Pirh2 modulates amyloid-ß aggregation through the regulation of glucose-regulated protein 78 and chaperone-mediated signaling.

Amyloid-ß (Aß) protein aggregation in the brain is a pathological hallmark of Alzheimer's disease (AD) however, the underlying molecular mechanisms regulating amyloid aggregation are not well understood. Here, we studied the propitious role of E3 ubiquitin ligase Pirh2 in Aß protein aggregation in view of its regulatory ligase activity in the ubiquitin-proteasome system employing both cellular and sporadic rodent models of AD. Pirh2 protein abundance was significantly increased during Streptozotocin (STZ) induced AD conditions, and transient silencing of Pirh2 significantly inhibited the Aß aggregation and modified the dendrite morphology along with the substantial decrease in choline level in the differentiated neurons. MALDI-TOF/TOF, coimmunoprecipitation, and UbcH7-linked in vitro ubiquitylation analysis confirmed the high interaction of Pirh2 with chaperone GRP78. Furthermore, Pirh2 silencing inhibits the STZ induced altered level of endoplasmic reticulum stress and intracellular Ca2+ levels in neuronal N2a cells. Pirh2 silencing also inhibited the AD conditions related to the altered protein abundance of HSP90 and its co-chaperones which may collectively involve in the reduced burden of amyloid aggregates in neuronal cells. Pirh2 silencing further stabilized the nuclear translocation of phospho-Nrf2 and inhibited the altered level of autophagy factors. Taken together, our data indicated that Pirh2 is critically involved in STZ induced AD pathogenesis through its interaction with ER-chaperone GRP78, improves the neuronal connectivity, affects the altered level of chaperones, co-chaperones, & autophagic markers, and collectively inhibits the Aß aggregation.

Dysbiosis of gut microbiota due to diet, alcohol intake, body mass index, and gastrointestinal diseases in India.

The human gut is composed of diverse microflora which is influenced by dietary intake. Body mass index (BMI) and lifestyle patterns also play a vital role in human health to alter gut microbial composition. Our study aims to determine the impact of alcohol intake, BMI, and diet on gut microbiota and its relationship with gastrointestinal disorders. Thirty-nine gastric biopsies were taken from patients with various gastrointestinal (GI) diseases, and all the patient's lifestyle behavior were recorded in a written proforma. 16S rRNA metagenome analysis for V3-V4 regions was used to examine microbial compositions. The richness and diversity of gut microbiota were analyzed by PERMANOVA using the Bray-Curtis dissimilarity index and principal component analysis. The difference in relative abundance was calculated by ANOVA (p < 0.05). Alpha diversity indexes between vegetarians and non-vegetarians showed no significant difference based on BMI, alcohol status, and GI diseases. We found that in overweight vegetarian individuals Faecalibacterium and Rumicococcus might play a role in the control of Helicobacter pylori. Similarly, the increased abundance of Akkermansia muciniphila in non-vegetarian individuals with normal BMI might play a role to decrease the level of harmful bacteria like H. pylori, and Corynebacterium sp. Also, the relative abundance of Corynebacterium sp. among the vegetarians and Streptococcus sp. in the non-vegetarians was increased in alcoholics while H. pylori was increased in non-alcoholics irrespective of diet. There is an increased abundance of Faecalibacterium prausnitzii in vegetarians among all categories; however, we did not find any correlation between disease outcomes. Our study shows that alcohol intake and dietary habits have independent effects on gut microbial composition. The relative abundance of F. prausnitzii was high among vegetarians in all categories. KEY POINTS: • The presence of H. pylori is less among alcoholics. • Good bacteria help to maintain a normal body mass index. • Gut microbiota richness is high in vegetarians and diversity in non-vegetarians.

Biochemical strategies of E3 ubiquitin ligases target viruses in critical diseases.

Viruses are known to cause various diseases in human and also infect other species such as animal plants, fungi, and bacteria. Replication of viruses depends upon their interaction with hosts. Human cells are prone to such unwanted viral infections. Disintegration and reconstitution require host machinery and various macromolecules like DNA, RNA, and proteins are invaded by viral particles. E3 ubiquitin ligases are known for their specific function, that is, recognition of their respective substrates for intracellular degradation. Still, we do not understand how ubiquitin proteasome system-based enzymes E3 ubiquitin ligases do their functional interaction with different viruses. Whether E3 ubiquitin ligases help in the elimination of viral components or viruses utilize their molecular capabilities in their intracellular propagation is not clear. The first time our current article comprehends fundamental concepts and new insights on the different viruses and their interaction with various E3 Ubiquitin Ligases. In this review, we highlight the molecular pathomechanism of viruses linked with E3 Ubiquitin Ligases dependent mechanisms. An enhanced understanding of E3 Ubiquitin Ligase-mediated removal of viral proteins may open new therapeutic strategies against viral infections.

Implications of intracellular protein degradation pathways in Parkinson's disease and therapeutics.

Parkinson's disease (PD) pathology is the most common motor neurodegenerative disease that occurs due to the progressive degeneration of dopaminergic neurons of the nigrostriatal pathway of the brain. The histopathological hallmark of the disease is fibrillary aggregate called Lewy bodies which majorly contain α-synuclein, suggesting the critical implication of diminished protein degradation mechanisms in disease pathogenesis. This α-synuclein-containing Lewy bodies are evident in both experimental models as well as in postmortem PD brain and are speculated to be pathogenic but still, the lineal association between these aggregates and the complexity of disease pathology is not yet well established and needs further attention. However, it has been reported that α-synuclein aggregates have consorted with the declined proteasome and lysosome activities. Therefore, in this review, we reappraise intracellular protein degradation mechanisms during PD pathology. This article focused on the findings of the last two decades suggesting the implications of protein degradation mechanisms in disease pathogenesis and based on shreds of evidence, some of the approaches are also suggested which may be adopted to find out the novel therapeutic targets for the management of PD patients.

Guanabenz mitigates the neuropathological alterations and cell death in Alzheimer's disease.

Alzheimer's disease (AD) pathology is characterized by cognitive impairment, increased acetylcholinesterase (AChE) activity, and impaired neuronal communication. Clinically, AChE inhibitors are being used to treat AD patients; however, these remain unable to prevent the disease progression. Therefore, further development of new therapeutic molecules is required having broad spectrum effects on AD-related various neurodegenerative events. Since repurposing is a quick mode to search the therapeutic molecules; henceforth, this study was conducted to evaluate the anti-Alzheimer activity of drug guanabenz which is already in use for the management of high blood pressure in clinics. The study was performed employing both cellular and rat models of AD along with donepezil as reference drug. Guanabenz treatment in both the experimental models showed significant protection against AD-specific behavioral and pathological indicators like AChE activity, tau phosphorylation, amyloid precursor protein, and memory retention. In conjunction, guanabenz also attenuated the AD-related oxidative stress, impaired mitochondrial functionality (MMP, cytochrome-c translocation, ATP level, and mitochondrial complex I activity), endoplasmic reticulum stress (GRP78, GADD153, cleaved caspase-12), neuronal apoptosis (Bcl-2, Bax, cleaved caspase-3), and DNA fragmentation. In conclusion, findings suggested the panoptic protective effect of guanabenz on disease-related multiple degenerative markers and signaling. Furthermore, clinical trial may shed light and expedite the availability of new therapeutic anti-Alzheimer's molecule for the wellbeing of AD patients.

4-Phenylbutyrate Mitigates the Motor Impairment and Dopaminergic Neuronal Death During Parkinson's Disease Pathology via Targeting VDAC1 Mediated Mitochondrial Function and Astrocytes Activation.

Parkinson's disease (PD) is a progressive motor neurodegenerative disorder significantly associated with protein aggregation related neurodegenerative mechanisms. In view of no disease modifying drugs, the present study was targeted to investigate the therapeutic effects of pharmacological agent 4-phenylbutyric acid (4PBA) in PD pathology. 4PBA is an FDA approved monocarboxylic acid with inhibitory activity towards histone deacetylase and clinically treats urea cycle disorder. First, we observed the significant protective effects of 4PBA on PD specific neuromuscular coordination, level of tyrosine hydroxylase, α-synuclein level and neurotransmitter dopamine in both substantia nigra and striatal regions of the experimental rat model of PD. Further results revealed that treatment with 4PBA drug exhibited significant protection against disease related oxidative stress and augmented nitrite levels. The disease pathology-related depletion in mitochondrial membrane potential and augmented level of calcium as well as mitochondrion membrane located VDAC1 protein level and cytochrome-c translocation were also significantly attenuated with 4PBA administration. Inhibited neuronal apoptosis and restored neuronal morphology were also observed with 4PBA treatment as measured by level of pro-apoptotic proteins t-Bid, Bax and cleaved caspase-3 along with cresyl violet staining in both substantia nigra and striatal regions. Lastly, PD-linked astrocyte activation was significantly inhibited with 4PBA treatment. Altogether, our findings suggest that 4PBA exerts broad-spectrum neuroprotective effects in PD animal model.

Analysis of Functional Status of Genetically Diverse OipA Gene in Indian Patients with Distinct Gastrointestinal Disease.

Helicobacter pylori (H. pylori,) a genetically diversified bacteria which colonizes human gastric epithelium, is now established causative agent for gastric cancer worldwide. Outer membrane protein (OMP)-coding genes of H. pylori are responsible for attachment and colonization of bacteria. These genes which code proteins on outer membrane of H. pylori is a group of 33 genes which with other virulent genes are causative of giving rise to disease-causing factors in the host. OipA (Outer inflammatory protein A), a participant of Hop family of OMP, is effective in acting as a biomarker for studying progression of diseases like gastric cancer. The functionality of oipA gene is regulated by phase variation within CT repeat pattern. It is the expression, i.e., "on"/"off" of oipA gene which is related with the development of distinct gastric diseases. 40 amplified DNA sequences were studied to investigate functional status of oipA. Our results reveal 57.2% isolates with functional oipA along with significant association with cagA (P = 0.0011) and vacAs1m1/s1m2 (P = 0.0034, P = 0.0093) genotypes, respectively. In conclusion, our results indicate diversity in CT repeat pattern among Indian H. pylori strains. The prevalence of functional oipA gene was found to be ranging between 50% and 64.2% though it did not show significant correlation between functional oipA and disease outcome.

Rivastigmine attenuates the Alzheimer's disease related protein degradation and apoptotic neuronal death signalling.

Rivastigmine is a clinical drug for patients of Alzheimer's disease (AD) exerting its inhibitory effect on acetylcholinesterase activity however, its effect on other disease-related pathological mechanisms are not yet known. This study was conducted to evaluate the effect of rivastigmine on protein aggregation and degradation related mechanisms employing streptozotocin (STZ) induced experimental rat model. The known inhibitory effect of rivastigmine on cognition and acetylcholinesterase activity was observed in both cortex and hippocampus and further its effect on tau level, amyloid aggregation, biochemical alterations, endoplasmic reticulum (ER) stress, calcium homeostasis, proteasome activity and apoptosis was estimated. STZ administration in rat brain caused significant cognitive impairment, augmented acetylcholinesterase activity, tau phosphorylation and amyloid aggregation which were significantly inhibited with rivastigmine treatment. STZ also caused significant biochemical alterations which were attenuated with rivastigmine treatment. Since AD pathology is related to protein aggregation and we have found disease-related amyloid aggregation, further the investigation was done to decipher the ER functionality and apoptotic signalling. STZ caused significantly altered level of ER stress related markers (GRP78, GADD153 and caspase-12) which were significantly inhibited with rivastigmine treatment. Furthermore, the effect of rivastigmine was estimated on proteasome activity in both regions. Rivastigmine treatment significantly enhances the proteasome activity and may contributes in removal of amyloid aggregation. In conclusion, findings suggested that along with inhibitory effect of rivastigmine on acetylcholinesterase activity and up to some extent on cognition, it has significant effect on disease-related biochemical alterations, ER functionality, protein degradation machinery and neuronal apoptosis.

Role of Platelet-Rich Plasma Therapy as an Adjuvant in Treatment of Melasma.

BACKGROUND: The management of melasma is an ongoing challenge. Platelet-rich plasma (PRP) therapy has been reported to be beneficial, but there is paucity of studies on PRP therapy in melasma. OBJECTIVE: To compare the efficacy of PRP therapy and hydroquinone versus hydroquinone alone in melasma. MATERIALS AND METHODS: Thirty patients were randomized to receive PRP microinjections on one side and normal saline on the other in a total of 3 sittings. Patients were concurrently advised 4% hydroquinone (HQ) cream application on both sides of the face. Efficacy was evaluated with hemi-modified Melasma Area Severity Index (MASI) scoring and a 4-scale patient satisfaction grading. RESULTS: Majority of the subjects (53.3%) in PRP + HQ group and 76.7% in HQ group had 25% to 50% improvement in their MASI scores. However, 40% in the PRP + HQ group and only 3.3% in the HQ group had 51% to 75% improvement. The difference in the percentage improvement was statistically significant. There was a greater percentage of subjects reporting a good response among the HQ + PRP group (53.3%) as compared with the HQ group (27%). CONCLUSION: Microinjections of PRP combined with topical HQ has better efficacy than topical HQ alone.

Proteasome Based Molecular Strategies Against Improper Cellular Proliferation.

Cells contain several proteins that routinely fulfill multiple requirements for normal physiological survival. Proteostasis dysfunction is linked with different complex human disorders, like cancer, neuron degeneration, and imperfect aging. The ubiquitin proteasome system (UPS) forms the primary proteostasis mechanism taking part in cytoprotection. Cancer cells are well known to possess enhanced cytoprotective properties, and different UPS elements are implicated to be dysregulated at several stages of tumor progression. Furthermore, many studies have found tumor cells to exhibit higher levels of various UPS components, possibly contributing to their robust endurance. In this article, we have presented different cellular protein quality control strategies, essential for maintaining healthy proteome. Here, we have also discussed key contributions and functions of UPS involved in molecular pathomechanisms for establishing cancer conditions. Along with this, the emerging different therapeutic strategies against defective proteome linked with improper cellular proliferation and cancer progression are also reviewed. UPS performs critical regulatory functions in modulating the cellular apoptotic pathways. The proteasomal system involvement as probable therapeutic targets influencing cancer cell apoptosis is also discussed. Our article summarizes the recent developments in proteasome-associated pathways regulating tumor cell proteome and survival. Additionally, how the engagement and cross functions of these physiological processes can induce apoptosis and may develop regulation over tumor progression. A better understanding of multifaceted protein quality control pathways may inform therapeutic interventions based on cellular proteostasis response determined against complex diseases.

Microglial TLR9: Plausible Novel Target for Therapeutic Regime Against Glioblastoma Multiforme.

An understanding of pattern recognition receptors (PRRs) and immunomodulatory approach based on activation of these receptors has provided insights critical for the management of neurological health disorders. Toll-like receptors (TLRs) are one of the most widely explored PRRs and have been exploited in the recent past for development of novel immunomodulatory therapeutic agents. Glioblastoma multiforme is characterized by significant infiltration of resident microglia and expresses all the members of the TLR family. The present report is focused on exciting findings pertaining to probable implications of TLR9 activation by unmethylated CG sequences for novel therapeutic intervention against glioblastoma multiforme, which could be a discrete step toward the effective management of neurological health issues.

Regulatory safety pharmacology and toxicity assessments of a standardized stem extract of Cassia occidentalis Linn. in rodents.

Cassia occidentalis Linn (CO) is an annual/perennial plant having traditional uses in the treatments of ringworm, gastrointestinal ailments and piles, bone fracture, and wound healing. Previously, we confirmed the medicinal use of the stem extract (ethanolic) of CO (henceforth CSE) in fracture healing at 250 mg/kg dose in rats and described an osteogenic mode of action of four phytochemicals present in CSE. Here we studied CSE's preclinical safety and toxicity. CSE prepared as per regulations of Current Good Manufacturing Practice for human pharmaceuticals/phytopharmaceuticals and all studies were performed in rodents in a GLP-accredited facility. In acute dose toxicity as per New Drug and Clinical Trial Rules, 2019 (prior name schedule Y), in rats and mice and ten-day dose range-finding study in rats, CSE showed no mortality and no gross abnormality at 2500 mg/kg dose. Safety Pharmacology showed no adverse effect on central nervous system, cardiovascular system, and respiratory system at 2500 mg/kg dose. CSE was not mutagenic in the Ames test and did not cause clastogenicity assessed by in vivo bone marrow genotoxicity assay. By a sub chronic (90 days) repeated dose (as per OECD, 408 guideline) study in rats, the no-observed-adverse-effect-level was found to be 2500 mg/kg assessed by clinico-biochemistry and all organs histopathology. We conclude that CSE is safe up to 10X the dose required for its osteogenic effect.

Repolarization of glioblastoma macrophage cells using non-agonistic Dectin-1 ligand encapsulating TLR-9 agonist: plausible role in regenerative medicine against brain tumor.

AIM OF THE STUDY: Glioblastoma multiforme (GBM) is the most severe forms of brain cancer, eventually becoming the leading cause of brain cancer-related death worldwide. Owing to the bleak surgical interventions and resistance to the different treatment regime, GBM is a parlous disease demanding newer therapeutical perspective for its treatment. Toll-like receptors (TLRs) are well-known members of pathogen recognition receptors (PRRs) and have been extensively explored for their therapeutic and prophylactic potential in an array of disease including cancer. Recent trends in drug delivery research has shown shift towards delivering short DNA sequences (CpG DNA) to endosomal TLR9 within immune cells (macrophages, dendritic cells, etc.) for the activation of desired inflammatory response using non-agonistic ß-glucan particles; a well-known ligand for Dectin-1 receptors. Our study is therefore focused to explore the role of nano-encapsulated CpG ODN as critical players in polarizing M2 scavenging to much desired pro-inflammatory type. MATERIALS AND METHODS: The nanoparticles entrapping CpG ODN 1826 were prepared by using a fungal polymer Schizophyllan (SPG). The constructed nanoparticles were characterized and assessed for their efficacy on rat glioblastoma cells (C6). RESULTS: The constructed Schizophyllan (SPG) nanoparticles entrapping CpG ODN 1826 (95.3%) were of 25.49 nm in diameter and thus capable of crossing blood-brain barrier. The rat glioblastoma (C6) cells evaluated for intracellular oxidative burst and cytokine levels pre- and post-incubation with nanoparticles exhibited marked elevation in the expression of intracellular ROS and IFN-γ as well as IL-1ß post treatment. CONCLUSION: The findings indicate towards potentiality of repolarizing the M2 macrophages to much desired M1 phase by inducing higgh levels of oxidative burst and inflammatory cytokines. Consequently, the apoptosis was induced in glioblastoma cells establishing the suitablity of CpG ODN carrying nanoformulations as emerging therapeutic intervention for GBM.

Neuroinflammatory responses in Parkinson's disease: relevance of Ibuprofen in therapeutics.

Parkinson's disease (PD) pathogenesis inevitably involves neuroinflammatory responses attained through contribution of both neuron and glial cells. Investigation done in both experimental models of PD and in samples of PD patients suggested the involvement of both central and peripheral inflammatory responses during PD pathogenesis. Such neuroinflammatory responses could be regulated by neuron-glia interaction which is one of the recently focused areas in the field of disease diagnosis, pathogenesis and therapeutics. Such aggravated neuroinflammatory responses during PD are very well associated with augmented levels of cyclooxygenase (COX). An increased expression of cyclooxygenase (COX) with a concomitant increase in the prostaglandin E2 (PGE2) levels has been observed during PD pathology. Ibuprofen is one of the non-steroidal anti-inflammatory drugs (NSAID) and clinically being used for PD patients. This review focuses on the neuroinflammatory responses during PD pathology as well as the effect of ibuprofen on various disease related signaling factors and mechanisms involving nitrosative stress, neurotransmission, neuronal communication and peroxisome proliferator-activated receptor-γ. Such mechanistic effect of ibuprofen has been mostly reported in experimental models of PD and clinical investigations are still required. Since oxidative neuronal death is one of the major neurodegenerative mechanisms in PD, the antioxidant capacity of ibuprofen along with its antidepressant effects have also been discussed. This review will direct the readers towards fulfilling the existing gaps in the mechanistic aspect of ibuprofen and enhance its clinical relevance in PD therapeutics and probably in other age-related neurodegenerative diseases.

Congenital Cutaneous Peripheral Primitive Neuroectodermal Tumor (pPNET) of Scalp: Youngest Case So Far.

Congenital cutaneous peripheral primitive neuroectodermal tumor (pPNET) is very rare and also very rarely located in scalp. Only two cases of PNET as primary tumor in scalp are reported so far in the literature. Non mutilating surgical excision, combined with chemotherapy and radiotherapy are used in treating these rare tumors. We present the youngest case report of PNET of scalp in 10-month-old girl who was managed by surgical excision with good cosmetic outcome and disease-free 20 months post-operative period.

Promising Polyphenols in Parkinson's Disease Therapeutics.

Parkinson's disease (PD) is a slow progressive, second most common neurodegenerative disease characterized by the loss of dopaminergic neurons from the nigrostriatal pathway. In spite of extensive research the therapeutics options of disease are limited which only offer symptomatic relief and could not prevent the disease progression. Therefore researchers are looking for the probable synthetic or natural compounds for the PD therapeutics. Due to mandatory chronic consumption of anti PD drug to the PD patients, the natural compounds are getting attention recently. Numerous studies have indicated the neuroprotective effects of natural polyphenols including epigallocatechin, quercetin, baicalein, resveratrol, luteolin, curcumin, puerarin, genistein, hyperoside naringin against dopaminergic neuronal death with relatively safe with uncommon, mild or transient side effects. However, their mechanistic interference in dopaminergic neuronal death mechanism is not very well defined. Herein, we have attempted to discuss the various natural polyphenols with their known effects on various PD related pathologies to understand their therapeutic utilization for PD patients either in prophylactic or therapeutic mode. Briefly we have also discussed the major disease mechanisms which could be targeted for utilization of these polyphenols specifically involving oxidative stress and mitochondrial dysfunction. We have also discuss the limitation and probable strategies for the clinical utilization of these polyphenols for the benefit of PD patients.

Noradrenergic pathways of locus coeruleus in Parkinson's and Alzheimer's pathology.

Noradrenergic system of brain supplies the neurotransmitter noradrenalin throughout the brain through widespread efferent projections and play pivotal role in cognitive activities and could be involve in motor and non-motor symptoms of Parkinson's disease (PD) pathology. Profound loss of noradrenergic pathways has been reported in both Parkinson's and Alzheimer's disease (AD) pathology however their employment in therapeutics is still scarce. Therefore the present review is providing the various aspects for involvement on noradrenergic pathways in PD and AD pathology as well as the imaging of locus coeruleus as indicative diagnostic marker for disease. The present review is describing about the role of tiny nucleus locus coeruleus located noradrenergic pathways in said pathologies and discussing the past research as well as lacunas in this regard.

Polyphenolic flavonoid (Myricetin) upregulated proteasomal degradation mechanisms: Eliminates neurodegenerative proteins aggregation.

Major neurodegenerative disorders are characterized by the formation of misfolded proteins aggregates inside or outside the neuronal cells. Previous studies suggest that aberrant proteins aggregates play a critical role in protein homeostasis imbalance and failure of protein quality control (PQC) mechanism, leading to disease conditions. However, we still do not understand the precise mechanisms of PQC failure and cellular dysfunctions associated with neurodegenerative diseases caused by the accumulation of protein aggregates. Here, we show that Myricetin, a flavonoid, can eliminate various abnormal proteins from the cellular environment via modulating endogenous levels of Hsp70 chaperone and quality control (QC)-E3 ubiquitin ligase E6-AP. We have observed that Myricetin treatment suppresses the aggregation of different aberrant proteins. Myricetin also enhances the elimination of various toxic neurodegenerative diseases associated proteins from the cells, which could be reversed by the addition of putative proteasome inhibitor (MG132). Remarkably, Myricetin can also stabilize E6-AP and reduce the misfolded proteins inclusions, which further alleviates cytotoxicity. Taken together these findings suggested that new mechanistic and therapeutic insights based on small molecules mediated regulation of disturbed protein quality control mechanism, which may result in the maintenance of the state of proteostasis.

New therapeutic activity of metabolic enhancer piracetam in treatment of neurodegenerative disease: Participation of caspase independent death factors, oxidative stress, inflammatory responses and apoptosis.

Piracetam, a nootropic drug that has been clinically used for decades but remains enigmatic due to no distinct understanding of its mechanism of action. The present study aimed to investigate the role of caspase independent pathway in piracetam mediated neuroprotection. LPS administration caused significant alterations in oxidative stress related parameters like glutathione, glutathione reductase and increased lipid peroxidation. LPS administration also caused augmented expression of inflammatory cytokines and astrocytes activation. Piracetam treatment offered significant protection against LPS induced oxidative and inflammatory parameters and inhibited astrocytes activation. LPS administration caused augmented level of reactive oxygen species and depleted mitochondrial membrane potential which were attenuated with piracetam treatment. This study for the first time demonstrates the role of caspase independent death factors in piracetam induced neuroprotective effects in rat brain. Translocation of mitochondrial resident apoptosis inducing factor and endonuclease G to nucleus through cytosol after LPS administration was significantly blocked with piracetam treatment. Further, LPS induced DNA fragmentation along with up regulated Poly [ADP-ribose] polymerase 1 (PARP1) levels were also inhibited with piracetam treatment. Apoptotic death was confirmed by the cleavage of caspase 3 as well as histological alteration in rat brain regions. LPS administration caused significantly increased level of cleaved caspase 3, altered neuronal morphology and decreased neuronal density which were restored with piracetam treatment. Collectively our findings indicate that piracetam offered protection against LPS induced inflammatory responses and cellular death including its antioxidative antiapoptotic activity with its attenuation against mitochondria mediated caspase independent pathway.

Updates on immunity and inflammation in Parkinson disease pathology.

Studies in the last decade have suggested the association of both neuroinflammatory processes and immune responses in Parkinson disease (PD) pathology. PD pathology is related to depleted dopamine levels, α-synuclein aggregation, and death of nigrostriatal dopaminergic neurons. Reports have suggested central and peripheral inflammation in the prodromal stage of the disease, which is sustained during disease progression. Alongside the activation of peripheral immune system exacerbates the dissonant central inflammatory responses and could contribute in synergistic neurodegeneration. Activated glial cells contribute significantly in the neuroinflammatory process during the occurrence of the disease and are also acknowledged as a hallmark of disease progression. However, the contribution of glial cells is not well defined in the context of neurodegeneration and neuroprotection. This review provides an overview of the roles of immune and inflammatory responses and their consequences in PD disease pathogenesis and also discusses possible therapeutic strategies for PD based on these findings.