The antidepressant-like effects of zinc (Zn) have been documented in some animal models of depression. In addition, antidepressants may reduce the abuse potential of opioids by affecting their rewarding effect. Hence, th...The antidepressant-like effects of zinc (Zn) have been documented in some animal models of depression. In addition, antidepressants may reduce the abuse potential of opioids by affecting their rewarding effect. Hence, this study was performed to investigate the effect of Zn on the expression of morphine-induced conditioned place preference (CPP) in male rats. We used an unbiased CPP paradigm for investigating the effect of Zn. The intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administrations of Zn (5-20 mg/kg, i.p., and 10 nmol/rat, respectively) with or without morphine did not induce conditioned place aversion (CPA) or CPP during acquisition phase. However, the same i.p. and i.c.v. administrations of Zn induced morphine-like CPP in the expression phase. Pre-treatment with dopamine receptor antagonists (SCH23390, sulpiride, and haloperidol) and serotonin receptor antagonists (WAY100135, ketanserin, and ondansetron) reversed the enhancement effect of Zn on the expression of morphine-induced CPP (especially 20mg/kg, i.p. and 10 nmol/rat, i.c.v.). These findings suggest that acute i.p. and i.c.v administration of Zn might enhance the rewarding properties of morphine through involvement with dopaminergic and serotonergic neuronal systems.
Objective Osteoporosis is the most common metabolic disease of the bones. Osteoporosis reduces bone density, predisposes a person to fractures, and imposes high costs on societies. Osteoporosis develops from a variety of...Objective Osteoporosis is the most common metabolic disease of the bones. Osteoporosis reduces bone density, predisposes a person to fractures, and imposes high costs on societies. Osteoporosis develops from a variety of causes, one of the most significant is vitamin D deficiency. This study investigates the impact of vitamin D on osteoporosis. Materials and Methods In this clinical trial, 400 patients referred to the Bone Density Clinic of Kowsar Hospital in Semnan were selected by convenience sampling method. Bone densitometry tests were carried out using DEXA (x-ray absorptiometry) and serum vitamin D levels were measured by the ELISA method. Subjects with vitamin D deficiency were treated for 8 weeks with (50,000 Vitamin D units per week. At the end of the treatment period, all subjects were evaluated for bone density and the results of both groups were compared. Results 13% of subjects had osteoporosis and 14.2% had osteopenia. 19% of subjects had vitamin D deficiency, 38.8% had insufficient levels of vitamin D, and 42.3% had sufficient vitamin D levels. The level of vitamin D in patients with osteoporosis (5.50 ± 5.5 ng/ml) was less than those with osteopenia (7.83 ± 4.8 ng/ml) and those with normal bone mineral density (23.88 ± 18.42 ng/ml) (P <0.001). The prevalence of osteoporosis in the intervention group after intervention with vitamin D was significantly lower than the control group (32.3 versus 67.7 and P <0.001). Conclusion The prevalence of serum vitamin D deficiency in osteopenic and osteoporotic individuals was higher than in normal subjects, with a significant relationship between age and sex. Thus, treatment with vitamin D improves bone density indices.
Oxidative phosphorylation is carried out by five complexes, which are the sites for electron transport and ATP synthesis. Among those, Complex V (also known as the F1F0 ATP Synthase or ATPase) is responsible for the gene...Oxidative phosphorylation is carried out by five complexes, which are the sites for electron transport and ATP synthesis. Among those, Complex V (also known as the F1F0 ATP Synthase or ATPase) is responsible for the generation of ATP through phosphorylation of ADP by using electrochemical energy generated by proton gradient across the inner membrane of mitochondria. A multi subunit structure that works like a pump functions along the proton gradient across the membranes which not only results in ATP synthesis and breakdown, but also facilitates electron transport. Since ATP is the major energy currency in all living cells, its synthesis and function have widely been studied over the last few decades uncovering several aspects of ATP synthase. This review intends to summarize the structure, function and inhibition of the ATP synthase.
Background It is well documented that biologically active components of microalgae can be utilized for treatment of different diseases. This study was conducted to evaluate the antihyperglycemic and antihyperlipidemic ac...Background It is well documented that biologically active components of microalgae can be utilized for treatment of different diseases. This study was conducted to evaluate the antihyperglycemic and antihyperlipidemic activities and weight control of Nannochloropsis oculata microalgae (NOM) in Streptozotocin-induced diabetic male rats. Methods Diabetes was induced by intraperitoneal administration of Streptozotocin (55 mg/kg). Healthy and diabetic rats were divided in to six groups. Healthy and diabetic rats orally received distilled water or NOM (10 and 20 mg/kg) for three weeks. Results Oral administration of NOM to diabetic rats significantly reduced the serum concentrations of glucose, cholesterol, triglycerides, LDL and increased the serum concentration of insulin and HDL-C (P<0.05). Treatment with NOM had no significant effect on blood parameters in healthy rats (P>0.05). Also, NOM maintained body weight in diabetic rats (P<0.05). Conclusion It can be concluded that NOM has antihyperglycemic and antihyperlipidemic activities in diabetic rats.
Stojanovski BM, Pelc LA, Zuo X
… +2 more, Pozzi N, Cera ED
Biomol Concepts
· 2018 Dec · PMID 30864392
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Full text
Meizothrombin is an active intermediate generated during the proteolytic activation of prothrombin to thrombin in the penultimate step of the coagulation cascade. Structurally, meizothrombin differs from thrombin because...Meizothrombin is an active intermediate generated during the proteolytic activation of prothrombin to thrombin in the penultimate step of the coagulation cascade. Structurally, meizothrombin differs from thrombin because it retains the auxiliary Gla domain and two kringles. Functionally, meizothrombin shares with thrombin the ability to cleave procoagulant (fibrinogen), prothrombotic (PAR1) and anticoagulant (protein C) substrates, although its specificity toward fibrinogen and PAR1 is less pronounced. In this study we report information on the structural architecture of meizothrombin resolved by SAXS and single molecule FRET as an elongated arrangement of its individual domains. In addition, we show the properties of a meizothrombin construct analogous to the anticoagulant thrombin mutant W215A/E217A currently in Phase I for the treatment of thrombotic complications and stroke. The findings reveal new structural and functional aspects of meizothrombin that advance our understanding of a key intermediate of the prothrombin activation pathway.
Extracellular histones support rodent and human embryo development in at least two ways. First, these molecules in uterine secretions protect embryos from inflammation caused by pathogens that gain access to the reproduc...Extracellular histones support rodent and human embryo development in at least two ways. First, these molecules in uterine secretions protect embryos from inflammation caused by pathogens that gain access to the reproductive tract. Also, histones in uterine secretions likely support penetration of the uterine epithelium by blastocysts during embryo implantation. Extracellular histones seem to preserve amino acid transport system B0,+ in blastocysts by inhibiting its activity. Preservation of system B0,+ is needed because, at the time of invasion of the uterine epithelium by motile trophoblasts, system B0,+ is likely reactivated to help remove tryptophan from the implantation chamber. If tryptophan is not removed, T-cells proliferate and reject the implanting blastocyst. Epigenetic modification of histones could alter their promotion of normal implantation through, say, incomplete tryptophan removal and, thus, allow partial T-cell rejection of the conceptus. Such partial rejection could impair placental development, embryonal/fetal nutrition, and weight gain prior to birth. Small-for-gestational-age offspring are predisposed to developing metabolic syndrome, obesity, and associated complications as adults. Shifting expression of these phenotypes might contribute to transgenerational variation and evolution. The spectrum of possible extracellular histone targets in early development warrant new research, especially since the effects of epigenetic histone modifications might be transgenerational.
Functional selectivity is a property of G-protein-coupled receptors (GPCRs) by which activation by different agonists leads to different signal transduction mechanisms. This phenomenon is also known as biased agonism and...Functional selectivity is a property of G-protein-coupled receptors (GPCRs) by which activation by different agonists leads to different signal transduction mechanisms. This phenomenon is also known as biased agonism and has attracted the interest of drug discovery programs in both academy and industry. This relatively recent concept has raised concerns as to the validity and real translational value of the results showing bias; firstly biased agonism may vary significantly depending on the cell type and the experimental constraints, secondly the conformational landscape that leads to biased agonism has not been defined. Remarkably, GPCRs may lead to differential signaling even when a single agonist is used. Here we present a concept that constitutes a biochemical property of GPCRs that may be underscored just using one agonist, preferably the endogenous agonist. "Biased receptor functionality" is proposed to describe this effect with examples based on receptor heteromerization and alternative splicing. Examples of regulation of final agonist-induced outputs based on interaction with β-arrestins or calcium sensors are also provided. Each of the functional GPCR units (which are finite in number) has a specific conformation. Binding of agonist to a specific conformation, i.e. GPCR activation, is sensitive to the kinetics of the agonist-receptor interactions. All these players are involved in the contrasting outputs obtained when different agonists are assayed.
Introduction Transient cerebral ischemia is a pandemic neurological disorder and the main aim of medical intervention is to reduce complications. Human umbilical cord mesenchymal cells (hUCMs) are capable of differentiat...Introduction Transient cerebral ischemia is a pandemic neurological disorder and the main aim of medical intervention is to reduce complications. Human umbilical cord mesenchymal cells (hUCMs) are capable of differentiating into neural-like cells (NLC) in vitro, therefore we investigated the neuroprotective potential of these cells in comparison to aspirin and in combination (NLC-Aspirin) on spatial memory and neural morphologic changes in male rats submitted to transient cerebral ischemia. Methods Ten days after the intervention, the improvement in learning and memory were assessed in the animals by Morris Water Maze. Thence, the animals were examined for the presence of PKH26 labeled cells in the ischemic area of the brain, the infarct volume and neural changes in the brain tissue. Results Significant spatial memory deficits in the ischemic animals were detected compared with the control animals. The learning and memory were significantly improved (p ≤ 0.05) in the aspirin and NLC groups compared with the ischemic animals. Co-treatment of aspirin and NLCs did not improve the outcome. Moreover, infarction volume and neural changes were significantly altered when aspirin or NLCs were administered. Conclusions Our data suggest the significant neuroprotective potential of aspirin and neural-like cells derived from hUCM cells in the treatment of brain ischemic stroke. Further studies are required to evaluate possible underlying mechanisms, and to evaluate the possible interactions between aspirin and stem cells in a joint treatment aimed at the recovery of cognitive impairments.
Four hundred and twenty-two million people have diabetes due to excess free body glucose in their body fluids. Diabetes leads to various problems including retinopathy, neuropathy, arthritis, damage blood vessels etc; it...Four hundred and twenty-two million people have diabetes due to excess free body glucose in their body fluids. Diabetes leads to various problems including retinopathy, neuropathy, arthritis, damage blood vessels etc; it also causes a delay in wound healing. Insufficiency of insulin is the main reason for diabetes-I and systemic insulin treatment is a remedy. The perspective of the potential use of insulin/insulin based drugs to treat chronic wounds in diabetic conditions is focused on in this review. At the site of the wound, TNF-ɑ, IFN-ϒ, IL-1β and IL-6 pro-inflammatory cytokines cause the generation of free radicals, leading to inflammation which becomes persistent in diabetes. Insulin induces expression of IL-4/IL-13, IL-10 anti-inflammatory cytokines etc which further down-regulates NFkβP50/P65 assembly. Insulin shifts the equilibrium towards NFkβP50/P50 which leads to down-regulation of inflammatory cytokines such as IL-6, IL-10 etc through STAT6, STAT3 and c-Maf activation causing nullification of an inflammatory condition. Insulin also promotes protein and lipid biosynthesis which indeed promotes wound recovery. Here, in this article, the contributions of insulin in controlling wound tissue microenvironments and remodulation of tissue have been summarised, which may be helpful to develop novel insulin-based formulation(s) for effective treatment of wounds in diabetic conditions.
Bacterial resistance to antibiotics poses enormous health and economic burdens to our society, and it is of the essence to explore old and new ways to deal with these problems. Here we review the current status of multi-...Bacterial resistance to antibiotics poses enormous health and economic burdens to our society, and it is of the essence to explore old and new ways to deal with these problems. Here we review the current status of multi-resistance genes and how they spread among bacteria. We discuss strategies to deal with resistant bacteria, namely the search for new targets and the use of inhibitors of protein-protein interactions, fragment-based methods, or modified antisense RNAs. Finally, we discuss integrated approaches that consider bacterial populations and their niches, as well as the role of global regulators that activate and/or repress the expression of multiple genes in fluctuating environments and, therefore, enable resistant bacteria to colonize new niches. Understanding how the global regulatory circuits work is, probably, the best way to tackle bacterial resistance.
Intense research in the areas of cellular and organismal aging using diverse laboratory model systems has enriched our knowledge in the processes and the signalling pathways involved in normal and pathological conditions...Intense research in the areas of cellular and organismal aging using diverse laboratory model systems has enriched our knowledge in the processes and the signalling pathways involved in normal and pathological conditions. The field finds itself in a position to take decisive steps towards clinical applications and interventions not only for targeted age-related diseases such as cardiovascular conditions and neurodegeneration but also for the modulation of health span and lifespan of a whole organism. Beyond nutritional interventions such as dietary restriction without malnutrition and various regimes of intermittent fasting, accumulating evidence provides promise for pharmacological interventions. The latter, mimic caloric or dietary restriction, tune cellular and organismal stress responses, affect the metabolism of microbiome with subsequent effects on the host or modulate repair pathways, among others. In this mini review, we summarise some of the evidence on drugs that can alter organismal lifespan and the prospects they might offer for promoting healthspan and delaying age-related diseases.
The aim of this study was to formulate a novel dual crosslinked hydrogel bead using Portulaca mucilage for colon-targeted delivery of 5-fluorouracil (5-FU) and evaluate its safety, specificity and efficacy. The ionotropi...The aim of this study was to formulate a novel dual crosslinked hydrogel bead using Portulaca mucilage for colon-targeted delivery of 5-fluorouracil (5-FU) and evaluate its safety, specificity and efficacy. The ionotropic gelation technique was employed to prepare the hydrogel beads of Portulaca mucilage. For this, the mucilage was initially crosslinked with alginate and calcium ions. Epichlorohydrin was employed as a crosslinker in the second crosslinking step. The formulation was subjected to in vitro and in vivo studies to evaluate morphology, size, cytotoxicity, and organ distribution. Human HT-29 colon cancer cell-line was used for in vitro assays and in vivo studies were performed in Wistar rats to assess the usefulness and effectiveness of the formulation for colon cancer therapy. Microsphere sizes ranged from 930 to 977μm and possessed a high level of drug encapsulation efficiency (ca. 78% w/w). Compared with 5-FU solution (Tmax = 1.2 h, mean resident time: MRT = 3.3h) the dual crosslinked Portulaca microspheres exhibited sustained drug release after oral administration to rats (Tmax = 16h, MRT = 14h). The relative bioavailability of 5-FU solution and the microspheres were 100 and 93.6% respectively. Tissue distribution studies indicated high concentration of 5-FU in colon. In-vitro anticancer assay demonstrated IC50 value of 11.50 μg/ml against HT-29 colon cancer cell line. The epichlorohydrin cross-linked Portulaca microspheres prepared in this study provided sustained release of 5-FU up to 16h in the colonic region and enhanced the antitumor activity of the neoplastic drug. The formulation is hence an ideal carrier system for colon-targeted drug delivery.
Objectives This study was conducted to evaluate the effects of oral supplementation of Spirogyra algae on oxidative damages and inflammatory responses in streptozotocin (STZ)-induced diabetic rats. Methods Diabetes was i...Objectives This study was conducted to evaluate the effects of oral supplementation of Spirogyra algae on oxidative damages and inflammatory responses in streptozotocin (STZ)-induced diabetic rats. Methods Diabetes was induced by administration of 55 mg/kg of streptozotocin. A total of sixty-four rats were divided into eight groups of eight rats each as follows:1) non-diabetic control; 2, 3, and 4) non-diabetic rats treated with 15, 30, and 45 mg of Spirogyra algae/kg/d; 5) control diabetic; and 6, 7, and 8) diabetic rats treated with 15, 30, and 45 mg of Spirogyra algae extract. At the end of the trial, the serum concentrations of glucose, interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), malondialdehyde (MDA), glutathione (GSH), total antioxidant status (TAS), C-reactive protein (CRP), insulin, triglycerides, and cholesterol were examined by specified procedures. Results Our findings indicated that the administration of STZ significantly increased the serum concentrations of glucose, triglycerides, cholesterol, CRP, IL-6, TNF-a, and MDA and decreased the serum levels of GSH and TAS (P<0.05) in diabetic rats. Oral administration of Spirogyra alleviated adverse effects of diabetes on oxidative stress and inflammatory factors in diabetic rats (P<0.05). Conclusion It can be stated that Spirogyra algae extract can be used for treatment of diabetes likely due to prevention of oxidative stress and alleviation of inflammation in the rat model.
Bacteriophages are ubiquitous and have been reported to have been found in many food products. Their presence is important as they have the ability to interact with their bacterial host in food matrices. Fermented soybea...Bacteriophages are ubiquitous and have been reported to have been found in many food products. Their presence is important as they have the ability to interact with their bacterial host in food matrices. Fermented soybean products, one of the most widely consumed ethnic foods among Asian people, are prepared naturally and include Japanese Natto, Indian Kinema, Korean Chongkukjang and Thai Thua Nao. This review highlights bacteriophages which have been isolated from fermented soybean products and also includes an overview of their diversity, occurrence as well as their significance.
Background Early life trauma (ELT) may drive mood disorder phenomenology, nitro-oxidative pathways and impairments in semantic memory. There are no data regarding the impact of ELT on affective phenomenology and whether...Background Early life trauma (ELT) may drive mood disorder phenomenology, nitro-oxidative pathways and impairments in semantic memory. There are no data regarding the impact of ELT on affective phenomenology and whether these pathways are mediated by staging or lowered lipid-associated antioxidant defences. Methods This study examined healthy controls (n=54) and patients with affective disorders including major depression, bipolar disorder and anxiety disorders (n=118). ELT was assessed using the Child Trauma Questionnaire. In addition, we measured affective phenomenology and assayed advanced oxidation protein products; malondialdehyde, paraoxonase 1 (CMPAase) activity, high-sensitivity C-reactive protein (hsCRP), and high-density lipoprotein (HDL) cholesterol. Results ELT was associated into with increased risk for mood and comorbid anxiety disorders and a more severe phenomenology, including staging characteristics, depression and anxiety severity, suicidal behaviours, type of treatments, disabilities, body mass index, smoking behaviour and hsCRP, as well as lowered health-related quality of life, antioxidant defences and semantic memory. The number of mood episodes and CMPAase/HDL-cholesterol levels could be reliably combined into a new vulnerability staging-biomarker index, which mediates in part the effects of ELT on affective phenomenology and oxidative stress. Moreover, the effects of female sex on mood disorders and affective phenomenology are mediated by ELT. Discussion The cumulative effects of different ELT drive many aspects of affective phenomenology either directly or indirectly through effects of staging and/or lipid-associated antioxidant defences. The results show that children, especially girls, with ELT are at great risk to develop mood disorders and more severe phenotypes of affective disorders.
Pancreatitis is increasingly recognized as not merely a local inflammation of the pancreas but also a disease with high frequency of systemic sequelae. Current understanding of the cellular mechanisms that trigger it and...Pancreatitis is increasingly recognized as not merely a local inflammation of the pancreas but also a disease with high frequency of systemic sequelae. Current understanding of the cellular mechanisms that trigger it and affect the development of sequelae are limited. Genetically engineered mouse models can be a useful tool to study the pathophysiology of pancreatitis. This article gives an overview of the genetically engineered mouse models that spontaneously develop pancreatitis and discusses those that most closely replicate different pancreatitis hallmarks observed in humans.
We investigated the effect of polymorphisms in four DNA repair genes, viz. RAD18 Arg302Gln (G>A) (rs373572), XPD Asp312Asn (G>A) (rs1799793), APE1 Asp148Glu (T>G) (rs3136820), and OGG1 Ser326Cys (C>G) (rs1052133) on the...We investigated the effect of polymorphisms in four DNA repair genes, viz. RAD18 Arg302Gln (G>A) (rs373572), XPD Asp312Asn (G>A) (rs1799793), APE1 Asp148Glu (T>G) (rs3136820), and OGG1 Ser326Cys (C>G) (rs1052133) on the risk for type 2 diabetes mellitus (T2DM) and hypertension (HT) in association with smoking, tobacco chewing, and alcohol consumption in a population from Northeast India. The study subjects were comprised of 70 patients suffering from both T2DM and HT and 83 healthy controls. Genotyping was performed using ARMS-PCR for XPD Asp312Asn (G>A) and PCR-CTPP for RAD18 Arg302Gln (G>A), APE1 Asp148Glu (T>G) and OGG1 Ser326Cys (C>G). The RAD18 Gln/Gln genotype was found to significantly increase the risk for T2DM and HT by 30 fold. Significant high risk was observed for individuals with XPD Asn/Asn-RAD18 Arg/Gln genotypes. Smoking was found to be the single most important independent risk factor for T2DM and HT. This study concludes that RAD18 Arg302Gln and XPD Asp312Asn polymorphisms might increase the risk for T2DM and HT in association with smoking, tobacco chewing, and/or alcohol consumption, while APE1 Asp148Glu (T>G) and OGG1 Ser326Cys (C>G) polymorphisms do not contribute to such risk.
A key player in driving cellular immunity, IFN-γ is capable of orchestrating numerous protective functions to heighten immune responses in infections and cancers. It can exhibit its immunomodulatory effects by enhancing...A key player in driving cellular immunity, IFN-γ is capable of orchestrating numerous protective functions to heighten immune responses in infections and cancers. It can exhibit its immunomodulatory effects by enhancing antigen processing and presentation, increasing leukocyte trafficking, inducing an anti-viral state, boosting the anti-microbial functions and affecting cellular proliferation and apoptosis. A complex interplay between immune cell activity and IFN-γ through coordinated integration of signals from other pathways involving cytokines and Pattern Recognition Receptors (PRRs) such as Interleukin (IL)-4, TNF-α, Lipopolysaccharide (LPS), Type-I Interferons (IFNS) etc. leads to initiation of a cascade of pro-inflammatory responses. Microarray data has unraveled numerous genes whose transcriptional regulation is influenced by IFN-γ. Consequently, IFN-γ stimulated cells display altered expression of many such target genes which mediate its downstream effector functions. The importance of IFN-γ is further reinforced by the fact that mice possessing disruptions in the IFN-γ gene or its receptor develop extreme susceptibility to infectious diseases and rapidly succumb to them. In this review, we attempt to elucidate the biological functions and physiological importance of this versatile cytokine. The functional implications of its biological activity in several infectious diseases and autoimmune pathologies are also discussed. As a counter strategy, many virulent pathogenic species have devised ways to thwart IFN-γ endowed immune-protection. Thus, IFN-γ mediated host-pathogen interactions are critical for our understanding of disease mechanisms and these aspects also manifest enormous therapeutic importance for the annulment of various infections and autoimmune conditions.
Chronic low back pain is a critical health problem and a leading cause of disability in aging populations. A major cause of low back pain is considered to be the degeneration of the intervertebral disc (IVD). Recent adva...Chronic low back pain is a critical health problem and a leading cause of disability in aging populations. A major cause of low back pain is considered to be the degeneration of the intervertebral disc (IVD). Recent advances in therapeutics, particularly cell and tissue engineering, offer potential methods for inhibiting or reversing IVD degeneration, which have previously been impossible. The use of growth factors is under serious consideration as a potential therapy to enhance IVD tissue regeneration. We reviewed the role of chosen prototypical growth factors and growth factor combinations that have the capacity to improve IVD restoration. A number of growth factors have demonstrated potential to modulate the anabolic and anticatabolic effects in both in vitro and animal studies of IVD tissue engineering. Members of the transforming growth factor-β superfamily, IGF-1, GDF-5, BMP-2, BMP-7, and platelet-derived growth factor have all been investigated as possible therapeutic options for IVD regeneration. The role of growth factors in IVD tissue engineering appears promising; however, further extensive research is needed at both basic science and clinical levels before its application is appropriate for clinical use.