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101.
Roy S Khanna V Mittra S Dhar A Singh S Mahajan DC Priyadarsiny P Davis JA Sattigeri J Saini KS Bansal VS 《Life sciences》2007,81(1):72-79
Thiazolidinediones (TZDs) are currently the most efficacious class of oral antidiabetics. However, they carry the burden of weight gain and haemodilution, which may lead to cardiovascular complications. The present study was designed to ascertain whether a combination of dipeptidyl peptidase IV (DPP IV) inhibitor with low dose of a thiazolidinedione absolves TZD associated weight gain and oedema without compromising its efficacy. In this study, we examined the efficacy and safety of lower dose (1 mg/kg/day) of rosiglitazone, a thiazolidinedione, in combination with 5 mg/kg/day dose of LAF-237 (vildagliptin), a known DPP IV inhibitor, in aged db/db mice after 14 days of treatment and compared the combination with therapeutic dose (10 mg/kg) of rosiglitazone. The combination therapy showed similar efficacy as that of 10 mg/kg/day rosiglitazone in lowering random blood glucose (53.8%, p<0.001 and 54.3%, p<0.001 respectively), AUC ((0-120) min) during oral glucose tolerance test (OGTT) (38.6 %, p<0.01; 38.3%, p<0.01 respectively) and triglyceride levels (63.9% and 61% respectively; p<0.01). Plasma active glucagon like peptide-1 (GLP-1) and insulin levels were found to be elevated significantly (p<0.01 and p<0.05 respectively) in both LAF-237 and combination treated groups following oral glucose load. LAF-237 alone had no effect on random glucose and glucose excursion during OGTT in severely diabetic db/db mice. Interestingly, the combination treatment showed no significant increase in body weight as compared to the robust weight gain by therapeutic dose of rosiglitazone. Rosiglitazone at 10 mg/kg/day showed significant reduction (p<0.05) in haematocrit, RBC count, haemoglobin pointing towards haemodilution associated with increased mRNA expression of Na(+), K(+)-ATPase-alpha and epithelial sodium channel gamma (ENaCgamma) in kidney. The combination therapy escaped these adverse effects. The results suggest that combination of DPP IV inhibitor with low dose of thiazolidinedione can interact synergistically to represent a therapeutic advantage for the clinical treatment of type 2 diabetes without the adverse effects of haemodilution and weight gain associated with thiazolidinediones. 相似文献
102.
Gupta A Tripathi AK Tripathi RL Madhu SV Banerjee BD 《Indian journal of biochemistry & biophysics》2007,44(5):373-378
Two important consequences of hyperglycemia in diabetes are development of oxidative stress and formation of advanced glycation end products (AGE) which are known to be associated with diabetic complications. Relationship between AGE formation and development of oxidative stress (OS) is yet to be established. In the present study, the involvement of AGE in PMN-mediated ROS generation and the associated OS were investigated in type 2 diabetic mellitus (DM) patients. We assessed OS parameters (serum MDA, FRAP and GSH), PMN oxidative functions (respiratory burst and superoxide production) and total serum AGE in 90 subjects divided equally in three groups--control group, Group I consisting of type 2 diabetic patients without microvascular complications and Group II consisting of type 2 diabetic patients with microvascular complications. PMNs isolated from both groups (I and II) exhibited higher level of respiratory burst (RB) and produced increased amount of superoxide anion as compared to the controls. The increase was more pronounced in diabetes with complications, as compared to those without. Serum malondialdehyde (MDA) level was elevated, whereas glutathione (GSH) and ferric reducing ability of plasma (FRAP) levels were significantly reduced in diabetes as compared to the controls, suggesting the presence of oxidative stress in DM. A positive correlation between PMN oxidative function and OS parameters suggested the involvement of PMN in the development of OS in DM. Serum AGE level was also elevated in diabetic groups as compared to the controls. Further, the positive correlation between serum AGE level and PMN oxidative function suggested the involvement of AGE in increased RB and generation of reactive oxygen species (ROS) by resting diabetic PMN. The results of the study indicate that AGE-PMN interaction possibly upregulates NADPH oxidase, leading to enhanced ROS generation and thus contributes to the pathogenesis in diabetes. 相似文献
103.
The role of mitochondria in causing diseases is becoming evident as more and more studies are focusing on this organelle of
the cell. This is largely attributed to its reactive oxygen species (ROS) production property. In the context of diabetes,
ROS is suggested to trigger different forms of insulin resistance involving different mechanisms. The suggestive role of a
mtDNA variant G10398A in increasing ROS production and the impaired response to oxidative stress due to T16189C variant is
worth addressing as genetic susceptibility factors in type 2 diabetes mellitus (T2DM). A case control study on 312 T2DM cases
and ethnically matched 466 controls involving two North Indian populations, referred as cohort 1 and cohort 2 (in a replicative
study), was undertaken to test such a genetic association. A statistically significant association was observed for 10398A
allele in both the cohorts [cohort1 (OR = 2.67 95% CI 1.77–4.00); cohort2 (OR = 1.76 95%CI 1.12–2.77)]. The analysis of G10398A/T16189C
haplotypic combinations revealed that 10398A/16189C haplotype provides a risk in both the cohorts. To sum up the study suggests
that 10398A and 16189C alleles provide susceptiblity to T2DM independently as well as together. 相似文献
104.
Rudimentary studies on aspects of biochemistry in India date back to 1927. But, in the field of Immunology, such studies were started by scholars only during early 1970s at the All India Institute of Medical Sciences, New Delhi, India. Science and Technology was not an immediate priority until 1961 due to domestic and political conditions in the country. We were then 11 years old since independence and our focus was on economic and social developments. Gradually, improvements were made in the field and now we have 15 to 20 major groups (small in size) of immunologists in the country, who have made significant contribution in the field during the last 8 to 10 years. Hence, we anticipate improvements in manpower and infrastructure in the near future. 相似文献
105.
Begley U Dyavaiah M Patil A Rooney JP DiRenzo D Young CM Conklin DS Zitomer RS Begley TJ 《Molecular cell》2007,28(5):860-870
106.
We have recently shown that the nitric oxide (NO) donor, SNAP, decreased the expression of Giα proteins and associated functions
in vascular smooth muscle cells. Because NO stimulates soluble guanylyl cyclase and increases the levels of guanosine 3′,5′-cyclic
monophosphate (cGMP), the present studies were undertaken to investigate whether cGMP can also modulate the expression of
Gi proteins and associated adenylyl cyclase signaling. A10 vascular smooth muscle cells (VSMCs) and primary cultured cells
from aorta of Sprague Dawley rats were used for these studies. The cells were treated with 8-bromoguanosine 3′,5′-cyclic monophosphate
(8Br-cGMP) for 24 h and the expression of Giα proteins was determined by immunobloting techniques. Adenylyl cyclase activity
was determined by measuring [32P]cAMP formation for [α-32P]ATP. Treatment of cells with 8-Br-cGMP (0.5 mM) decreased the expression of Giα-2 and Giα-3 by about 30–45%, which was restored towards control levels by KT5823, an inhibitor
of protein kinase G. On the other and hand, the levels of Gsα protein were not altered by this treatment. The decreased expression
of Giα proteins by 8Br-cGMP treatment was reflected in decreased Gi functions. For example, the inhibition of forskolin (FSK)-stimulated
adenylyl cyclase activity by low concentrations of GTPγS (receptor-independent Gi functions) was significantly decreased by
8Br-cGMP treatment. In addition, exposure of the cells to 8Br-cGMP also resulted in the attenuation of angiotensin (Ang) II-
and C-ANP4–23 (a ring-deleted analog of atrial natriuretic peptide [ANP]-mediated inhibition of adenylyl cyclase activity (receptor-dependent
functions of Gi). On the other hand, Gsα-mediated stimulations of adenylyl cyclase by GTPγS, isoproterenol and FSK were significantly
augmented in 8Br-cGMP-treated cells. These results indicated the 8Br-cGMP decreased the expression of Giα proteins and associated
functions in VSMCs. From these studies, it can be suggested that 8Br-cGMP-induced decreased levels of Gi proteins and resultant
increased levels of cAMP may be an additional mechanism through which cGMP regulates vascular tone and thereby blood pressure. 相似文献
107.
Necessary and sufficient factors for the import of transfer RNA into the kinetoplast mitochondrion 总被引:1,自引:0,他引:1
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The mechanism of active transport of transfer RNA (tRNA) across membranes is largely unknown. Factors mediating the import of tRNA into the kinetoplast mitochondrion of the protozoon Leishmania tropica are organized into a multiprotein RNA import complex (RIC) at the inner membrane. Here, we present the complete characterization of the identities and functions of the subunits of this complex. The complex contains three mitochondrion- and eight nuclear-encoded subunits; six of the latter are necessary and sufficient for import. Antisense-mediated knockdown of essential subunits resulted in the depletion of mitochondrial tRNAs and inhibition of organellar translation. Functional complexes were reconstituted with recombinant subunits expressed in Escherichia coli. Several essential RIC subunits are identical to specific subunits of respiratory complexes. These findings provide new information on the evolution of tRNA import and the foundation for detailed structural and mechanistic studies. 相似文献
108.
Jin-Ying Gou Kun Li Kati Wu Xiaodong Wang Huiqiong Lin Dario Cantu Cristobal Uauy Albor Dobon-Alonso Takamufi Midorikawa Kentaro Inoue Juan Sánchez Daolin Fu Ann Blechl Emma Wallington Tzion Fahima Madhu Meeta Lynn Epstein Jorge Dubcovsky 《The Plant cell》2015,27(6):1755-1770
Stripe rust is a devastating fungal disease of wheat caused by Puccinia striiformis f. sp tritici (Pst). The WHEAT KINASE START1 (WKS1) resistance gene has an unusual combination of serine/threonine kinase and START lipid binding domains and confers partial resistance to Pst. Here, we show that wheat (Triticum aestivum) plants transformed with the complete WKS1 (variant WKS1.1) are resistant to Pst, whereas those transformed with an alternative splice variant with a truncated START domain (WKS1.2) are susceptible. WKS1.1 and WKS1.2 preferentially bind to the same lipids (phosphatidic acid and phosphatidylinositol phosphates) but differ in their protein-protein interactions. WKS1.1 is targeted to the chloroplast where it phosphorylates the thylakoid-associated ascorbate peroxidase (tAPX) and reduces its ability to detoxify peroxides. Increased expression of WKS1.1 in transgenic wheat accelerates leaf senescence in the absence of Pst. Based on these results, we propose that the phosphorylation of tAPX by WKS1.1 reduces the ability of the cells to detoxify reactive oxygen species and contributes to cell death. This response takes several days longer than typical hypersensitive cell death responses, thus allowing the limited pathogen growth and restricted sporulation that is characteristic of the WKS1 partial resistance response to Pst. 相似文献
109.
Vibha Pandey Yogeshwar Vikram Dhar Parul Gupta Sumit K Bag Neelam Atri Mehar Hasan Asif Prabodh Kumar Trivedi Pratibha Misra 《BMC bioinformatics》2015,16(1)
Background
Sterol glycosyltransferases (SGTs) are ubiquitous but one of the most diverse group of enzymes of glycosyltransferases family. Members of this family modulate physical and chemical properties of secondary plant products important for various physiological processes. The role of SGTs has been demonstrated in the biosynthesis of pharmaceutically important molecules of medicinal plants like Withania somnifera.Results
Analysis suggested conserved behaviour and high similarity in active sites of WsSGTs with other plant GTs. Substrate specificity of WsSGTs were analysed through docking performance of WsSGTs with different substrates (sterols and withanolides). Best docking results of WsSGTL1 in the form of stable enzyme-substrate complex having lowest binding energies were obtained with brassicasterol, transandrosteron and WsSGTL4 with solasodine, stigmasterol and 24-methylene cholesterol.Conclusion
This study reveals topological characters and conserved nature of two SGTs from W. somnifera (WsSGTs) i.e. WsSGTL1 and WsSGTL4. However, besides being ubiquitous in nature and with broad substrate specificity, difference between WsSGTL1 and WsSGTL4 is briefly described by difference in stability (binding energy) of enzyme-substrate complexes through comparative docking.Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0563-7) contains supplementary material, which is available to authorized users. 相似文献110.
Nepali K Agarwal A Sapra S Mittal V Kumar R Banerjee UC Gupta MK Satti NK Suri OP Dhar KL 《Bioorganic & medicinal chemistry》2011,19(18):5569-5576
A series of forty two N-(1,3-diaryl-3-oxopropyl)amides were synthesized via an efficient, modified Dakin-West reaction and were evaluated for in vitro xanthine oxidase inhibitory activity for the first time. Structure-activity relationship analyses have been presented. Selected active xanthine oxidase inhibitors (3r, 3s, and 3zh) were assessed in vivo to study their anti-hyperuricemic effect in potassium oxonate induced hyperuricemic mice model. Compound 3s emerged as the most potent xanthine oxidase inhibitor (IC(50)=2.45 μM) as well as the most potent anti-hyperuricemic agent. The basis of significant inhibition of xanthine oxidase by 3s was rationalized by its molecular docking into catalytic site of xanthine oxidase. 相似文献