Department of Pharmacy
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Item Epigenetic mechanisms in Alzheimer's Disease: Therapeutic potential of Class specific HDAC inhibitors in insulin resistance induced cognitive impairments(JSTAGE, 2018) Taliyan, RajeevNumerous epidemiological studies have demonstrated that insulin resistance contributes to Alzheimer's disease (AD) pathogenesis. However the molecular mechanisms is still remain elusive but various studies have highlighted the epigenetic alterations and involvement of histone deacetylases (HDACs) in insulin resistance and cognitive deficits. In our previous study, we have explored the potential of pan HDAC inhibitor, SAHA, in high fat diet induced insulin resistance. In the present study, we have investigated the potential of isoform specific HDAC inhibitors in insulin resistance induced cognitive impairment in mice. Methods: Mice were subjected to either normal pellet diet (NPD) or high fat diet (HFD) for 8 weeks. HFD fed mice were treated with Class I specific HDAC inhibitor, CI-994 or Class II specific HDAC inhibitor, MC-1568 once daily for 2 weeks. Serum insulin, glucose, triglycerides, total cholesterol and HDL-cholesterol levels were measured. A battery of behavioural parameters was performed to assess cognitive functions. Results: HFD fed mice exhibit characteristic features of insulin resistance, showed a severe deficit in learning and memory. HFD feeding results in significant increase in Amyloid beta1-42 levels as compared with NPD fed mice In contrast, the mice treated with MC-1568 showed significant improvement in insulin resistance condition, marked decrease in Amyloid beta1-42 and significantly ameliorate the HFD induced decrease in BDNF and CREB level as compared to HFD group. Whereas, the mice treated with Class I HDAC inhibitor, CI-994 failed to show any improvement in insulin resistance and cognitive deficits. Conclusion: Based upon these results, it could be suggested that Class II HDAC inhibitors exert better neuroprotective effects as compared to Class I HDAC inhibitors associated with insulin resistant condition.Item GaN HEMT based Biosensor for Low-Level Detection of Interferon-Gamma (IFN-γ)(2019) Taliyan, RajeevThis paper reports on the detection of a very small quantity (ng/ml) of circulatory biomarker Interferon- gamma (IFN-y) using highly sensitive Gallium Nitride (GaN) High Electron Mobility Transistor (HEMT) based biosensor. To the best of our knowledge, no prior work reports on the detection of this much low concentration of IFN-y using HEMT. Interferon-gamma (IFN-y) is a cytokine which is involved in the generation of immunological responses. A response to IFN-y is mediated by IFN-y Receptor (IFN-yR), a cell surface receptor that activates downstream signals to regulate gene expression. It is a predictive circulatory biomarker in ovarian carcinoma [1], mycobacterial infection, rheumatoid arthritis [2] and traumatic brain injury. Low-level detection of this biomarker is important to detect the early stage of the disease. The early— detection of the rise in biomarkers could help physicians prevent, or at least reduce, the extent of potential damage. Therefore, in the context of current status, this work is of great importance for early stage detection and management of the disease by detecting the low quantity of this biomarker using an efficient GaN-based HEMT biosensor. A GaN I-IEMT based Biosensor is designed and fabricated on a Sapphire substrate with a gate length of 5 µm and a gate width of 100 µm. The sensor is passivated using silicon Nitride-based dielectric film except an opening over the gate for biosensing application. Figure 1 shows the designed and fabricated HEMT biosensor. The bio-active GaN HEMT has been developed by incubating various concentrations (Sample A; 1:100 and B; 1:200) of IFN-y antibody over the surface functionalized GaN HEMT device for 24 hours. The non-specific binding site on the device has been blocked with blocking reagent after the device gets coated with antibody. The developed device is further stored at 4°C until it proceeds for detection of IFN-y antigen in the ng/ml range. Change in the drain current (6) is measured with respect to the drain voltage (Vds) for each test related to antibody dilution and antigen. Sample A (1:100) delivered the best results and showed a 74 % reduction in the Ids. Figure 2 shows the change in the I& after drop casting antigen in a very low concentration of 1 ng/ml on the sensor surface.Item High fat diet feeding exacerbates the toxic effects of 6-hydroxydopamine in rats: Possible involvement of histone acetylation(Elsevier, 2016-01) Taliyan, RajeevClinical evidence has shown a correlation between Parkinson's disease (PD) and type 2 diabetes, as abnormal glucose tolerance has been reported in >50% of PD patients. Recently, insulin resistance was found to be present in 62% of PD patients with dementia, of whom 30% were glucose intolerant [1]. However, the underlying pathways are still elusive. Therefore, the present study was designed to explore the effect of insulin resistance on striatal dopaminergic neurons in an animal model of PD.Item [P2–130]: AR-A014418, A GSK-3β INHIBITOR, ATTENUATES ALZHEIMER'S- LIKE PATHOLOGY IN HIGH FAT DIET-INDUCED COGNITIVE DEFICIT IN MICE(Wiley, 2017-07) Taliyan, RajeevAlzheimer's disease (AD) is characterized by the progressive deposition of fibrillar amyloid-β (Aβ) in the form of extracellular plaques and hyperphosphorylated tau as intraneuronal neuro fibrillary tangles (NFTs). Studies have reported that increased Glycogen synthase kinase-3β (GSK-3β) activity has been associated with hyper phosphorylation of tau. However, the molecular mechanisms of association still remain elusive. Thus, the present study was designed to explore the potential of GSK-3β inhibitor, AR-A014418 in high fat diet (HFD) induced cognitive impairment and AD like pathology.Item Histone deacetylase inhibitor, Valproic acid, ameliorates insulin resistance induced cognitive deficit in mice(Elsevier, 2017-10) Taliyan, RajeevInsulin resistance has been reported as a strong risk factor for Alzheimer’s disease (AD). However the molecular mechanisms of association between these still remain elusive. Recently, elevated level of histone deacetylases (HDACs) and reduced histone acetylation has been reported in AD patients.Thus, targeting HDACs could provide a novel therapeutic strategy for treating these co-morbid condition.Item Possible mechanism of hyperglycemia induced decrease in antinociceptive effect of analgesics in rats(IJPSR, 2010-04) Taliyan, RajeevDiabetes induced neuropathic pain is recognized as one of the most difficult pain to treat and conventional analgesic are well known to be partially effective or ineffective. Non-steroidal anti-inflammatory drugs and opioids are effective antinociceptive drugs, however, their antinociceptive activity decreased in diabetic neuropathy. The study was designed to investigate the mechanism of diabetes induced decrease in the antinociceptive effect of analgesics in rats. Streptozotocin (STZ) (20 mg/kg, i. p. 4 days) was administered to induce experimental diabetes in the rats. One week after the administration of STZ, the tail-flick and paw withdrawal test was performed. Spleen homogenate supernatant (SHS) was prepared from spleen of 28th day diabetic rats and administered to normal rats (400 μl, i. v.) for 28 days. Thermal hyperalgesia was noted in both diabetic and SHS (400 μl, i. v.) treated non-diabetic rats. Moreover, analgesic effect of morphine (8mg/kg, s.c.), lysine acetylsalicylic acid (400mg/kg i. v) and indomethacin (10 mg/kg, i. p.) was progressively decrease in diabetic and SHS of 28 day diabetic treated non diabetic rats. However, analgesic effect of morphine (8mg/kg s. c.), lysine acetylsalicylic acid (400mg/kg i.v) and indomethacin (10 mg/kg, i. p.) were improved in splenctomised diabetic rat. Administration of Cyclosporine (25 mg/kg, i.p), an IL-2 inhibitor, attenuated diabetes and SHS induced decrease in nociceptive threshold. It is concluded that spleen derived factor (s) and cytokines may be responsible for the observed decrease in antinociceptive effect of analgesics in diabetic rats.Item Development of GaN HEMTs based biosensor(Springer, 2019-02) Taliyan, RajeevIn this paper, we report on the development of GaN HEMTs for sensing/biosensing applications. Various process steps are optimized at each stages for the development of device. Device shows the 0.5 A/mm drain current, 160 ms/mm transconductance and −4.2 V pinch of voltage for 50 µm Lsd. Devices are packaged for the detection of salt and BPA. Various molar solutions of salt are tested on gateless devices and surprisingly, it is able to detect even the femto molar level of salt. As endocrine disruptors, BPA (Bisphenol A) is tested on gated devices which shows change of about 760 µA in drain current.Item Diabetic Neuropathic Pain: An Update and Novel Pharmacological Strategies for Relief of Pain(Science Alert, 2010) Taliyan, RajeevDiabetic neuropathy is one of the most painful complications of diabetes mellitus, involving progressive neuronal damage and dysfunction and up to 30% of patients with diabetes mellitus developed diabetic neuropathy. Pain caused by diabetic neuropathy is debilitating and often is refractory to classical analgesic, including morphine. The mechanisms underlying cause of diabetic neuropathic pain are complex and both peripheral and central components of the sensory systems are reported to be involved in progression and maintenance of neuropathy. This study summarises data on pathogenesis and on existing and new analgesics such as NSAIDS, opioids, anti-epileptic, membrane stabilising and anti-depressant drugs, that are the mainstay of treatment for alleviating diabetic neuropathic pain. In addition, novel pharmacological approaches and strategies for analgesics such as use of drug combination and their implications will be discussed.Item Beneficial Effect of Cyclosporine in Experimental Diabetes Induced Neuropathic Pain in Rats(Science Alert, 2010) Taliyan, RajeevThe present study was designed to investigate the effect of cyclosporine on hyperglycemia induced decrease antinociceptive effect of morphine in rats. Streptozotocin (STZ) (50 mg kg-1, i.p., once) was administered to induce experimental diabetes in the rats. Pain sensitivity was measured using tail-flick and paw withdrawal test. Urinary and serum nitrite concentration was estimated using Greiss reagent. Spleen Homogenate Supernatant (SHS) was prepared from spleen of 28th day diabetic rats and administered to normal rats (400 μL. i.v.) for 28 days. Experimental diabetes significantly decreased paw withdrawal latency to thermal stimuli on day 28 as compared to age matched control rats, indicating that diabetic rats exhibit thermal hyperalgesia. Moreover, analgesic effect of morphine (4 and 8 mg kg-1 s.c.), was progressively decreased in diabetic and SHS treated non diabetic rats. Further, the levels of nitric oxide were also elevated in 28th day diabetic and SHS treated non diabetic rats. However, administration of Cyclosporine (12.5 and 25 mg kg-1 i.p.), an IL-2 inhibitor and splenectomy attenuated diabetes and SHS induced decrease in nociceptive threshold and increase in serum and urinary nitrite levels. It is concluded that cyclosporine have beneficial effect in diabetic neuropathy and also improved the analgesic effect of morphine.Item Effect of pioglitazone on the abrogated cardioprotective effect of ischemic preconditioning in hyperlipidemic rat heart(Medknow, 2016) Taliyan, RajeevThe signaling pathways upstream of glycogen synthase kinase-3β (GSK-3β) get reduced during ischemic preconditioning (IPC) in hyperlipidemic rat heart. Pioglitazone, an insulin sensitizer, exerts cardioprotection through GSK-3β. The objective of the study is to investigate the role of pioglitazone on the attenuated cardioprotective effect of IPC in hyperlipidemic rat heart.