Indian journal of biochemistry & biophysics最新文献

Ultraviolet C (UVC) irradiation (λ: 200-280 nm) causes release of several secretory cytokines responsible for inflammation. Our objective was to investigate whether inflammatory response was also induced in bystander cells. For this purpose, the conditioned medium containing the released factors from UVC irradiated A375 cells was used in this study to evaluate the expression of inflammatory markers, such as tumour necrosis factor alpha (TNFα), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and p38 mitogen-activated protein kinase (p38 MAPK) in its bystander cells. Inflammatory responses in bystander cells subjected to further irradiation by UVC or other damaging agent like H2O2 were also examined. It was observed that TNFα, NFκB and p38 MAPK were not induced in UVC-bystander cells, but their expression was suppressed in the UVC-bystander cells treated with UVC or H2O2. This lowering in inflammatory response might be due to smaller depletion in the reduced glutathione (GSH) content present in these treated bystander cells. The study indicated that UVC-induced bystander effect was an intrinsic protective response in cells, capable of suppressing inflammation induced in cells on exposure to damaging agents.

There are a number of sites that are required for the production and/or action of all-trans retinoic acid (ATRA). In particular, interruption of different components of the chain of trafficking and metabolism has been associated with cancers arising in numerous organs of the body. Preliminary work suggests that such interruptions may be a factor in lung disorders induced by the smoke exposure. The active metabolite of retinoid, ATRA offers a therapeutic strategy to protect against functional abnormality in the lung, including chronic obstructive pulmonary disease (COPD). This review deals with the lung retinoid metabolism and mediators of retinoid trafficking and signaling with special emphasis on their roles in health and disease.

N-myristoyltransferase (NMT) is an essential eukaryotic enzyme which catalyzes the transfer of the myristoyl group to the terminal glycine residue of a number of proteins including those involved in signal transduction and apoptotic pathways. In higher eukaryotes, two isoforms of NMT have been identified (NMT1 and NMT2) which share about 76% amino acid sequence identity in humans. Protein-protein interactions of NMTs reveal that m-calpain interacts with NMT1 whereas caspase-3 interacts with NMT2. These findings reveal differential interactions of both isoforms of NMT with various signaling molecules. This minireview provides an overview of the regulation of N-myristoyltransferase by calpain and caspase systems.

Aneurysms develop as a result of chronic inflammation of vascular bed, where progressive destruction of structural proteins, especially elastin and collagen of smooth muscle cells has been shown to manifest. The underlying mechanisms are an increase in local production of proinflammatory cytokines and subsequent increase in proteases, especially matrix metalloproteinases (MMPs) that degrade the structural proteins. The plasminogen system: urokinase-type PA (u-PA), tissue-type PA (t-PA) and plasminogen activator inhibitor-1 (PAI-1) and the MMPs system-MMPs and TIMPs contribute to the progression and development of aneurysms. Recent studies suggest that aneurysms may be genetically determined. To date, most observable candidate genes for aneurysm (elastin, collagen, fibrillin, MMPs and TIMPs) have been explored with little substantiation of the underlying cause and effect. Recently, overexpression of the MMP-2 gene has been suggested as an important phenomenon for aneurysm formation. Along with MMPs, matrix formation also depends on JNK (c-Jun N-terminal kinase) as its activation plays important role in downregulating several genes of matrix production. Under stress, activation of JNK by various stimuli, such as angiotensin II, tumor necrosis factor-α and interleukin-1β has been noted significantly in vascular smooth muscle cells. Several therapeutic indications corroborate that inhibition of MMP-2 and JNK is useful in preventing progression of vascular aneurysms. This review deals with the role of proteases in the progression of vascular aneurysm.

Guanine nucleotide regulatory proteins (G proteins) play a key role in the regulation of various signal transduction systems, including adenylyl cyclase/cAMP and phospholipase C (PLC)/phosphatidyl inositol (PI) turnover, which are implicated in the modulation of a variety of physiological functions, such as platelet functions, including platelet aggregation, secretion, and clot formation and cardiovascular functions, including arterial tone and reactivity. Several abnormalities in adenylyl cyclase activity, cAMP levels and G proteins have been shown to be responsible for the altered cardiac performance and vascular functions observed in cardiovascular disease states. The enhanced or unaltered levels of inhibitory G proteins (Giα) and mRNA have been reported in different models of hypertension, whereas Gsα levels are shown to be unaltered. The enhanced levels of Giα proteins precede the development of blood pressure and suggest that overexpression of Gi proteins may be one of the contributing factors for the pathogenesis of hypertension. The levels of vasoactive peptides including ET-1 and Ang II and growth factors are augmented in hypertension and contribute to the enhanced expression of Giα proteins in hypertension. In addition, oxidative stress due to enhanced levels of Ang II and ET-1 is enhanced in hypertension and may also be responsible for the enhanced expression of Giα proteins observed in hypertension. Furthermore, Ang II- and ET-1-induced transactivation of growth factor receptor through the activation of MAP kinase signaling is also shown to contribute to the augmented levels of Giα in hypertension. Thus, it appears that the enhanced levels of vasoactive peptides by increasing oxidative stress and transactivation growth factor receptors enhance MAP kinase activity that contribute to the enhanced expression of Giα proteins responsible for the pathogenesis of hypertension. In this review, we describe the role of vasoactive peptides and the signaling mechanisms responsible for the enhanced expression of Giα proteins in hypertension.

The endocrine control of oocyte maturation in fish and amphibians has proved to be a valuable model for investigating the rapid and non-genomic steroid actions at the cell surface. Considerable progress has made over the last decade in elucidating signaling pathways in steroid-induced oocyte maturation. In addition to steroids, various growth factors have also been reported to be involved in this process and progress being made to elucidate their mechanism of actions. Exposure of fully-grown oocytes to steroids or growth factors (insulin/IGFs) initiates various signaling cascade, leading to formation and activation of maturation-promoting factor (MPF), a key enzyme that catalyzes entry into M-phase of meiosis I and II. Whereas the function of MPF in promoting oocyte maturation is ubiquitous, there are differences in signaling pathways between steroids- and growth factors-induced oocyte maturation in amphibian and fish. Here, we have reviewed the recent advances on the signaling pathways in insulin- and IGF-I-induced oocyte maturation in these two groups of non-mammalian vertebrates. New findings demonstrating the involvement of PI3 kinase and MAP kinase in induction of oocyte maturation by insulin and IGF-I are presented.

Beta-adrenoceptors (β-AR), members of the G protein-coupled receptors play important roles in the regulation of heart function. A positive inotropic action of catecholamines is mediated through their interaction with β-AR, located on the sarcolemma, while they can also mediate some deleterious effects, such as cardiac arrhythmias or myocardial apoptosis. The well-known β-AR-associated signaling in heart is composed of a coupled mechanism among both β1- and β2-AR and stimulatory G protein (G(s)). This coupled mechanism further leads to the activation of adenylyl cyclase and thereby increases in intracellular cAMP level. However, recent studies have emphasized the contribution of constitutive β3-AR coupling to G(i) proteins, thereby initiating additional signal transduction pathways, particularly under physiopathological conditions. Diabetic cardiomyopathy, as a distinct entity is recognized due to its diminished responsiveness to β1-AR agonist stimulation in the heart from diabetic rats with no important changes in the responses mediated with β2-AR. Furthermore, an upregulation of β3-AR has been shown in diabetic rat heart with a strong negative inotropic effect on left ventricular function. Experimental data provide evidences that the mechanisms for the negative inotropic effect with β3-AR activation appear to involve a pertussis toxin (PTX)-sensitive G protein and the activation of a nitric oxide synthase pathway. On the other hand, β-blockers demonstrate marked beneficial effects in heart dysfunction with scavenging free radicals and/or acting as an antioxidant with both sex- and dose-dependent manner. However, further investigations are needed to clarify the roles of both altered expression and/or responsiveness of β-AR and the benefits with β-blocker treatment in diabetes. This review discusses the role of β-AR activation, particularly β3-AR in cardiac pathological remodeling under hyperglycemia.

Cardiac fibroblasts (CFs) maintain the cardiac extracellular matrix (ECM) through myocardial remodelling. The remodelling process can become dysregulated during various forms of heart disease which leads to an overall accumulation of ECM. This results in cardiac fibrosis which increases the risk of heart failure in many patients. During heart disease, quiescent CFs undergo phenoconversion to an activated cell type called cardiac myofibroblasts (CMFs). Factors influencing phenoconversion include transforming growth factor β (TGF-β) which via SMADs (small mothers against decapentaplegic) activates the myofibroblast marker gene αSMA (α smooth muscle actin). Signaling molecules as diverse as NAD(P)H oxidase 4 (Nox4) and Wnt have been found to interact with TGF-β signalling via SMADs. Pathways, including FAK/TAK/JNK and PI3K/Akt/rac have also been implicated in activating phenoconversion of fibroblasts. Another major contributor is mechanical stress exerted on CFs by ECM changes, which involves activation of ERK and subsequent αSMA expression. Other factors, such as the mast cell protease tryptase and the seeding density also affect the phenoconversion of fibroblast cultures in vitro. Further, reversal of myofibroblast phenotype has been reported by a negative regulator of TGF-β, Ski, as well as the hormone relaxin and the second messenger cAMP. Targeting the signaling molecules involved in promoting phenoconversion of CFs to CMFs presents a possible method of controlling cardiac fibrosis. Here, we provide a brief review of signaling mechanisms responsible for phenoconversion and identify critical targets for the treatment of cardiac fibrosis.

Leishmania parasites determine the outcome of the infection by inducing inflammatory response that suppresses macrophage's activation. Defense against Leishmania is dependent on Th1 inflammatory response by turning off macrophages' microbicidal property by upregulation of COX-2, as well as immunosuppressive PGE-2 production. To understand the role of L. donovani secretory serine protease (pSP) in these phenomena, pSP was inhibited by its antibody and serine protease inhibitor, aprotinin. Western blot and TAME assay demonstrated that pSP antibody and aprotinin significantly inhibited protease activity in the live Leishmania cells and reduced infection index of L. donovani-infected macrophages. Additionally, ELISA and RT-PCR analysis showed that treatment with pSP antibody or aprotinin hold back COX-2-mediated immunosuppressive PGE-2 secretion with enhancement of Th1 cytokine like IL-12 expression. This was also supported in Griess test and NBT assay, where inhibition of pSP with its inhibitors elevated ROS and NO production. Overall, our study implies the pSP is involved in down-regulation of macrophage microbicidal activity by inducing host inflammatory responses in terms of COX-2-mediated PGE-2 release with diminished reactive oxygen species generation and thus suggests its importance as a novel drug target of visceral leishmaniasis.

Caloric restriction, defined as a reduction in calorie intake below ad libitum, without malnutrition can have beneficial effects. In this study, we evaluated the impact of caloric restriction of 30 and 60% on calorimetric parameters and oxidative stress in cardiac tissue in rats. Rats were randomly divided into 3 groups (n = 8): G1 = control; G2 = rats exposed to dietary restriction of 30%; and G3 = rats exposed to dietary restriction of 60%. Energy restriction decreased final body weight, oxidation of carbohydrates and lipid, oxygen consumption (VO2), carbon dioxide production (VCO2), resting metabolic rate (RMR), but elevated respiratory quotient (RQ). G3 animals also displayed an imbalance in the oxidant/antioxidant system, as revealed by the decrease in the lipid hydroperoxide (LH) level and GSH-Px activity in heart tissue. In conclusion, dietary restriction decreased oxidative metabolism, as seen by the colorimetric profiles and controlled oxidative stress in cardiac tissue.