Sleep Disturbance and Alzheimer's Disease: The Glial Connection.

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-ß (Aß)/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.

Dietary intervention with Tinospora cordifolia improved aging-related decline in locomotor coordination and cerebellar cell survival and plasticity in female rats.

Reduced bone mineral density, and muscle strength are the hallmark of aging-related motor coordination deficits and related neuropathologies. Since cerebellum regulates motor movements and balance perception of our body, therefore it may be an important target to control the age-related progression of motor dysfunctions. Dry stem powder of Tinospora cordifolia (TCP) was tested as a food supplement to elucidate its activity to attenuate age-associated locomotor dysfunctions. Intact acyclic middle-aged female rats were used in this study as the model system of the transition phase from premenopause to menopause in women along with cycling young adult rats. Normal chow or 30% High Fat Diet (HFD), supplemented with or without TCP was fed to animals for 12 weeks and then tested for locomotor performance on rotarod followed by post-sacrifice protein expression studies. In comparison to young adults, middle-aged animals showed an increase in number of falls and lesser time spent in rotarod performance test, whereas, animals given TCP supplemented feed showed improvement in performance with more pronounced effects observed in normal chow than HFD fed middle-aged rats. Further, due to its multicomponent nature TCP was found to target the expression of various markers of neuroinflammation, apoptosis, cell survival, and synaptic plasticity in the cerebellum region. The current findings suggest that TCP supplementation in the diet may prove to be a potential interventional strategy for the management of frailty and fall-associated morbidities caused by aging-related deterioration of bone mineral density, and muscle strength.

MicroRNA-29b Modulates ß-Secretase Activity in SH-SY5Y Cell Line and Diabetic Mouse Brain.

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 ß-secretase (BACE-1) enzyme which is involved in the formation of amyloid-beta (Aß) 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.

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease.

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 (Aß) 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.

Systemic inflammation without gliosis mediates cognitive deficits through impaired BDNF expression in bile duct ligation model of hepatic encephalopathy.

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 observed in glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (Iba-1) expression at transcriptional and translation level in brain of BDL rats. Immunohistochemical and flowcytometric analysis revealed reduced number of GFAP-immunopositive astrocytes and Iba1-immunopositive microglia in the brain regions of BDL rats. Further, a significant decline was observed in cognitive functions in BDL rats assessed using Morris water maze and novel object recognition tests. Expression of pro and mature form of brain derived neurotrophic factor (BDNF) and its upstream transcription element showed significant reduction in brain of BDL rats. Taken together, the results of the present study suggest that systemic inflammation and reduced expression of BDNF and its upstream transcription factor plays a key role in cognitive decline in HE.

Mitochondrial dysfunctions contribute to energy deficits in rodent model of hepatic encephalopathy.

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 CO2 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.

Mitochondria as a centrally positioned hub in the innate immune response.

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-IL1ß and pro-IL-18) to active cytokines (IL-1ß 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.

Cell cycle activation in p21 dependent pathway: An alternative mechanism of organophosphate induced dopaminergic neurodegeneration.

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 G0/G1 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.

4-hydroxy tempo improves mitochondrial and neurobehavioral deficits in experimental model of Huntington's disease.

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.

Dichlorvos-induced cell cycle arrest and DNA damage repair activation in primary rat microglial cells.

Dichlorvos, an organophosphate (OP), is known to cause oxidative stress in the central nervous system (CNS). Previously we have shown that dichlorvos treatment promoted the levels of proinflammatory molecules and ultimately induced apoptotic cell death in primary microglial cells. Here we studied the effect of dichlorvos on crucial cell cycle regulatory proteins and the DNA damage sensor ataxia-telangiectasia mutated (ATM). We found a significant increase in p53 and its downstream target, p21, levels in dichlorvos-treated microglial cells compared with control cells. Moreover, dichlorvos exposure promoted the levels of different cell cycle regulatory proteins. These results along with flow cytometry results suggested that primary microglial cells were arrested at G1 and G2/M phase after dichlorvos exposure. We have shown in a previous study that dichlorvos can induce DNA damage in microglia; here we found that microglial cells also tried to repair this damage by inducing a DNA repair enzyme, i.e., ATM. We observed a significant increase in the levels of ATM after dichlorvos treatment compared with control.

Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression.

The present investigation was carried out to elucidate a possible molecular mechanism related to the effects of aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of Peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) and its downstream targets i.e. Nuclear respiratory factor-1(NRF-1), Nuclear respiratory factor-2(NRF-2) and Mitochondrial transcription factor A (Tfam) in mitochondrial biogenesis. Aluminium lactate (10mg/kgb.wt./day) was administered intragastrically to rats for 12 weeks. After 12 weeks of exposure, we found an increase in ROS levels, mitochondrial DNA oxidation and decrease in citrate synthase activity in the Hippocampus (HC) and Corpus striatum (CS) regions of rat brain. On the other hand, there was a decrease in the mRNA levels of the mitochondrial encoded subunits-NADH dehydrogenase (ND) subunits i.e. ND1, ND2, ND3, Cytochrome b (Cytb), Cytochrome oxidase (COX) subunits i.e. COX1, COX3, ATP synthase (ATPase) subunit 6 along with reduced expression of nuclear encoded subunits COX4, COX5A, COX5B of Electron transport chain (ETC). Besides, a decrease in mitochondrial DNA copy number and mitochondrial content in both regions of rat brain was observed. The PGC-1α was down-regulated in aluminium treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α in aluminium treated rats. Electron microscopy results revealed a significant increase in the mitochondrial swelling, loss of cristae, chromatin condensation and decreases in mitochondrial number in case of aluminium treated rats as compared to control. So, PGC-1α seems to be a potent target for aluminium neurotoxicity, which makes it an almost ideal target to control or limit the damage that has been associated with the defective mitochondrial function seen in neurodegenerative diseases.

The hidden players: Shedding light on the significance of post-translational modifications and miRNAs in Alzheimer's disease development.

Alzheimer's disease (AD) is the most prevalent, expensive, lethal, and burdening neurodegenerative disease of this century. The initial stages of this disease are characterized by a reduced ability to encode and store new memories. Subsequent cognitive and behavioral deterioration occurs during the later stages. Abnormal cleavage of amyloid precursor protein (APP) resulting in amyloid-beta (Aß) accumulation along with hyperphosphorylation of tau protein are the two characteristic hallmarks of AD. Recently, several post-translational modifications (PTMs) have been identified on both Aß as well as tau proteins. However, a complete understanding of how different PTMs influence the structure and function of proteins in both healthy and diseased conditions is still lacking. It has been speculated that these PTMs might play vital roles in the progression of AD. In addition, several short non-coding microRNA (miRNA) sequences have been found to be deregulated in the peripheral blood of Alzheimer patients. The miRNAs are single-stranded RNAs that control gene expression by causing mRNA degradation, deadenylation, or translational repression and have been implicated in the regulation of several neuronal and glial activities. The lack of comprehensive understanding regarding disease mechanisms, biomarkers, and therapeutic targets greatly hampers the development of effective strategies for early diagnosis and the identification of viable therapeutic targets. Moreover, existing treatment options for managing the disease have proven to be ineffective and provide only temporary relief. Therefore, understanding the role of miRNAs and PTMs in AD can provide valuable insights into disease mechanisms, aid in the identification of biomarkers, facilitate the discovery of novel therapeutic targets, and inspire innovative treatments for this challenging condition.

Dichlorvos exposure results in activation induced apoptotic cell death in primary rat microglia.

Dichlorvos [2,2-dichlorovinyl dimethyl phosphate] is one of the most common in-use organophosphate (OP) in developing nations. Previous studies from our lab have shown chronic Dichlorvos exposure leads to neuronal cell death in rats. However, the extent of damage caused by Dichlorvos to other cells of the central nervous system (CNS) is still not clear. Microglial cells are the primary threat sensors of CNS which become activated in many pathological conditions. Activation of microglial cells results in reactive microgliosis, manifested by increased cellular damage in the affected regions. Using rat primary microglial cultures, here we show that Dichlorvos exposure can activate and induce apoptotic cell death in microglia. We observed significant up-regulation of pro-inflammatory molecules like nitric oxide, TNF-α, and IL-1ß when microglia were treated with Dichlorvos (10 µM). Significant up-regulation of CD11b, microglial specific activation marker, was also observed after 24 h of Dichlorvos treatment. The activated microglial cells eventually undergo cell death after 48 h of Dichlorvos treatment. The DNA fragmentation pattern of Dichlorvos treated microglia along with increased expression of Bax in mitochondria, cytochrome c release from mitochondria, and caspase-3 activation led us to assume that microglia were undergoing apoptosis. Thus, the present study showed that Dichlorvos can induce microglial activation and ultimately apoptotic cell death. These findings gave new perspective to the current knowledge of Dichlorvos (OPs) mediated CNS damage and presents microglial activation as a potential therapeutic target for preventing the OP induced neuronal damage.

Dietary Supplementation With Tinospora cordifolia Improves Anxiety-Type Behavior and Cognitive Impairments in Middle-Aged Acyclic Female Rats.

The midlife transition period in women marks the progressive flattening of neurological health along with increased adiposity, dyslipidemia, frailty, and inflammatory responses mainly attributed to the gradual decline in estrogen levels. Conflicting reports of hormone replacement therapy (HRT) necessitate the exploration of novel therapeutic interventions using bioactive natural products having the least toxicity and a holistic mode of action for the preservation of metabolic homeodynamics with aging in women. The present study was planned to investigate the effects of aging and/or a high-fat diet (HFD) on cognitive impairments and anxiety and further their management by dietary supplement with the Tinospora cordifolia stem powder (TCP). Acyclic female rats were included in this study as the model system of the perimenopause phase of women along with young 3-4 months old rats as controls. Rats were fed on with and without TCP supplemented normal chow or HFD for 12 weeks. Animals fed on a TCP supplemented normal chow showed consistent management of body weight over a 12-week regimen although their calorie intake was much higher in comparison to their age-matched controls. Post-regimen, neurobehavioral tests, such as novel object recognition and elevated plus maze, performed on these animals showed improvement in their learning and memory abilities as well as the anxiety-like behavior. Furthermore, due to the presence of multiple components, TCP was observed to modulate the expression of key marker proteins to ameliorate neuroinflammation and apoptosis and promote cell survival and synaptic plasticity in the hippocampus and the prefrontal cortex (PFC) regions of the brain. These findings suggest that TCP supplementation in diet during the midlife transition period in women may be a potential interventional strategy for the management of menopause-associated anxiety and cognitive impairments and healthy aging.

Altered glucose homeostasis in response to aluminium phosphide induced cellular oxygen deficit in rat.

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 enzymes, but decreased in liver of ALP treated rats. Lactate levels were increased in plasma and brain, but decreased in liver of ALP treated rats. Pyruvate levels increased in the plasma and liver, but no change was observed in the brain tissue. ALP did not cause any change in the gluconeogenic enzymes like glucose-6-phosphatase and fructose-1,6-bisphophatase in brain, but a significant increase was observed in the liver. Results of the study showed that ALP induced cellular energy deficit leads to compromised energy status of liver and brain coupled with substantial alterations in glucose homeostasis. However, the activity of glucose-6-phosphate dehydrogenase decreased significantly in both the tissues.

Sulforaphane Attenuates Aß Oligomers Mediated Decrease in Phagocytic Activity of Microglial Cells.

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 amyloid beta (Aß) 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 Aß. In the present study, we have checked the effect of toxic amyloid beta oligomers (Aßo) on the microglial phagocytic activity. Our findings revealed that at lower concentrations, Aßo are not toxic to the cells and they can survive even with longer exposures but with decreased phagocytic activity. However, at higher concentrations Aßo become toxic and resulted in modulation of various genes which regulates microglial phagocytic activity. Sulforaphane (SFN) treatment has shown to induce the phagocytic activity of Aßo treated microglial cells. In addition, low dose Aßo 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 Aßo mediated decrease in microglial phagocytic activity.

Neurobehavioral impairments, generation of oxidative stress and release of pro-apoptotic factors after chronic exposure to sulphur mustard in mouse brain.

Recent global events have focused attention on the potential threat of international and domestic chemical terrorism, as well as the possibility of chemical warfare proliferation. Sulphur mustard (SM) is one of the potent chemical warfare agents (CWA), which initiates a cascade of events that converge on the redox mechanisms common to brain injury. The present study was designed to examine the effects of chronic SM exposure on neurobehavioral impairments, mitochondrial oxidative stress in male Swiss Albino mice and its role in inducing apoptotic neuronal cell death. The animals were divided into four groups (control, low, medium and high dose) of 5 animals each. Exposure to SM was given percutaneously daily for 12 weeks. The results demonstrated impairment in neurobehavioral indices viz. rota rod, passive avoidance and water maze tests in a dose dependent manner. There was a significant increase in lipid peroxidation and protein carbonyl content whereas, decrease in the activity of manganese superoxide dismutase (MnSOD), glutathione reductase and glutathione peroxidase suggesting impaired antioxidant defense system. Immunoblotting of cytochrome c, Bcl-2, Bax and activation of caspase-3 suggest induction of apoptosis in a dose dependent manner. Finally, increased p53 expression suggests that it may target the mitochondrial pathway for inducing apoptosis in response to DNA damage signals. In conclusion, chronic SM exposure may have the potential to generate oxidative stress which may trigger the release of cytochrome c as well as caspase-3 activation in neurons leading to cell death by apoptosis in a dose dependent manner which may in the end be responsible for the disruption of cognitive functions in mice.

Modulation of CD44, EGFR and RAC Pathway Genes (WAVE Complex) in Epithelial Cancers.

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.

Evaluating the Role of Microglial Cells in Clearance of Aß from Alzheimer's Brain.

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. In the past 15 years, not a single drug came out of clinical trials. The researchers have yet to discover a drug that could specifically target AD; in fact, the drugs that are about to launch in the global market either belong 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 a 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 Aß are continuously phagocytosed by microglia in healthy individuals, but this ability would decrease with age and lead to development of AD. In this review, we have explored the possibility of whether microglial cells could be utilized as an early predictor of the AD progression. Here, we discuss the innate immune response of microglial cells, the factors affecting microglia response, microglial receptors to which Aß could bind, and microglial phenotype markers. Last, we conclude with a list of available AD therapeutics along with their mechanism.

Resveratrol loaded solid lipid nanoparticles attenuate mitochondrial oxidative stress in vascular dementia by activating Nrf2/HO-1 pathway.

Vascular dementia (VaD) is the leading cause of cognitive decline resulting from vascular lesions. Recent studies have shown that mitochondrial dysfunctions and oxidative stress are involved in cognitive decline. The aim of the present study was to evaluate the beneficial effects of resveratrol-loaded solid lipid nanoparticles (R-SLNs) in permanent bilateral common carotid artery occlusion (BCCAO) induced model of VaD. R-SLNs prepared had average size of 286 nm and 91.25% drug encapsulation efficiency with sustained release. Moreover, R-SLNs had 4.5 times higher levels of resveratrol (RSV) in brain compared to when administered as free RSV. Neurobehavioral analyses revealed that R-SLNs administration successfully ameliorated cognitive decline observed in BCCAO rats. Administration of R-SLNs to BCCAO animals showed significant reduction in mitochondrial reactive oxygen species (ROS) generation, lipid peroxidation, and protein carbonyls. In addition, R-SLNs significantly improved redox ratio and Mn-superoxide dismutase (Mn-SOD) activity. R-SLNs administration resulted in significant reduction in hypoxia-inducible factor 1α (HIF-1α) levels, whereas, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) levels were increased after R-SLNs treatment. Taken together, the results demonstrate that R-SLNs could be a novel and promising therapeutic strategy in VaD as well in other age-related neurodegenerative disorders.