinal cord. Recently, however, a study in humans showed a significant overlapping in these two populations. In this study, we investigated the distribution of various nociceptive markers in the lumbar DRG and spinal cord of the dromedary camel. Immunohistochemical data showed a remarkable percentage of total neurons in the DRG expressed IB4 binding (54.5%), calcitonin gene-related peptide (CGRP; 49.5%), transient receptor potential vanilloid 1 (TRPV1; 48.2%), and nitric oxide synthase (NOS; 30.6%). The co-localization data showed that 89.6% and 74.0% of CGRP- and TRPV1-labeled neurons, respectively, were IB4 positive. In addition, 61.6% and 84.2% of TRPV1- and NOS-immunoreactive neurons, respectively, were also co-localized with CGRP. The distribution of IB4, CGRP, TRPV1, substance P, and NOS immunoreactivities in the spinal cord were observed in lamina I and outer lamina II (IIo). Quantitative data showed that 82.4% of IB4-positive nerve terminals in laminae I and IIo were co-localized with CGRP, and 86.0% of CGRP-labeled terminals were co-localized with IB4. Similarly, 85.1% of NOS-labeled nerve terminals were co-localized with CGRP. No neuropeptide Y (NPY) or cholecystokinin (CCK) immunoreactivities were detected in the DRG, and no co-localization between IB4, NPY, and CCK were observed in the spinal cord. Our results demonstrate marked convergence of nociceptive markers in the primary afferent neurons in camels, which is similar to humans rather than the mouse. The data also emphasizes the importance of interspecies differences when selecting ideal animal models for studying nociception and treating chronic pain.

Wail N Khraise,1 Tala W Khraise,1 Bright Starling Emerald,2 Mohammed Z Allouh2,3 1Department of Anesthesia and Recovery, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 3Department of Anatomy, Faculty of Medicine, Jordan University of Science and Technology, Irbid, JordanCorrespondence: Mohammed Z AllouhDepartment of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab EmiratesTel +97 137 137 551Email m_allouh@uaeu.ac.aeWail N KhraiseDepartment of Anesthesia and Recovery, Faculty of Medicine, Jordan University of Science and Technology, Irbid, JordanTel +962 79 905 1295Email wnkhraise@just.edu.joPurpose: Coronavirus disease 2019 (COVID-19) is an ongoing infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) agent, and is generally known as novel coronavirus. The impact of the disease has had apparent effects on health, social, and economic levels. This study aimed to investigate the epidemiologic features, clinical presentations, laboratory examination, and outcomes of COVID-19 patients in Jordan.Patients and Methods: This retrospective study included all COVID-19 patients admitted to the quarantine center at King Abdullah University Hospital in Jordan between March 16 and May 21, 2020. Patient information was abstracted from hospital electronic records and included patient demographics, symptoms, comorbidities, laboratory tests, infection period, and outcome.Results: Approximately 42% of the quarantined individuals were asymptomatic. The majority of symptomatic patients had mild to moderate symptoms of the disease. Only ten patients (9.3%) had severe symptoms, with one of them progressed to a critical stage and died 15 days after admission. Erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and D-dimer levels were significantly elevated in many patients. More than two-thirds (69.8%) of the symptomatic patients were females. Elevated ESR and LDH levels, along with longer periods of infection, were significantly associated with symptomatic patients.Conclusion: A large proportion of Jordanian patients were asymptomatic carriers of the virus. This finding emphasizes the importance of a continuous surveillance process to discover these contagious carriers to control the disease spread. Additionally, we suggest that future analyses should investigate for sexual variation in the inflammatory response to this viral infection since most of our symptomatic patients were females. Finally, the role of ESR and LDH biomarkers should be investigated further for the possibility of earlier identification of patients with greater risk.Keywords: coronavirus, COVID-19, infection, pandemic, respiratory, SARS

Protein

Background: Oxidative and glycolytic muscle fibers differ in their ultrastructure, metabolism, and responses to physiological stimuli and pathological insults. We examined whether these fibers respond differentially to exogenous anabolic androgenic steroids (AASs) by comparing morphological and histological changes between the oxidative anterior latissimus dorsi (ALD) and glycolytic pectoralis major (PM) fibers in adult avian muscles. Methods: Adult female White Leghorn chickens (Gallus gallus) were randomly divided into five groups: a vehicle control and four mesterolone treatment groups (4, 8, 12, and 16 mg/kg). Mesterolone was administered orally every three days for 4 weeks. Immunocytochemical techniques and morphometric analyses were employed to measure the changes in muscle weight, fiber size, satellite cell (SC) composition, and number of myonuclei. Results: Mesterolone increased both body and muscle weights and induced hypertrophy in glycolytic PM fibers but not in oxidative ALD fibers. Mesterolone induced SC proliferation in both muscles; however, the myonuclear accretion was noticeable only in the PM muscle. In both muscles, the collective changes maintained a constant myonuclear domain size and the changes were dose independent.Conclusion: Mesterolone induced distinct dose-independent effects in avian oxidative and glycolytic skeletal muscle fibers; these findings might be clinically valuable in the treatment of age-related sarcopenia.

The metabolic sensor Per-Arnt-Sim (Pas) domain-containing serine/threonine kinase (PASK) is expressed predominantly in the cytoplasm of different cell types, although a small percentage is also expressed in the nucleus. Herein, we show that the nuclear PASK associates with the mammalian H3K4 MLL2 methyltransferase complex and enhances H3K4 di- and tri-methylation. We also show that PASK is a histone kinase that phosphorylates H3 at T3, T6, S10 and T11. Taken together, these results suggest that PASK regulates two different H3 tail modifications involving H3K4 methylation and H3 phosphorylation. Using muscle satellite cell differentiation and functional analysis after loss or gain of Pask expression using the CRISPR/Cas9 system, we provide evidence that some of the regulatory functions of PASK during development and differentiation may occur through the regulation of these histone modifications.

Human embryonic stem cells (hESCs) were used as a model of embryonic neurogenesis to identify the effect of excess fat uptake on neurodevelopment (Ardah et al., 2018). Herein, by directed differentiation of hESCs into neurons using established protocols, this data was generated for expression profiles of select lncRNAs during in vitro embryonic neurogenesis and their differential expression due to excess fat (palmitate) uptake. The undifferentiated hESCs were treated with 250 µM palmitate after identifying it as the highest concentration which is non-toxic to these cells. The palmitate treated hESCs were differentiated towards neurons keeping the levels of palmitate consistent throughout the differentiation process and fat uptake was confirmed by Oil Red O staining. The expression analysis of lncRNAs was performed by RT-qPCR on vehicle control and palmitate treated cells from 4 stages of differentiation, D0 (undifferentiated hESCs), D12 (neural stem cells), D44 (neural progenitors) and D70 (neurons) using lncRNAs array plates from Arraystar Inc. which contains 372 functionally identified lncRNAs found to be associated with lipid metabolism and other pathways (Cat# AS-NR-004).

Protein O-GlcNAcylation is a dynamic, nutrient-sensitive mono-glycosylation deposited on numerous nucleo-cytoplasmic and mitochondrial proteins, including transcription factors, epigenetic regulators, and histones. However, the role of protein O-GlcNAcylation on epigenome regulation in response to nutrient perturbations during development is not well understood. Herein we recapitulated early human embryonic neurogenesis in cell culture and found that pharmacological up-regulation of O-GlcNAc levels during human embryonic stem cells’ neuronal differentiation leads to up-regulation of key neurogenic transcription factor genes. This transcriptional de-repression is associated with reduced H3K27me3 and increased H3K4me3 levels on the promoters of these genes, perturbing promoter bivalency possibly through increased EZH2-Thr311 phosphorylation. Elevated O-GlcNAc levels also lead to increased Pol II-Ser5 phosphorylation and affect H2BS112O-GlcNAc and H2BK120Ub1 on promoters. Using an in vivo rat model of maternal hyperglycemia, we show similarly elevated O-GlcNAc levels and epigenetic dysregulations in the developing embryo brains because of hyperglycemia, whereas pharmacological inhibition of O-GlcNAc transferase (OGT) restored these molecular changes. Together, our results demonstrate O-GlcNAc mediated sensitivity of chromatin to nutrient status, and indicate how metabolic perturbations could affect gene expression during neurodevelopment.

Diabetes mellitus (DM) is a chronic condition characterised by β cell dysfunction and persistent hyperglycaemia. The disorder can be due to the absence of adequate pancreatic insulin production or a weak cellular response to insulin signalling. Among the three types of DM, namely, type 1 DM (T1DM), type 2 DM (T2DM), and gestational DM (GDM); T2DM accounts for almost 90% of diabetes cases worldwide.Epigenetic traits are stably heritable phenotypes that result from certain changes that affect gene function without altering the gene sequence. While epigenetic traits are considered reversible modifications, they can be inherited mitotically and meiotically. In addition, epigenetic traits can randomly arise in response to environmental factors or certain genetic mutations or lesions, such as those affecting the enzymes that catalyse the epigenetic modification. In this review, we focus on the role of DNA methylation, a type of epigenetic modification, in the pathogenesis of T2DM.

Introduction: Obesity is a metabolic disease that accumulates an excessive level of fat. It also leads to comorbidities such as cardiovascular diseases, type 2 diabetes, high blood pressure, osteoarthritis and hormonal imbalances. Obesity has also been associated with an increased risk of developing cancers and may also enhance cancer-related mortality. The global prevalence rate of obesity and overweight, especially among children, is on the rise, and the United Arab Emirates (UAE) is no exception. Methods: A recent report suggests that the prevalence of overweight and obesity is 17% and 16%, respectively, in the UAE among children between 6 and 18 years of age. Thus, this is a serious health problem that needs urgent attention. Hence in this review we have analysed the risk factors which influence DNA Methylation in Childhood Obesity by using published literature. Results: Although genetic factors contribute to childhood obesity, epigenetic factors also play a significant role in its development. Discussion: This review article discusses the different risk factors and their contribution/s through epigenetic modification, DNA methylation and the associated changes in gene expression that eventually lead to childhood obesity. Understanding how these risk factors modulate gene expression could help to avoid or reduce the impact of exposures to such factors and thus may help to evolve a healthy future generation.

Embryonic and adult stem cells possess the capability of self-renewal and lineage-specific differentiation. The intricate balance between self-renewal and differentiation is governed by developmental signals and cell-type-specific gene regulatory mechanisms. A perturbed intra/extracellular environment during lineage specification could affect stem cell fate decisions resulting in pathology. Growing evidence demonstrates that metabolic pathways govern epigenetic regulation of gene expression during stem cell fate commitment through the utilization of metabolic intermediates or end products of metabolic pathways as substrates for enzymatic histone/DNA modifications. UDP-GlcNAc is one such metabolite that acts as a substrate for enzymatic mono-glycosylation of various nuclear, cytosolic, and mitochondrial proteins on serine/threonine amino acid residues, a process termed protein O-GlcNAcylation. The levels of GlcNAc inside the cells depend on the nutrient availability, especially glucose. Thus, this metabolic sensor could modulate gene expression through O-GlcNAc modification of histones or other proteins in response to metabolic fluctuations. Herein, we review evidence demonstrating how stem cells couple metabolic inputs to gene regulatory pathways through O-GlcNAc-mediated epigenetic/transcriptional regulatory mechanisms to govern self-renewal and lineage-specific differentiation programs. This review will serve as a primer for researchers seeking to better understand how O-GlcNAc influences stemness and may catalyze the discovery of new stem-cell-based therapeutic approaches.

A perturbed maternal metabolic environment such as chronically elevated circulating free fatty acids have been shown to affect stem cell fate during embryonic neurogenesis. However, molecular mechanisms behind this are not well defined, especially in human. Here in using directed differentiation of human embryonic stem cells (hESCs) into cortical neurons as model, we show that chronically elevated saturated fatty acid (palmitate) results in decreased proliferation of neural stem cells and increased differentiation into neurons. This phenotype could be due to palmitate mediated increased expression of key genes needed for neuronal differentiation such as EOMES, TBR1, NEUROD1 and RELN and reduced expression of SREBP regulated lipogenic genes at early stages of cortical differentiation. Furthermore, palmitate treatment increased histone acetylation globally and at select gene promoters among affected genes. We also found differential expression of several lncRNAs associated with cellular stress and metabolic diseases in the presence of palmitate including BDNF-AS suggesting the contribution of additional epigenetic regulatory mechanisms. Together, our results show that saturated fatty acid affects developmental neurogenesis through modulation of gene expression and through epigenetic regulatory mechanisms.

Although the existence of a close relationship between the early maternal developmental environment, fetal size at birth and the risk of developing disease in adulthood has been suggested, most studies, however, employed experimentally induced intrauterine growth restriction as a model to link this with later adult disease. Because embryonic size variation also occurs under normal growth and differentiation, elucidating the molecular mechanisms underlying these changes and their relevance to later adult disease risk becomes important. The birth weight of rat pups vary according to the uterine horn positions. Using birth weight as a marker, we compared two groups of rat pups – lower birth weight (LBW, 5th to 25th percentile) and average birth weight (ABW, 50th to 75th percentile) – using morphological, biochemical and molecular biology, and genetic techniques. Our results show that insulin metabolism, Pi3k/Akt and Pparγ signaling and the genes regulating growth and metabolism are significantly different in these groups. Methylation at the promoter of the InsII (Ins2) gene and DNA methyltransferase 1 in LBW pups are both increased. Additionally, the Dnmt1 repressor complex, which includes Hdac1, Rb (Rb1) and E2f1, was also upregulated in LBW pups. We conclude that the Dnmt1 repressor complex, which regulates the restriction point of the cell cycle, retards the rate at which cells traverse the G1 or G0 phase of the cell cycle in LBW pups, thereby slowing down growth. This regulatory mechanism mediated by Dnmt1 might contribute to the production of small-size pups and altered physiology and pathology in adult life., Summary: This study suggests an important link between the early embryonic environment and later adult physiology and pathology. At least one process by which this might be coordinated is through the regulatory mechanisms mediated by Dnmt1.

The nutrient responsive O-GlcNAcylation is a dynamic post-translational protein modification found on several nucleocytoplasmic proteins. Previous studies have suggested that hyperglycemia induces the levels of total O-GlcNAcylation inside the cells. Hyperglycemia mediated increase in protein O-GlcNAcylation has been shown to be responsible for various pathologies including insulin resistance and Alzheimer's disease. Since maternal hyperglycemia during pregnancy is associated with adverse neurodevelopmental outcomes in the offspring, it is intriguing to identify the effect of increased protein O-GlcNAcylation on embryonic neurogenesis. Herein using human embryonic stem cells (hESCs) as model, we show that increased levels of total O-GlcNAc is associated with decreased neural progenitor proliferation and premature differentiation of cortical neurons, reduced AKT phosphorylation, increased apoptosis and defects in the expression of various regulators of embryonic corticogenesis. As defects in proliferation and differentiation during neurodevelopment are common features of various neurodevelopmental disorders, increased O-GlcNAcylation could be one mechanism responsible for defective neurodevelopmental outcomes in metabolically compromised pregnancies such as diabetes.

OBJECTIVES Nociceptin has been reported to play an important role in the regulation of pancreatic exocrine secretion. Most of the studies performed on nociceptin are mainly physiological rather than morphological in nature. The present study investigated the pattern of distribution of nociceptin in the endocrine pancreas of normal and diabetic rats. METHODS Immunohistochemistry, immunofluorescence, Western blot, and double-labeled immunoelectron microscopy were used in this study. Diabetes was induced using streptozotocin (60 mg/kg body weight). RESULTS Nociceptin-immunoreactive cells were observed in the central and peripheral regions of the islets of both normal and diabetic rat pancreas. The number of nociceptin-positive cells was significantly (P < 0.05) lower in the islet of diabetic rats compared with the control. Immunofluorescence study showed that nociceptin colocalizes with insulin in pancreatic β-cells. The degree of colocalization of nociceptin with insulin was severely deranged after the onset of diabetes. Moreover, immunogold particles conjugated with either nociceptin or insulin were observed on the granules of pancreatic β-cell. The number of nociceptin-labeled colloidal gold particles was significantly lower after the onset of diabetes. CONCLUSIONS Nociceptin is present in pancreatic islets cells and colocalizes with insulin. Nociceptin may have a physiological role in the metabolism of insulin.

Human embryonic stem cells (hESCs) are being used extensively in array of studies to understand different mechanisms such as early human embryogenesis, drug toxicity testing, disease modeling, and cell replacement therapy. The protocols for the directed differentiation of hESCs towards specific cell types often require long-term cell cultures. To avoid bacterial contamination, these protocols include addition of antibiotics such as pen-strep and gentamicin. Although aminoglycosides, streptomycin, and gentamicin have been shown to cause cytotoxicity in various animal models, the effect of these antibiotics on hESCs is not clear. In this study, we found that antibiotics, pen-strep, and gentamicin did not affect hESC cell viability or expression of pluripotency markers. However, during directed differentiation towards neural and hepatic fate, significant cell death was noted through the activation of caspase cascade. Also, the expression of neural progenitor markers Pax6, Emx2, Otx2, and Pou3f2 was significantly reduced suggesting that gentamicin may adversely affect early embryonic neurogenesis whereas no effect was seen on the expression of endoderm or hepatic markers during differentiation. Our results suggest that the use of antibiotics in cell culture media for the maintenance and differentiation of hESCs needs thorough investigation before use to avoid erroneous results.

Hypoxia injury (HI) with its long-term neurological complications is one of the leading causes of morbidity and mortality in the world. Currently, the treatment regimens for hypoxia are aimed only at ameliorating the damage without complete cure. The need, therefore, for novel therapeutic drugs to treat HI continues.This study investigates the protective effects of the ethanol extract of Cyperus rotundus L. (Cyperaceae) (EECR), a medicinal plant used in Ayurvedic traditional medicine against sodium nitrite-induced hypoxia in rats.We have evaluated the protective effect of 200 and 400 mg/kg of EECR against sodium nitrite-induced hypoxia injury in rats by assessing the cognitive functions, motor, and behavioral effects of EECR treatment along with the histological changes in the brain. By comparing the protective effects of standard drugs galantamine, a reversible cholinesterase inhibitor and pyritinol, an antioxidant nootropic drug against sodium nitrite-induced hypoxia in rats, we have tested the protective ability of EECR.EECR at doses of 200 and 400 mg/kg was able to protect against the cognitive impairments, and the locomotor activity and muscular coordination defects, which are affected by sodium nitrite-induced hypoxia injury in rats.Based on our results, we suggest that the medicinal herb C. rotundus possesses a protective effect against sodium nitrite-induced hypoxia in rats. Further studies on these protective effects of EECR may help in designing better therapeutic regimes for hypoxia injury.

Our previous work has shown associations between childhood adiposity and perinatal methylation status of several genes in umbilical cord tissue, including endothelial nitric oxide synthase (eNOS). There is increasing evidence that eNOS is important in bone metabolism; we therefore related the methylation status of the eNOS gene promoter in stored umbilical cord to childhood bone size and density in a group of 9-year-old children. We used Sequenom MassARRAY to assess the methylation status of two CpGs in the eNOS promoter, identified from our previous study, in stored umbilical cords of 66 children who formed part of a Southampton birth cohort and who had measurements of bone size and density at age 9 years (Lunar DPXL DXA instrument). Percentage methylation varied greatly between subjects. For one of the two CpGs, eNOS chr7:150315553 + , after taking account of age and sex, there were strong positive associations between methylation status and the child's whole-body bone area (r = 0.28, P = 0.02), bone mineral content (r = 0.34, P = 0.005), and areal bone mineral density (r = 0.34, P = 0.005) at age 9 years. These associations were independent of previously documented maternal determinants of offspring bone mass. Our findings suggest an association between methylation status at birth of a specific CpG within the eNOS promoter and bone mineral content in childhood. This supports a role for eNOS in bone growth and metabolism and implies that its contribution may at least in part occur during early skeletal development.

Objective: While genomic variation explains only a modest proportion of the risk of cardiovascular and metabolic disease, animal models demonstrate that maternal environmental influences alter epigenetic processes in the offspring, with important effects on their later body composition and cardiometabolic function. Whether such processes operate in humans has not been examined. Methods: Using DNA extracted from stored umbilical cord tissue from healthy neonates who were subsequently extensively phenotyped, we related the DNA methylation status of specific CpGs 5’ from candidate genes to body composition measured by DXA scanning at age 9 years. Appropriate institutional ethics committee clearance and participants’ informed consent were obtained. Results: Methylation, measured by the Sequenom MassARRAY system, varied greatly at particular CpG sites. Of 68 CpGs studied, 31 had a median methylation >5% and a 5-95% range >10%. Independently of sex, there were strong correlations of the degree of methylation in specific CpGs in eNOS with childhood fat mass (Pearson correlation rp 50.42, n566) and trunk/limb fat ratio (rp 50.33, n566), and in RXRA methylation with fat mass and percentage fat mass (rp 50.32 and 0.29, respectively, n564) (all p,0.005, taking account of methylation at other CpG sites). Methylation at these sites was not linked to birth weight. Controlling for sex, perinatal epigenetic marks explained more than 40% of the variance in body composition at age 9 years. Conclusions: Epigenetic marks at birth predict a significant proportion of the variance in later childhood adiposity, indicating that substantial components of later metabolic disease risk are induced before birth. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later chronic non-communicable disease. MAH and JSJ are supported by the British Heart Foundation. PDG and AS are funded by the National Research Centre for Growth and Development (New Zealand). BSE is supported by the Agency for Science, Technology and Research (Singapore). This work was supported by the charity WellChild (previously Children Nationwide), by the University of Southampton, by the UK Medical Research Council and the EpiGen consortium.

Prolonged, moderate cerebral hypothermia is consistently neuroprotective after experimental hypoxia–ischaemia; however, it has not been tested in the preterm brain. Preterm (0.7 gestation) fetal sheep received complete umbilical cord occlusion for 25 min followed by cerebral hypothermia (fetal extradural temperature reduced from 39.4 ± 0.3 to 29.5 ± 2.6°C) from 90 min to 70 h after the end of occlusion or sham cooling. Occlusion led to severe acidosis and profound hypotension, which recovered rapidly after release of occlusion. After 3 days recovery the EEG spectral frequency, but not total intensity, was increased in the hypothermia-occlusion group compared with normothermia-occlusion. Hypothermia was associated with a significant overall reduction in loss of immature oligodendrocytes in the periventricular white matter (P < 0.001), and neuronal loss in the hippocampus and basal ganglia (P < 0.001), with suppression of activated caspase-3 and microglia (isolectin-B4 positive). Proliferation was significantly reduced in periventricular white matter after occlusion (P < 0.05), but not improved after hypothermia. In conclusion, delayed, prolonged head cooling after a profound hypoxic insult in the preterm fetus was associated with a significant reduction in loss of neurons and immature oligodendroglia, with evidence of EEG and haemodynamic improvement after 3 days recovery, but also with a persisting reduction in proliferation of cells in the periventricular region. Further studies are required to evaluate the long-term impact of cooling on brain growth and maturation.

Hyperlipidemia is known to be a major risk factor for the development of cardiovascular diseases (CVDs) which include atherosclerosis, coronary heart disease, and stroke. Although there are a large number of anti-hyperlipidemic drugs available, unfortunately, they all have side effects.Terminalia chebula Retz. (Combretaceae) is a plant used to treat cardiac disorders in the traditional Ayurveda medicine in India. The objective of this study was to assess the anti-hyperlipidemic properties of a methanol (MeOH) bark extract of T. chebula.Acute toxicity studies were performed according to the Organisation for Economic Cooperation and Development (OECD) guideline no. 423 using various doses (5, 50, 300, and 2000 mg/kg) of T. chebula bark. Anti-hyperlipidemic effect of MeOH bark extract of T. chebula at doses of 200, 400, and 600 mg/kg and fasting glucose levels after treatment with MeOH bark extract of T. chebula at doses of 200, 400, and 600 mg/kg were analyzed using commercially available kits.Acute toxicity studies did not show any morbidity and mortality at various doses. The MeOH extract of T. chebula bark at doses of 200, 400, and 600 mg/kg significantly lowered serum cholesterol and triglyceride levels. Moreover, the extract of T. chebula and the positive control atorvastatin-treated groups of animals showed a significant increase in the serum high-density lipoprotein (HDL) cholesterol levels in diet-induced hypercholesterolemic animals.The overall results confirm that the bark extract of T. chebula possesses significant anti-hyperlipidemic activity.

Preterm infants have a high rate of neurodevelopmental handicap. Recent imaging studies have revealed that adverse outcomes are strongly associated with reduced brain growth and neural complexity in later life. Increasing data suggest that these chronic deficits primarily reflect acute neuronal and glial injury sustained during adverse in utero events, such as exposure to severe hypoxia-ischemia and inflammation. In the present review we examine recent evidence that this chronic impairment is partly due to upregulation of physiological apoptosis, related to input deprivation, and output isolation secondary to acute white and gray matter damage and axonal injury. However, progenitor cells in the subventricular zone (SVZ) are also vulnerable to injury, and loss of part of this critical population likely further compromises brain development. Based on these concepts the impact of proposed interventions such as induced hypothermia and endogenous growth factors are likely to be complex, but potentially offer focused ways of improving the outcomes of premature birth.

Expression of homeobox A1 (HOXA1) results in oncogenic transformation of immortalized human mammary epithelial cells with aggressive tumor formation in vivo. However, the mechanisms by which HOXA1 mediates oncogenic transformation is not well defined. To identify molecules that could potentially be involved in HOXA1-mediated oncogenic transformation, microarray analysis was utilized to characterize and compare the gene expression pattern in response to forced expression or depletion of HOXA1 in human mammary carcinoma cells. Gene expression profiling identified that genes involved in the p44/42 mitogen-activated protein (MAP) kinase activation pathway (GRB2, MAP kinase kinase (MEK1) and SDFR1) or p44/42 MAP kinase-regulated genes (IER3, EPAS1, PCNA and catalase) are downstream expression targets of HOXA1. Forced expression of HOXA1 increased GRB2 and MEK1 mRNA and protein expression and increased p44/42 MAP kinase phosphorylation, activity and Elk-1-mediated transcription. Use of a MEK1 inhibitor demonstrated that increased p44/42 MAP kinase activity is required for the HOXA1-mediated increase in cell proliferation, survival, oncogenicity and oncogenic transformation. Thus, modulation of the p44/42 MAP kinase pathway is one mechanism by which HOXA1 mediates oncogenic transformation of the human mammary epithelial cell.

We report cloning and characterization of coro, which codes for the Drosophila homologue of the F-actin binding protein coronin. Viable alleles of coro produce a variety of phenotypes in leg, wing and eye development, which are similar to the phenotypes observed as a result of mutations in genes associated with the actin cytoskeleton and/or membrane trafficking. Homozygous lethal mutations in coro results in the disruption of the actin cytoskeleton in wing imaginal discs. Formation of both basolateral septate junctions and apical adherens junctions are also adversely affected in epithelial cells. Both viable and lethal alleles of coro show genetic interactions with syntaxin1A, a gene required for membrane trafficking. They also show enhanced response to over-expression of Decapentaplegic (Dpp) and its receptor Thick vein. Tracing of Dpp morphogen using a Dpp::GFP fusion construct suggested defects in the endocytic pathway, which resulted in uniform distribution of Dpp along the AP axis rather than a gradient from the AP boundary. Our results provide a genetic link between endocytosis/exocytosis events involving F actin-coated vesicles and the establishment of morphogen gradient.

The genes engrailed (en), hedgehog (hh), wingless (wg) and decapentaplegic (dpp) have been shown to play vital organising roles in the development and differentiation of thoracic imaginal discs. We have analysed the roles of these genes in organising the development and differentiation of the genital discs, which are bilaterally symmetrical and possess different primordia, namely, the male and female genital primordia and an anal primordium. Our results suggest that the organising activity of en in genital discs programs the normal development and differentiation of the genital disc by regulating the expression of hh. Hh in turn induces wg and dpp, the genes whose products act as secondary signalling molecules. Moreover, the complementary patterns of wg and dpp expression are essential for the bilateral symmetry and are maintained by mutual repression.

Background Although an adverse early-life environment has been linked to an increased risk of developing the metabolic syndrome, the molecular mechanisms underlying altered disease susceptibility as well as their relevance to humans are largely unknown. Importantly, emerging evidence suggests that these effects operate within the normal range of birth weights and involve mechanisms of developmental palsticity rather than pathology. Method To explore this further, we utilised a non-human primate model Macaca fascicularis (Cynomolgus macaque) which shares with humans the same progressive history of the metabolic syndrome. Using microarray we compared tissues from neonates in the average birth weight (50-75th centile) to those of lower birth weight (5-25th centile) and studied the effect of different growth trajectories within the normal range on gene expression levels in the umbilical cord, neonatal liver and skeletal muscle. Results We identified 1973 genes which were differentially expressed in the three tissue types between average and low birth weight animals (P < 0.05). Gene ontology analysis identified that these genes were involved in metabolic processes including cellular lipid metabolism, cellular biosynthesis, cellular macromolecule synthesis, cellular nitrogen metabolism, cellular carbohydrate metabolism, cellular catabolism, nucleotide and nucleic acid metabolism, regulation of molecular functions, biological adhesion and development. Conclusion These differences in gene expression levels between animals in the upper and lower percentiles of the normal birth weight range may point towards early life metabolic adaptations that in later life result in differences in disease risk.