Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart

<p>Abstract</p> <p>Background</p> <p>Nitric oxide (NO) has been noted to produce ischemic preconditioning (IPC)-mediated cardioprotection. Caveolin is a negative regulator of NO, which inhibits endothelial nitric oxide synthase (eNOS) by making caveolin-eNOS complex. The expression of caveolin is increased during diabetes mellitus (DM). The present study was designed to investigate the involvement of caveolin in attenuation of the cardioprotective effect of IPC during DM in rat.</p> <p>Methods</p> <p>Experimental DM was induced by single dose of streptozotocin (50 mg/Kg, <it>i.p</it>,) and animals were used for experiments four weeks later. Isolated heart was mounted on Langendorff's apparatus, and was subjected to 30 min of global ischemia and 120 min of reperfusion. IPC was given by four cycles of 5 min of ischemia and 5 min of reperfusion with Kreb's-Henseleit solution (K-H). Extent of injury was measured in terms of infarct size by triphenyltetrazolium chloride (TTC) staining, and release of lactate dehydrogenase (LDH) and creatin kinase-MB (CK-MB) in coronary effluent. The cardiac release of NO was noted by measuring the level of nitrite in coronary effluent.</p> <p>Results</p> <p>IPC- induced cardioprotection and release of NO was significantly decreased in diabetic rat heart. Pre-treatment of diabetic rat with daidzein (DDZ) a caveolin inhibitor (0.2 mg/Kg/s.c), for one week, significantly increased the release of NO and restored the attenuated cardioprotective effect of IPC. Also perfusion of sodium nitrite (10 μM/L), a precursor of NO, significantly restored the lost effect of IPC, similar to daidzein in diabetic rat. Administration of 5-hydroxy deaconate (5-HD), a mito K_ATPchannel blocker, significantly abolished the observed IPC-induced cardioprotection in normal rat or daidzein and sodium nitrite perfused diabetic rat heart alone or in combination.</p> <p>Conclusions</p> <p>Thus, it is suggested that attenuation of the cardioprotection in diabetic heart may be due to decrease the IPC mediated release of NO in the diabetic myocardium, which may be due to up -regulation of caveolin and subsequently decreased activity of eNOS.</p

Alcoholic Neuropathy: Involvement of Multifaceted Signalling Mechanisms

Background: Alcoholic neuropathy is a chronic disorder caused by excessive consumption of alcohol. Damage to the nerves results in unusual sensations in the limbs, decrease mobility and loss of some body functions. Objective: Alcohol is considered a major villain for exclusively creating the debilitating condition of the neuropathic state. This review critically examines the key mediators involved in the pathogenesis of alcoholic neuropathy and the targets which upon selective inhibition alleviates the progression of alcoholic neuropathy. Method: A thorough study of research and review articles available on the internet from PubMed, MEDLINE, and concerned sites was performed on alcoholic neuropathy. Result: A deal of impairment in axonal transportation is quiet common with the progression of alcoholic neuropathy. Nutritional deficiencies lead to axonal neuropathies that escalate a variety of complications that further worsens the state. PKC and PKA play a significant role in the pathogenesis of alcoholic neuropathy. PKC plays a well-marked role in modulating NMDA receptor currents manifesting to excitation in the neurons. MMPs are involved in the number of pathologies that destructs CNS and reduction in the level of endogenous antioxidants like -tocopherol, vitamin E with ethanol promotes oxidative stress by generating free radicals and lipid peroxidation. Conclusion: Oxidative stress is implicated in the activation of MMPs causing blood-brain barrier disruption, the latter involved in the trafficking and passages of molecules in and out of the cell. Chronic alcohol consumption leads to the downregulation of CNS receptors consequently precipitating the condition of alcoholic neuropathy. </jats:sec

CYP2D6 phenotyping in North Indian subjects in Delhi

The recognition of the importance of inter-subject variation in drug metabolism has increased markedly over the past 20 years. Inter-subject variation may be genetically determined, environmentally induced, or most commonly, a combination of both, resulting in genetic polymorphism. The objective of the present study is to examine the CYP2D6 phenotypes in north Indian population. The study was carried out on seventy-five unrelated healthy north Indian subjects. They were phenotyped with respect to their ability to metabolize dextromethorphan to dextorphan. Oral dextromethorphan (30 mg) was administered to each subject. Urine was collected during 0 to 8 h period after dosing and was analyzed for dextromethorphan and dextorphan by liquid chromatography mass spectrometry (LC-MS/MS). The log 10 (metabolic ratio), calculated as the ratio of dextromethorphan to dextorphan, was bimodally distributed. An antimode value of 0.3 was obtained by plotting a frequency histogram of the log metabolic ratios. The frequency of occurrence of poor metabolizers of dextromethorphan in north Indian subjects from Delhi was found to be 2.6%. Ethiopian Pharmaceutical Journal Vol. 24, 2006: 65-7

DataSheet_1_Synthesis and anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid against B16F10 cells via induction of endoplasmic reticulum stress-mediated autophagy through ERK/AKT signaling pathway.pdf

Melanoma is an aggressive form of cancer with poor prognosis and survival rates and limited therapeutic options. Here, we report the anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid (NPC-402), a derivative of glycyrrhtinic acid, from a reputed medicinal plant Glycyrrhiza glabra against B16F10 cells. We studied the cytotoxic effect of NPC-402 on melanoma cells and investigated the role of mitogen-activated protein (MAP) kinase, AKT axis, and endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated autophagy as the involved signaling cascade by studying specific marker proteins. In this study, 4-phenylbutyric acid (4PBA, a chemical chaperone) and small interference RNA (siRNA) knockdown of C/EBP Homologous Protein (CHOP)/growth arrest- and DNA damage-inducible gene 153(GAD153) blocked NPC-402-mediated autophagy induction, thus confirming the role of ER stress and autophagy in melanoma cell death. NPC-402 induced oxidative stress and apoptosis in melanoma cells, which were effectively mitigated by treatment with N-acetylcysteine (NAC). In vivo studies showed that intraperitoneal (i.p.) injection of NPC-402 at 10 mg/kg (5 days in 1 week) significantly retarded angiogenesis in the Matrigel plug assay and reduced the tumor size and tumor weight without causing any significant toxic manifestation in C57BL/6J mice. We conclude that NPC-402 has a high potential to be developed as a chemotherapeutic drug against melanoma.</p

DataSheet_2_Synthesis and anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid against B16F10 cells via induction of endoplasmic reticulum stress-mediated autophagy through ERK/AKT signaling pathway.pdf

Melanoma is an aggressive form of cancer with poor prognosis and survival rates and limited therapeutic options. Here, we report the anti-melanoma effect of 3-O-prenyl glycyrrhetinic acid (NPC-402), a derivative of glycyrrhtinic acid, from a reputed medicinal plant Glycyrrhiza glabra against B16F10 cells. We studied the cytotoxic effect of NPC-402 on melanoma cells and investigated the role of mitogen-activated protein (MAP) kinase, AKT axis, and endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated autophagy as the involved signaling cascade by studying specific marker proteins. In this study, 4-phenylbutyric acid (4PBA, a chemical chaperone) and small interference RNA (siRNA) knockdown of C/EBP Homologous Protein (CHOP)/growth arrest- and DNA damage-inducible gene 153(GAD153) blocked NPC-402-mediated autophagy induction, thus confirming the role of ER stress and autophagy in melanoma cell death. NPC-402 induced oxidative stress and apoptosis in melanoma cells, which were effectively mitigated by treatment with N-acetylcysteine (NAC). In vivo studies showed that intraperitoneal (i.p.) injection of NPC-402 at 10 mg/kg (5 days in 1 week) significantly retarded angiogenesis in the Matrigel plug assay and reduced the tumor size and tumor weight without causing any significant toxic manifestation in C57BL/6J mice. We conclude that NPC-402 has a high potential to be developed as a chemotherapeutic drug against melanoma.</p

Data from: Improved access to early diagnosis and complete treatment of malaria in Odisha, India

Background In 2013, the Comprehensive Case Management Programme (CCMP) was initiated to assess the impact of universal access to diagnosis and treatment and improved surveillance on malaria transmission in different settings in Odisha state, India. Methods Pairs of intervention and control sub-districts (blocks), matched on malaria incidence were selected in four districts with different transmission intensities. CCMP activities included training and supervision, ensuring no stock-outs of malaria tests and drugs, analysing verified surveillance data, stratifying areas based on risk factors, and appointing alternative providers to underserved areas. Composite risk scores were calculated for each sub-centre using principal component analysis. Post−pre changes (2013–2015 versus 2011–2012) for annual blood examination rates (ABER) and annual parasite incidence (API) across intervention and control groups were assessed using difference-in-difference (DID) estimates, adjusted for malaria transmission risk. Results In the intervention sub-centres, the mean increase in ABER was 6.41 tests/sub-centre (95%CI 4.69, 8.14; p<0.01) and in API was 9.2 cases diagnosed/sub-centre (95%CI 5.18, 13.21; p<0.01). The control sub-centres reported lower increases in ABER (2.84 [95%CI 0.35, 5.34]; p<0.05) and API (3.68 [95%CI 0.45, 6.90]; p<0.05). The control-adjusted post–pre changes in API showed that 5.52 more cases (95%CI 0.34, 10.70; p<0.05) were diagnosed, and a 3.6 more cases (95%CI 0.58, 6.56; p<0.05) were tested per sub-centre in the intervention versus control areas. Larger differences in post–pre changes in API between intervention and control sub-centres were registered in the higher transmission-risk areas compared with the lower risk areas. All the changes were statistically significant. Conclusions Intensive intervention activities targeted at improved access to malaria diagnosis and treatment produced a substantial increase in blood examination and case notification, especially in inaccessible, hard-to-reach pockets. CCMP provides insights into how to achieve universal coverage of malaria services through a routine, state-run programme

Impact of the malaria comprehensive case management programme in Odisha, India

Background The Comprehensive Case Management Project (CCMP), was a collaborative implementation research initiative to strengthen malaria early detection and complete treatment in Odisha State, India. Methods A two-arm quasi-experimental design was deployed across four districts in Odisha, representing a range of malaria endemicity: Bolangir (low), Dhenkanal (moderate), Angul (high), and Kandhamal (hyper). In each district, a control block received routine malaria control measures, whereas a CCMP block received a range of interventions to intensify surveillance, diagnosis, and case management. Impact was evaluated by difference-in-difference (DID) analysis and interrupted time-series (ITS) analysis of monthly blood examination rate (MBER) and monthly parasite index (MPI) over three phases: phase 1 pre-CCMP (2009–2012) phase 2 CCMP intervention (2013–2015), and phase 3 post-CCMP (2016–2017). Results During CCMP implementation, adjusting for control blocks, DID and ITS analysis indicated a 25% increase in MBER and a 96% increase in MPI, followed by a –47% decline in MPI post-CCMP, though MBER was maintained. Level changes in MPI between phases 1 and 2 were most marked in Dhenkanal and Angul with increases of 976% and 287%, respectively, but declines in Bolangir (−57%) and Kandhamal (−22%). Between phase 2 and phase 3, despite the MBER remaining relatively constant, substantial decreases in MPI were observed in Dhenkanal (−78%), and Angul (−59%), with a more modest decline in Bolangir (−13%), and an increase in Kandhamal (14%). Conclusions Overall, CCMP improved malaria early detection and treatment through the enhancement of the existing network of malaria services which positively impacted case incidence in three districts. In Kandhamal, which is hyperendemic, the impact was not evident. However, in Dhenkanal and Angul, areas of moderate-to-high malaria endemicity, CCMP interventions precipitated a dramatic increase in case detection and a subsequent decline in malaria incidence, particularly in previously difficult-to-reach communities. </jats:sec

Study population, number of malaria tests conducted, and number of positive malaria tests by year.

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