Aditya Sunkaria - Academia.edu (original) (raw)

Papers by Aditya Sunkaria

Neurochemical Research, 2022

Poor quality and quantity of sleep are very common in elderly people throughout the world. Growin... more Poor quality and quantity of sleep are very common in elderly people throughout the world. Growing evidence has suggested that sleep disturbances could accelerate the process of neurodegeneration. Recent reports have shown a positive correlation between sleep deprivation and amyloid-β (Aβ)/tau aggregation in the brain of Alzheimer's patients. Glial cells have long been implicated in the progression of Alzheimer's disease (AD) and recent findings have also suggested their role in regulating sleep homeostasis. However, how glial cells control the sleep-wake balance and exactly how disturbed sleep may act as a trigger for Alzheimer's or other neurological disorders have recently gotten attention. In an attempt to connect the dots, the present review has highlighted the role of glia-derived sleep regulatory molecules in AD pathogenesis. Role of glia in sleep disturbance and Alzheimer's progression.

Cellular and Molecular Neurobiology, 2020

Hyperglycemia is one of the major risk factors responsible for memory impairment in diabetes whic... more Hyperglycemia is one of the major risk factors responsible for memory impairment in diabetes which may lead to Alzheimer’s disease (AD) at a later stage. MicroRNAs are a class of non-coding RNAs that are found to play a role in diabetes. Downregulation of microRNA-29b in diabetes is well reported. Moreover, microRNA-29b is also reported to target the 3′ UTR of β-secretase (BACE-1) enzyme which is involved in the formation of amyloid-beta (Aβ) in AD via cleavage of amyloid precursor protein (APP). Therefore, the present study was designed to elucidate whether microRNA-29b could be a link between diabetes and dementia. In the in vitro and in vivo diabetic model, we found downregulation of microRNA-29b due to hyperglycemia. After human microRNA-29b treatment, there was a significant improvement in the short-term and spatial memory in diabetic mice. Also, the human microRNA-29b treatment decreased oxidative stress and BACE-1 activity in diabetes. The present findings revealed that the downregulation of microRNA-29b in diabetes could be associated with memory impairment and increased BACE-1 activity. These results would give a future direction to study the role played by microRNAs in diabetes-associated memory impairment and hence aid in the development of therapeutics to treat the same.

Neuroscience, 2020

Microglia are the brain mononuclear phagocytes which plays a key role in neurodegenerative diseas... more Microglia are the brain mononuclear phagocytes which plays a key role in neurodegenerative diseases, like Alzheimer's. Till date, microglia have been explored mostly for their neuro-inflammatory functions. Recent studies have shifted their focus towards less explored functions which involve non-autonomous clearance of protein aggregates. However, these functions are significantly affected by aging and neurodegeneration. In Alzheimer's disease (AD), microglia have been reported to clear Aβ deposits via phagocytosis or release various pro-inflammatory cytokines. Whether microglia could be beneficial or detrimental to the brain, it all depends upon the type and strength of stimulus. So, if their beneficial properties could be selectively harnessed without activating pro-inflammatory response, a potential therapeutic strategy could be developed to check the formation of protein aggregates like Aβ. In the present study, we have checked the effect of toxic Aβ oligomers (Aβo) on the microglial phagocytic activity. Our findings revealed that at lower concentrations, Aβo are not toxic to the cells and they can survive even with longer exposures but with decreased phagocytic activity. However, at higher concentrations Aβo become toxic and resulted in modulation of various genes which regulates microglial phagocytic activity. Sulforaphane (SFN) has shown to attenuate the effect of low dose Aβo exposure and also slightly enhance the phagocytic activity. In addition, low dose Aβo and SFN treatment have not shown modulation in the levels of pro-inflammatory mediators of microglia. Taken together, these findings suggest that SFN treatment may ameliorate the Aβo mediated decrease in microglial phagocytic activity.

Drug Development Research, 2019

Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting milli... more Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting millions of people worldwide. Diabetes is associated with various complications like nephropathy, neuropathy, retinopathy, diabetic foot, cognitive impairment, and many more. Evidence suggests that cognitive dysfunction is a rising complication of diabetes which adversely affects the brain of patients suffering from diabetes. Age-related memory impairment is a complication having its major effect on people suffering from diabetes and Alzheimer's. Patients suffering from diabetes are at two times higher risk of developing cognitive dysfunction as compared with normal individuals. Multiple factors which are involved in diabetes related complications are found to play a role in the development of neurodegeneration in Alzheimer's. The problem of insulin deficiency and insulin resistance is well reported in diabetes but there are many studies which suggest dysregulation of insulin levels as a reason behind the development of Alzheimer's. As the link between diabetes and Alzheimer disease (AD) is deepening, there is a need to understand the plausible tie-ins between the two. Emerging role of major factors like insulin imbalance, advanced glycation end products and micro-RNA's involved in diabetes and Alzheimer's have been discussed here. This review helps in understanding the plausible mechanism underlying the pathophysiology of amyloid beta (Aβ) plaque formation and tau hyperphosphorylation as well provides information about studies carried out in this area of research. The final thought is to enhance the scientific knowledge on this correlation and develop future therapeutics to treat the same.

Current Pharmaceutical Design, 2019

Cancer hallmarks help in understanding the diversity of various neoplasms. Epithelial cancers pla... more Cancer hallmarks help in understanding the diversity of various neoplasms. Epithelial cancers play an immense role in the tumor biology through Epithelial-Mesenchymal Transition (EMT) process. Receptor tyrosine kinase, as well as phosphatidyl ionositol-3 kinase pathways, play an important role in the regulation of cell proliferation, survival, and differentiation during EMT. Till date, numerous studies have shown modulation in the expression profile of potential targets like CD44, EGFR, and Rac in epithelial cancers. CD44 interacts with EGFR and recruits other molecules which further activate the Rac pathway intermediates. This review mainly focused on modulation of genes like CD44, EGFR, and Rac pathway intermediates which play a crucial role in the tumor progression, metastasis, proliferation, and invasion characteristics in epithelial cancers with EMT properties. Hence, targeting Rac pathway might be a more strategically relevant approach in treating epithelial cancers.

ACS Chemical Neuroscience, 2019

Ever increasing incidence of Alzheimer's diseases (AD) has been reported all over the globe and p... more Ever increasing incidence of Alzheimer's diseases (AD) has been reported all over the globe and practically no drug is currently available for its treatment. Since last 15 years, not a single drug came out of clinical trials. The researchers are yet to discover a drug that could specifically target AD, in fact the drugs that are about to launch in the global market either belongs to natural compounds or are already approved drugs targeting other diseases. So, we need to shift our focus on finding novel targets which are more specific and could either detect or inhibit the disease progression at very early stage. Microglia are the only resident innate immune cells of the brain that are originated from erythromyeloid progenitors. They migrate to the brain during early embryonic development, although their number is less (~ 5 to 10%) but they could act as guardians of the brain. It has been shown that the extracellular deposits of Aβ continuously phagocytosed by microglia in healthy individuals, but this ability would decrease with the age and lead to development of AD. In this review, we have explored the possibility whether microglial cells could be utilized as an early predictor of the AD progression. Here, we have discussed about innate immune response of microglial cells, the factors affecting microglia response, microglial receptors to which Aβ could bind, and microglial phenotype markers. Lastly, we concluded with the list of available AD therapeutics along with their mechanism.

Metabolic Brain Disease, 2017

Perturbations in the cerebral energy metabolism are anticipated to be an important factor by whic... more Perturbations in the cerebral energy metabolism are anticipated to be an important factor by which ammonia may exert its toxic effects on the central nervous system. The present study was designed to investigate the role of impaired mitochondrial functions and cerebral energy metabolism in the development hepatic encephalopathy (HE) induced by of bile duct ligation (BDL). After four weeks of BDL, a significant increase in hepatic hydroxyproline and collagen content was observed which confirmed biliary fibrosis. Brain regions viz. cortex, hippocampus, striatum and cerebellum of BDL rats had impaired activity of mitochondrial respiratory chain enzymes. This was accompanied by increase in mitochondrial reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl levels in the brain. Mitochondrial redox ratio was significantly reduced in the brain of BDL rats. In addition, mitochondria from brain of BDL rats were depolarized and swollen compared to the sham controls. Ultrastructure analysis of mitochondria from cortex and hippocampus of BDL animals revealed aberrant cristae, ruptured membranes and non-dense matrix. Further, a significant decrease was observed in creatine kinase activity, glucose uptake and CO 2 production in the brain regions of BDL rats. ATP/ADP ratio, a critical parameter of cellular energy status, was also significantly reduced in brain regions of rats with HE. Overall, the findings clearly demonstrate that BDL induced HE involves mitochondrial respiratory chain dysfunctions, mitochondrial depolarization and swelling that accentuates oxidative stress which in turn leads to compromise in cerebral energy metabolism thereby contributing to the pathophysiology of chronic HE.

Brain, behavior, and immunity, 2018

Chronic liver disease per se induces neuroinflammation that contributes to cognitive deficits in ... more Chronic liver disease per se induces neuroinflammation that contributes to cognitive deficits in hepatic encephalopathy (HE). However, the processes by which pro-inflammatory molecules result in cognitive impairment still remains unclear. In the present study, a significant increase in the activity of liver function enzymes viz. alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) was observed along with increase in plasma ammonia levels after four weeks of bile duct ligation (BDL) in rats suggesting hepatocellular damage. A significant increase was observed in mRNA expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) in brain regions and liver of BDL rats. Concomitantly, IL-6, TNF-α and MCP-1 protein levels were also increased in brain regions, liver and serum of BDL rats suggesting the involvement of blood-brain-axis in inflammatory response. However, a significant decrease was obs...

Neuroscience, Jan 26, 2017

Ubiquitin-proteasome system (UPS) has emerged as major molecular mechanism which modulates synapt... more Ubiquitin-proteasome system (UPS) has emerged as major molecular mechanism which modulates synaptic plasticity. However, very little is known about what happens if this system fails during postnatal brain development. In the present study, MG132 was administered intracerebroventricularly in BALB/c mice pups at postnatal day one (P1), a very crucial period for synaptogenesis. Both 20S proteasome and calpain activities were found to be reduced in the mid brain of MG132-administered pups after 24 h. Mice (P40) which received MG132 on P1 were subjected to Morris water maze (MWM) training. Analysis showed spatial learning and memory of MG132 mice was significantly impaired when compared to age-matched controls. Hematoxylin and eosin as well as Cresyl Violet staining revealed substantial loss of cellular connections, distorted architecture and increased pyknosis in hippocampal CA1 and CA3 regions of MG132 mice. Immunohistochemical analysis of MG132 mice showed increased accumulation of in...

The Journal of nutritional biochemistry, 2018

Proteasomes are known to degrade proteins involved in various processes like metabolism, signal t... more Proteasomes are known to degrade proteins involved in various processes like metabolism, signal transduction, cell-cycle regulation, inflammation, and apoptosis. Evidence showed that protein degradation has a strong influence on developing neurons as well as synaptic plasticity. Here, we have shown that sulforaphane (SFN) could prevent the deleterious effects of postnatal proteasomal inhibition on spatial reference and working memory of adult mice. One day old Balb/c mice received intracerebroventricular injections of MG132 and SFN. Sham received an equal volume of aCSF. We observed that SFN pre-administration could attenuate MG132 mediated decrease in proteasome and calpain activities. In vitro findings revealed that SFN could induce proteasomal activity by enhancing the expression of catalytic subunit-β5. SFN pre-administration prevented the hippocampus based spatial memory impairments during adulthood, mediated by postnatal MG132 exposure. Histological examination showed deleteri...

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2017

Mitochondria are vital organelles involved in numerous cellular functions ranging from energy met... more Mitochondria are vital organelles involved in numerous cellular functions ranging from energy metabolism to cell survival. Emerging evidence suggests that mitochondria provide a platform for signaling pathways involved in innate immune response. Mitochondrial ROS (mtROS) production, mitochondrial DNA (mtDNA) release, mitochondrial antiviral signaling protein (MAVS) are key triggers in the activation of innate immune response following variety of stress signals that include infection, tissue damage and metabolic dysregulation. The process is mediated through pattern recognition receptors (PRRs) that consist of retinoic acid inducible gene like receptors (RLRs), c-type lectin receptors (CLRs), toll type receptors (TLRs) and nuclear oligomerization-domain like receptors (NLRs). These signals converge to form a multiprotein complex called inflammasome that leads to caspase-1 activation to promote processing of precursor cytokines (pro-IL1β and pro-IL-18) to active cytokines (IL-1β and IL-18). It appears that mitochondria induced inflammasome activation contributes to inflammatory process in many diverse disorders. Therefore, strategies aimed at modulating mitochondria mediated inflammasome activation might be beneficial in many pathophysiological conditions. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2017

In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic n... more In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G 0 /G 1 phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.

Neurotoxicology, Jan 19, 2015

The present investigation was carried out to elucidate a possible molecular mechanism related to ... more The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of PGC-1α and its downstream targets i.e. NRF-1, NRF-2 and Tfam in mitochondrial biogenesis. Aluminium lactate (10mg/kg b.wt/day) was administered intragastrically to rats, which were pre-treated with quercetin 6h before aluminium (10mg/kg b.wt/day, intragastrically) for 12 weeks. We found a decrease in ROS levels, mitochondrial DNA oxidation and Citrate synthase activity in the Hippocampus (HC) and Corpus striatum (CS) regions of rat brain treated with quercetin. Besides this an increase in the mRNA levels of the mitochondrial encoded subunits- ND1, ND2, ND3, Cytb, COX1, COX3 and ATPase6 along with increased expression of nuclear encoded subunits COX4, COX5A and COX5B of Electron transport chain (ETC). In que...

Neurochemistry International, 2015

Oxidative stress has for long been linked to the neuronal cell death in many neurodegenerative co... more Oxidative stress has for long been linked to the neuronal cell death in many neurodegenerative conditions. Conventional antioxidant therapies have been less effective in preventing neuronal damage caused by oxidative stress due to their inability to cross the blood brain barrier. Nanoparticle antioxidants constitute a new wave of antioxidant therapies for prevention and treatment of diseases involving oxidative stress. It is believed that nanoparticle antioxidants will have strong and persistent interactions with biomolecules would be more effective against free radical induced damage. Nanoantioxidants include inorganic nanoparticles possessing intrinsic antioxidant properties, nanoparticles functionalized with antioxidants or antioxidant enzymes to function as an antioxidant delivery system. Nanoparticles containing antioxidants have shown promise as highperformance therapeutic nanomedicine in attenuating oxidative stress with potential applications in treating and preventing neurodegenerative conditions. However, to realize the full potential of nanoantioxidants, negative aspects associated with the use of nanoparticles need to be overcome to validate their long term applications.

Journal of biomolecular structure & dynamics, Jan 25, 2015

Glyoxalase-I (GLO-I) is a component of the ubiquitous detoxification system involved in conversio... more Glyoxalase-I (GLO-I) is a component of the ubiquitous detoxification system involved in conversion of methylglyoxal (MG) to D-lactate in the glycolytic pathway. MG toxicity arises from its ability to form advanced glycation end products (AGEs). GLO-I has been reported to be frequently overexpressed in various types of cancer cells. In this study, we performed structure based virtual screening of focussed flavonoids commercial library to identify potential and specific inhibitors of GLO-I. The compounds were ranked based on Glide extra precision docking score and five hits (curcumin, quercetin, morin, naringin and silibinin) were selected on the basis of their interaction with active site amino acid residues of GLO-I. Mixed mode QM/MM calculation was performed on the top scoring hit to ascertain the role of zinc ion in ligand binding. In addition the identified hits were subjected to MM/GBSA binding energy prediction, ADME prediction and similarity studies. The hits were tested in vi...

International Journal of Nanomedicine, 2012

Background: Excessive generation of radical oxygen species (ROS) is a contributor to skin patholo... more Background: Excessive generation of radical oxygen species (ROS) is a contributor to skin pathologies. Resveratrol (RSV) is a potent antioxidant. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can ensure close contact and increase the amount of drug absorbed into the skin. In this study, RSV was loaded into SLN and NLC for dermal applications. Methods: Nanoparticles were prepared by high shear homogenization using Compritol 888ATO, Myglyol, Poloxamer188, and Tween80. Particle size (PS), polydispersity index (PI), zeta potential (ZP), drug entrapment efficiency (EE), and production yield were determined. Differential scanning calorimetry (DSC) analysis and morphological transmission electron microscopy (TEM) examination were conducted. RSV concentration was optimized with cytotoxicity studies, and net intracellular accumulation of ROS was monitored with cytofluorimetry. The amount of RSV was determined from different layers of rat abdominal skin. Results: PS of uniform RSV-SLN and RSV-NLC were determined as 287.2 nm ± 5.1 and 110.5 nm ± 1.3, respectively. ZP was −15.3 mV ± 0.4 and −13.8 mV ± 0.1 in the same order. The drug EE was 18% higher in NLC systems. TEM studies showed that the drug in the shell model was relevant for SLN, and that the melting point of the lipid in NLC was slightly lower. Concentrations below 50 µM were determined as suitable RSV concentrations for both SLN and NLC in cell culture studies. RSV-NLC showed less fluorescence, indicating less ROS production in cytofluorometric studies. Ex vivo skin studies revealed that NLC are more efficient in carrying RSV to the epidermis. Conclusion: This study suggests that both of the lipid nanoparticles had antioxidant properties at a concentration of 50 µM. When the two systems were compared, NLC penetrated deeper into the skin. RSV-loaded NLC with smaller PS and higher drug loading appears to be superior to SLN for dermal applications.

ACS Chemical Neuroscience, 2014

Microglial cells have been implicated in various neurodegenerative diseases. Previous studies fro... more Microglial cells have been implicated in various neurodegenerative diseases. Previous studies from our lab have shown that dichlorvos (an organophosphate) could induce Parkinson's like features in rats. Recently, we have shown that dichlorvos can induce microglial activation, and if not checked in time could ultimately induce neuronal apoptosis. However, this activation does not always pose a threat to the neurons. Activated microglia also secrete various neuronal growth factors, suggesting that they have beneficial roles in CNS repair. Therefore, it is essential to control their detrimental functions selectively. Here, we tried to find out how microglial cells behave when exposed to dichlorvos in either the presence or absence of potent nitric oxide scavenger and superoxide dismutase mimetic, 4-hydroxy TEMPO (4-HT). Wistar rat pups (1 day) were used to isolate and culture primary microglial cells. We found 4-HT pretreatment successfully attenuated the dichlorvos mediated microglial activation. Moreover, 4-HT pretreatment decreased the up-regulated levels of p53 and its downstream effector, p21. The expression of various cell cycle regulators such as Chk2, CDC25a, and cyclin A remained close to their basal levels when 4-HT pretreatment was given. DNA fragmentation analysis showed significant reduction in the DNA damage of 4-HT pretreated microglia as compared to dichlorvos treated cells. In addition to this, we found 4-HT pretreatment prevented the microglial cells from undergoing apoptotic cell death even after 48 h of dichlorvos exposure. Taken together, our results showed 4-HT pretreatment could successfully ameliorate the dichlorvos induced microglial cell damage.

Synapse, 2015

Mitochondrial dysfunctions have been implicated in the progression of Huntington's disease (HD). ... more Mitochondrial dysfunctions have been implicated in the progression of Huntington's disease (HD). To date, several free radical scavengers have been tested in experimental HD, but only a few have shown promise. Although most antioxidants rapidly reduce ROS but in the process they are oxidized, which limits their ability to protect. Therefore, in the present study we employed a potent recycling antioxidant, 4-hydroxy tempo (4-HT), because it can reinstate its reduced state even after its oxidation during scavenging of ROS. Female Wistar rats were administered 3-nitropropionic acid (3-NP) and/or 4-HT for 21 days, after which animals were subjected to biochemical and behavioral assessments. Our results showed that 4-HT treatment significantly attenuated the 3-NP induced decrease in the activities of mitochondrial electron transport chain enzymes. In addition, 4-HT administration restored the increased nitrite and lipid peroxidation levels. Apart from this, 4-HT also attenuated the 3-NP induced decrease in superoxide dismutase and catalase activities. Further, 4-HT administration resulted in significant improvement in 3-NP induced cognitive and motor impairments. Taken together, the results of the study demonstrate that 4-HT is beneficial in 3-NP induced model of HD and thus could be a potential therapeutic agent in management of this disease.

Indian journal of experimental biology, 2010

The present study was designed to analyze the effect of acute aluminium phosphide (ALP) (10 mg/kg... more The present study was designed to analyze the effect of acute aluminium phosphide (ALP) (10 mg/kg body wt.) exposure on the glucose homeostasis in rat liver and brain. ALP has been implicated in the inhibition of cytochrome oxidase causing reduced oxygen uptake and decreased ATP synthesis eventually resulting in cellular energy crisis. A significant decrease in plasma glucose levels in the ALP treated rats has been observed. Therefore, decreased ATP levels coupled with hypoglycemia may further intensify the cellular energy deficits. In order to meet the sudden increase in the local energy demand, the brain tissue utilizes its stored energy in the form of glycogen breakdown as observed by a decrease in the glycogen levels in both liver and brain which was accompanied by a marked increase in the activity of glycogen phosphorylase in both the tissues. The glycolytic rate was found to be enhanced in brain tissue as evident by increased activities of hexokinase and phosphofructokinase en...

Neurochemical Research, 2022

Poor quality and quantity of sleep are very common in elderly people throughout the world. Growin... more Poor quality and quantity of sleep are very common in elderly people throughout the world. Growing evidence has suggested that sleep disturbances could accelerate the process of neurodegeneration. Recent reports have shown a positive correlation between sleep deprivation and amyloid-β (Aβ)/tau aggregation in the brain of Alzheimer's patients. Glial cells have long been implicated in the progression of Alzheimer's disease (AD) and recent findings have also suggested their role in regulating sleep homeostasis. However, how glial cells control the sleep-wake balance and exactly how disturbed sleep may act as a trigger for Alzheimer's or other neurological disorders have recently gotten attention. In an attempt to connect the dots, the present review has highlighted the role of glia-derived sleep regulatory molecules in AD pathogenesis. Role of glia in sleep disturbance and Alzheimer's progression.

Cellular and Molecular Neurobiology, 2020

Hyperglycemia is one of the major risk factors responsible for memory impairment in diabetes whic... more Hyperglycemia is one of the major risk factors responsible for memory impairment in diabetes which may lead to Alzheimer’s disease (AD) at a later stage. MicroRNAs are a class of non-coding RNAs that are found to play a role in diabetes. Downregulation of microRNA-29b in diabetes is well reported. Moreover, microRNA-29b is also reported to target the 3′ UTR of β-secretase (BACE-1) enzyme which is involved in the formation of amyloid-beta (Aβ) in AD via cleavage of amyloid precursor protein (APP). Therefore, the present study was designed to elucidate whether microRNA-29b could be a link between diabetes and dementia. In the in vitro and in vivo diabetic model, we found downregulation of microRNA-29b due to hyperglycemia. After human microRNA-29b treatment, there was a significant improvement in the short-term and spatial memory in diabetic mice. Also, the human microRNA-29b treatment decreased oxidative stress and BACE-1 activity in diabetes. The present findings revealed that the downregulation of microRNA-29b in diabetes could be associated with memory impairment and increased BACE-1 activity. These results would give a future direction to study the role played by microRNAs in diabetes-associated memory impairment and hence aid in the development of therapeutics to treat the same.

Neuroscience, 2020

Microglia are the brain mononuclear phagocytes which plays a key role in neurodegenerative diseas... more Microglia are the brain mononuclear phagocytes which plays a key role in neurodegenerative diseases, like Alzheimer's. Till date, microglia have been explored mostly for their neuro-inflammatory functions. Recent studies have shifted their focus towards less explored functions which involve non-autonomous clearance of protein aggregates. However, these functions are significantly affected by aging and neurodegeneration. In Alzheimer's disease (AD), microglia have been reported to clear Aβ deposits via phagocytosis or release various pro-inflammatory cytokines. Whether microglia could be beneficial or detrimental to the brain, it all depends upon the type and strength of stimulus. So, if their beneficial properties could be selectively harnessed without activating pro-inflammatory response, a potential therapeutic strategy could be developed to check the formation of protein aggregates like Aβ. In the present study, we have checked the effect of toxic Aβ oligomers (Aβo) on the microglial phagocytic activity. Our findings revealed that at lower concentrations, Aβo are not toxic to the cells and they can survive even with longer exposures but with decreased phagocytic activity. However, at higher concentrations Aβo become toxic and resulted in modulation of various genes which regulates microglial phagocytic activity. Sulforaphane (SFN) has shown to attenuate the effect of low dose Aβo exposure and also slightly enhance the phagocytic activity. In addition, low dose Aβo and SFN treatment have not shown modulation in the levels of pro-inflammatory mediators of microglia. Taken together, these findings suggest that SFN treatment may ameliorate the Aβo mediated decrease in microglial phagocytic activity.

Drug Development Research, 2019

Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting milli... more Diabetes mellitus (DM) is a gradually rising metabolic disease which is currently affecting millions of people worldwide. Diabetes is associated with various complications like nephropathy, neuropathy, retinopathy, diabetic foot, cognitive impairment, and many more. Evidence suggests that cognitive dysfunction is a rising complication of diabetes which adversely affects the brain of patients suffering from diabetes. Age-related memory impairment is a complication having its major effect on people suffering from diabetes and Alzheimer's. Patients suffering from diabetes are at two times higher risk of developing cognitive dysfunction as compared with normal individuals. Multiple factors which are involved in diabetes related complications are found to play a role in the development of neurodegeneration in Alzheimer's. The problem of insulin deficiency and insulin resistance is well reported in diabetes but there are many studies which suggest dysregulation of insulin levels as a reason behind the development of Alzheimer's. As the link between diabetes and Alzheimer disease (AD) is deepening, there is a need to understand the plausible tie-ins between the two. Emerging role of major factors like insulin imbalance, advanced glycation end products and micro-RNA's involved in diabetes and Alzheimer's have been discussed here. This review helps in understanding the plausible mechanism underlying the pathophysiology of amyloid beta (Aβ) plaque formation and tau hyperphosphorylation as well provides information about studies carried out in this area of research. The final thought is to enhance the scientific knowledge on this correlation and develop future therapeutics to treat the same.

Current Pharmaceutical Design, 2019

Cancer hallmarks help in understanding the diversity of various neoplasms. Epithelial cancers pla... more Cancer hallmarks help in understanding the diversity of various neoplasms. Epithelial cancers play an immense role in the tumor biology through Epithelial-Mesenchymal Transition (EMT) process. Receptor tyrosine kinase, as well as phosphatidyl ionositol-3 kinase pathways, play an important role in the regulation of cell proliferation, survival, and differentiation during EMT. Till date, numerous studies have shown modulation in the expression profile of potential targets like CD44, EGFR, and Rac in epithelial cancers. CD44 interacts with EGFR and recruits other molecules which further activate the Rac pathway intermediates. This review mainly focused on modulation of genes like CD44, EGFR, and Rac pathway intermediates which play a crucial role in the tumor progression, metastasis, proliferation, and invasion characteristics in epithelial cancers with EMT properties. Hence, targeting Rac pathway might be a more strategically relevant approach in treating epithelial cancers.

ACS Chemical Neuroscience, 2019

Ever increasing incidence of Alzheimer's diseases (AD) has been reported all over the globe and p... more Ever increasing incidence of Alzheimer's diseases (AD) has been reported all over the globe and practically no drug is currently available for its treatment. Since last 15 years, not a single drug came out of clinical trials. The researchers are yet to discover a drug that could specifically target AD, in fact the drugs that are about to launch in the global market either belongs to natural compounds or are already approved drugs targeting other diseases. So, we need to shift our focus on finding novel targets which are more specific and could either detect or inhibit the disease progression at very early stage. Microglia are the only resident innate immune cells of the brain that are originated from erythromyeloid progenitors. They migrate to the brain during early embryonic development, although their number is less (~ 5 to 10%) but they could act as guardians of the brain. It has been shown that the extracellular deposits of Aβ continuously phagocytosed by microglia in healthy individuals, but this ability would decrease with the age and lead to development of AD. In this review, we have explored the possibility whether microglial cells could be utilized as an early predictor of the AD progression. Here, we have discussed about innate immune response of microglial cells, the factors affecting microglia response, microglial receptors to which Aβ could bind, and microglial phenotype markers. Lastly, we concluded with the list of available AD therapeutics along with their mechanism.

Metabolic Brain Disease, 2017

Perturbations in the cerebral energy metabolism are anticipated to be an important factor by whic... more Perturbations in the cerebral energy metabolism are anticipated to be an important factor by which ammonia may exert its toxic effects on the central nervous system. The present study was designed to investigate the role of impaired mitochondrial functions and cerebral energy metabolism in the development hepatic encephalopathy (HE) induced by of bile duct ligation (BDL). After four weeks of BDL, a significant increase in hepatic hydroxyproline and collagen content was observed which confirmed biliary fibrosis. Brain regions viz. cortex, hippocampus, striatum and cerebellum of BDL rats had impaired activity of mitochondrial respiratory chain enzymes. This was accompanied by increase in mitochondrial reactive oxygen species (ROS), malondialdehyde (MDA) and protein carbonyl levels in the brain. Mitochondrial redox ratio was significantly reduced in the brain of BDL rats. In addition, mitochondria from brain of BDL rats were depolarized and swollen compared to the sham controls. Ultrastructure analysis of mitochondria from cortex and hippocampus of BDL animals revealed aberrant cristae, ruptured membranes and non-dense matrix. Further, a significant decrease was observed in creatine kinase activity, glucose uptake and CO 2 production in the brain regions of BDL rats. ATP/ADP ratio, a critical parameter of cellular energy status, was also significantly reduced in brain regions of rats with HE. Overall, the findings clearly demonstrate that BDL induced HE involves mitochondrial respiratory chain dysfunctions, mitochondrial depolarization and swelling that accentuates oxidative stress which in turn leads to compromise in cerebral energy metabolism thereby contributing to the pathophysiology of chronic HE.

Brain, behavior, and immunity, 2018

Chronic liver disease per se induces neuroinflammation that contributes to cognitive deficits in ... more Chronic liver disease per se induces neuroinflammation that contributes to cognitive deficits in hepatic encephalopathy (HE). However, the processes by which pro-inflammatory molecules result in cognitive impairment still remains unclear. In the present study, a significant increase in the activity of liver function enzymes viz. alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) was observed along with increase in plasma ammonia levels after four weeks of bile duct ligation (BDL) in rats suggesting hepatocellular damage. A significant increase was observed in mRNA expression of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) in brain regions and liver of BDL rats. Concomitantly, IL-6, TNF-α and MCP-1 protein levels were also increased in brain regions, liver and serum of BDL rats suggesting the involvement of blood-brain-axis in inflammatory response. However, a significant decrease was obs...

Neuroscience, Jan 26, 2017

Ubiquitin-proteasome system (UPS) has emerged as major molecular mechanism which modulates synapt... more Ubiquitin-proteasome system (UPS) has emerged as major molecular mechanism which modulates synaptic plasticity. However, very little is known about what happens if this system fails during postnatal brain development. In the present study, MG132 was administered intracerebroventricularly in BALB/c mice pups at postnatal day one (P1), a very crucial period for synaptogenesis. Both 20S proteasome and calpain activities were found to be reduced in the mid brain of MG132-administered pups after 24 h. Mice (P40) which received MG132 on P1 were subjected to Morris water maze (MWM) training. Analysis showed spatial learning and memory of MG132 mice was significantly impaired when compared to age-matched controls. Hematoxylin and eosin as well as Cresyl Violet staining revealed substantial loss of cellular connections, distorted architecture and increased pyknosis in hippocampal CA1 and CA3 regions of MG132 mice. Immunohistochemical analysis of MG132 mice showed increased accumulation of in...

The Journal of nutritional biochemistry, 2018

Proteasomes are known to degrade proteins involved in various processes like metabolism, signal t... more Proteasomes are known to degrade proteins involved in various processes like metabolism, signal transduction, cell-cycle regulation, inflammation, and apoptosis. Evidence showed that protein degradation has a strong influence on developing neurons as well as synaptic plasticity. Here, we have shown that sulforaphane (SFN) could prevent the deleterious effects of postnatal proteasomal inhibition on spatial reference and working memory of adult mice. One day old Balb/c mice received intracerebroventricular injections of MG132 and SFN. Sham received an equal volume of aCSF. We observed that SFN pre-administration could attenuate MG132 mediated decrease in proteasome and calpain activities. In vitro findings revealed that SFN could induce proteasomal activity by enhancing the expression of catalytic subunit-β5. SFN pre-administration prevented the hippocampus based spatial memory impairments during adulthood, mediated by postnatal MG132 exposure. Histological examination showed deleteri...

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2017

Mitochondria are vital organelles involved in numerous cellular functions ranging from energy met... more Mitochondria are vital organelles involved in numerous cellular functions ranging from energy metabolism to cell survival. Emerging evidence suggests that mitochondria provide a platform for signaling pathways involved in innate immune response. Mitochondrial ROS (mtROS) production, mitochondrial DNA (mtDNA) release, mitochondrial antiviral signaling protein (MAVS) are key triggers in the activation of innate immune response following variety of stress signals that include infection, tissue damage and metabolic dysregulation. The process is mediated through pattern recognition receptors (PRRs) that consist of retinoic acid inducible gene like receptors (RLRs), c-type lectin receptors (CLRs), toll type receptors (TLRs) and nuclear oligomerization-domain like receptors (NLRs). These signals converge to form a multiprotein complex called inflammasome that leads to caspase-1 activation to promote processing of precursor cytokines (pro-IL1β and pro-IL-18) to active cytokines (IL-1β and IL-18). It appears that mitochondria induced inflammasome activation contributes to inflammatory process in many diverse disorders. Therefore, strategies aimed at modulating mitochondria mediated inflammasome activation might be beneficial in many pathophysiological conditions. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2017

In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic n... more In the previous study, we demonstrated that dichlorvos induces oxidative stress in dopaminergic neuronal cells and subsequent caspase activation mediates apoptosis. In the present study, we evaluated the effect and mechanism of dichlorvos induced oxidative stress on cell cycle activation in NGF-differentiated PC12 cells. Dichlorvos exposure resulted in oxidative DNA damage along with activation of cell cycle machinery in differentiated PC12 cells. Dichlorvos exposed cells exhibited an increased expression of p53, cyclin-D1, pRb and decreased expression of p21suggesting a re-entry of differentiated cells into the cell cycle. Cell cycle analysis of dichlorvos exposed cells revealed a reduction of cells in the G 0 /G 1 phase of the cell cycle (25%), and a concomitant increase of cells in S phase (30%) and G2/M phase (43.3%) compared to control PC12 cells. Further, immunoblotting of cytochrome c, Bax, Bcl-2 and cleaved caspase-3 revealed that dichlorvos induces a caspase-dependent cell death in PC12 cells. These results suggest that Dichlorvos exposure has the potential to generate oxidative stress which evokes activation of cell cycle machinery leading to apoptotic cell death via cytochrome c release from mitochondria and subsequent caspase-3 activation in differentiated PC12 cells.

Neurotoxicology, Jan 19, 2015

The present investigation was carried out to elucidate a possible molecular mechanism related to ... more The present investigation was carried out to elucidate a possible molecular mechanism related to the protective effect of quercetin administration against aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of PGC-1α and its downstream targets i.e. NRF-1, NRF-2 and Tfam in mitochondrial biogenesis. Aluminium lactate (10mg/kg b.wt/day) was administered intragastrically to rats, which were pre-treated with quercetin 6h before aluminium (10mg/kg b.wt/day, intragastrically) for 12 weeks. We found a decrease in ROS levels, mitochondrial DNA oxidation and Citrate synthase activity in the Hippocampus (HC) and Corpus striatum (CS) regions of rat brain treated with quercetin. Besides this an increase in the mRNA levels of the mitochondrial encoded subunits- ND1, ND2, ND3, Cytb, COX1, COX3 and ATPase6 along with increased expression of nuclear encoded subunits COX4, COX5A and COX5B of Electron transport chain (ETC). In que...

Neurochemistry International, 2015

Oxidative stress has for long been linked to the neuronal cell death in many neurodegenerative co... more Oxidative stress has for long been linked to the neuronal cell death in many neurodegenerative conditions. Conventional antioxidant therapies have been less effective in preventing neuronal damage caused by oxidative stress due to their inability to cross the blood brain barrier. Nanoparticle antioxidants constitute a new wave of antioxidant therapies for prevention and treatment of diseases involving oxidative stress. It is believed that nanoparticle antioxidants will have strong and persistent interactions with biomolecules would be more effective against free radical induced damage. Nanoantioxidants include inorganic nanoparticles possessing intrinsic antioxidant properties, nanoparticles functionalized with antioxidants or antioxidant enzymes to function as an antioxidant delivery system. Nanoparticles containing antioxidants have shown promise as highperformance therapeutic nanomedicine in attenuating oxidative stress with potential applications in treating and preventing neurodegenerative conditions. However, to realize the full potential of nanoantioxidants, negative aspects associated with the use of nanoparticles need to be overcome to validate their long term applications.

Journal of biomolecular structure & dynamics, Jan 25, 2015

Glyoxalase-I (GLO-I) is a component of the ubiquitous detoxification system involved in conversio... more Glyoxalase-I (GLO-I) is a component of the ubiquitous detoxification system involved in conversion of methylglyoxal (MG) to D-lactate in the glycolytic pathway. MG toxicity arises from its ability to form advanced glycation end products (AGEs). GLO-I has been reported to be frequently overexpressed in various types of cancer cells. In this study, we performed structure based virtual screening of focussed flavonoids commercial library to identify potential and specific inhibitors of GLO-I. The compounds were ranked based on Glide extra precision docking score and five hits (curcumin, quercetin, morin, naringin and silibinin) were selected on the basis of their interaction with active site amino acid residues of GLO-I. Mixed mode QM/MM calculation was performed on the top scoring hit to ascertain the role of zinc ion in ligand binding. In addition the identified hits were subjected to MM/GBSA binding energy prediction, ADME prediction and similarity studies. The hits were tested in vi...

International Journal of Nanomedicine, 2012

Background: Excessive generation of radical oxygen species (ROS) is a contributor to skin patholo... more Background: Excessive generation of radical oxygen species (ROS) is a contributor to skin pathologies. Resveratrol (RSV) is a potent antioxidant. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) can ensure close contact and increase the amount of drug absorbed into the skin. In this study, RSV was loaded into SLN and NLC for dermal applications. Methods: Nanoparticles were prepared by high shear homogenization using Compritol 888ATO, Myglyol, Poloxamer188, and Tween80. Particle size (PS), polydispersity index (PI), zeta potential (ZP), drug entrapment efficiency (EE), and production yield were determined. Differential scanning calorimetry (DSC) analysis and morphological transmission electron microscopy (TEM) examination were conducted. RSV concentration was optimized with cytotoxicity studies, and net intracellular accumulation of ROS was monitored with cytofluorimetry. The amount of RSV was determined from different layers of rat abdominal skin. Results: PS of uniform RSV-SLN and RSV-NLC were determined as 287.2 nm ± 5.1 and 110.5 nm ± 1.3, respectively. ZP was −15.3 mV ± 0.4 and −13.8 mV ± 0.1 in the same order. The drug EE was 18% higher in NLC systems. TEM studies showed that the drug in the shell model was relevant for SLN, and that the melting point of the lipid in NLC was slightly lower. Concentrations below 50 µM were determined as suitable RSV concentrations for both SLN and NLC in cell culture studies. RSV-NLC showed less fluorescence, indicating less ROS production in cytofluorometric studies. Ex vivo skin studies revealed that NLC are more efficient in carrying RSV to the epidermis. Conclusion: This study suggests that both of the lipid nanoparticles had antioxidant properties at a concentration of 50 µM. When the two systems were compared, NLC penetrated deeper into the skin. RSV-loaded NLC with smaller PS and higher drug loading appears to be superior to SLN for dermal applications.

ACS Chemical Neuroscience, 2014

Microglial cells have been implicated in various neurodegenerative diseases. Previous studies fro... more Microglial cells have been implicated in various neurodegenerative diseases. Previous studies from our lab have shown that dichlorvos (an organophosphate) could induce Parkinson's like features in rats. Recently, we have shown that dichlorvos can induce microglial activation, and if not checked in time could ultimately induce neuronal apoptosis. However, this activation does not always pose a threat to the neurons. Activated microglia also secrete various neuronal growth factors, suggesting that they have beneficial roles in CNS repair. Therefore, it is essential to control their detrimental functions selectively. Here, we tried to find out how microglial cells behave when exposed to dichlorvos in either the presence or absence of potent nitric oxide scavenger and superoxide dismutase mimetic, 4-hydroxy TEMPO (4-HT). Wistar rat pups (1 day) were used to isolate and culture primary microglial cells. We found 4-HT pretreatment successfully attenuated the dichlorvos mediated microglial activation. Moreover, 4-HT pretreatment decreased the up-regulated levels of p53 and its downstream effector, p21. The expression of various cell cycle regulators such as Chk2, CDC25a, and cyclin A remained close to their basal levels when 4-HT pretreatment was given. DNA fragmentation analysis showed significant reduction in the DNA damage of 4-HT pretreated microglia as compared to dichlorvos treated cells. In addition to this, we found 4-HT pretreatment prevented the microglial cells from undergoing apoptotic cell death even after 48 h of dichlorvos exposure. Taken together, our results showed 4-HT pretreatment could successfully ameliorate the dichlorvos induced microglial cell damage.

Synapse, 2015

Mitochondrial dysfunctions have been implicated in the progression of Huntington's disease (HD). ... more Mitochondrial dysfunctions have been implicated in the progression of Huntington's disease (HD). To date, several free radical scavengers have been tested in experimental HD, but only a few have shown promise. Although most antioxidants rapidly reduce ROS but in the process they are oxidized, which limits their ability to protect. Therefore, in the present study we employed a potent recycling antioxidant, 4-hydroxy tempo (4-HT), because it can reinstate its reduced state even after its oxidation during scavenging of ROS. Female Wistar rats were administered 3-nitropropionic acid (3-NP) and/or 4-HT for 21 days, after which animals were subjected to biochemical and behavioral assessments. Our results showed that 4-HT treatment significantly attenuated the 3-NP induced decrease in the activities of mitochondrial electron transport chain enzymes. In addition, 4-HT administration restored the increased nitrite and lipid peroxidation levels. Apart from this, 4-HT also attenuated the 3-NP induced decrease in superoxide dismutase and catalase activities. Further, 4-HT administration resulted in significant improvement in 3-NP induced cognitive and motor impairments. Taken together, the results of the study demonstrate that 4-HT is beneficial in 3-NP induced model of HD and thus could be a potential therapeutic agent in management of this disease.

Indian journal of experimental biology, 2010

The present study was designed to analyze the effect of acute aluminium phosphide (ALP) (10 mg/kg... more The present study was designed to analyze the effect of acute aluminium phosphide (ALP) (10 mg/kg body wt.) exposure on the glucose homeostasis in rat liver and brain. ALP has been implicated in the inhibition of cytochrome oxidase causing reduced oxygen uptake and decreased ATP synthesis eventually resulting in cellular energy crisis. A significant decrease in plasma glucose levels in the ALP treated rats has been observed. Therefore, decreased ATP levels coupled with hypoglycemia may further intensify the cellular energy deficits. In order to meet the sudden increase in the local energy demand, the brain tissue utilizes its stored energy in the form of glycogen breakdown as observed by a decrease in the glycogen levels in both liver and brain which was accompanied by a marked increase in the activity of glycogen phosphorylase in both the tissues. The glycolytic rate was found to be enhanced in brain tissue as evident by increased activities of hexokinase and phosphofructokinase en...