Neuroepigenetic Changes in DNA Methylation Affecting Diabetes-Induced Cognitive Impairment.

Chronic diabetic conditions have been associated with certain cerebral complications, that include neurobehavioral dysfunctional patterns and morphological alterations of neurons, especially the hippocampus. Neuroanatomical studies done by the authors have shown decreased total dendritic length, intersections, dendritic length per branch order and nodes in the CA1 hippocampal region of the diabetic brain as compared to its normal control group, indicating reduced dendritic arborization of the hippocampal CA1 neurons. Epigenetic alterations in the brain are well known to affect age-associated disorders, however its association with the evolving diabetes-induced damage in the brain is still not fully understood. DNA hypermethylation within the neurons, tend to silent the gene expression of several regulatory proteins. The findings in the study have shown an increase in global DNA methylation in palmitic acid-induced lipotoxic Neuro-2a cells as well as within the diabetic mice brain. Inhibiting DNA methylation, restored the levels of HSF1 and certain HSPs, suggesting plausible effect of DNMTs in maintaining the proteostasis and synaptic fidelity. Neuroinflammation, as exhibited by the astrocyte activation (GFAP), were further significantly decreased in the 5-azadeoxycytidine group (DNMT inhibitor). This was further evidenced by decrease in proinflammatory cytokines TNF⍺, IL-6, and mediators iNOS and Phospho-NFkB. Our results suggest that changes in DNA methylation advocate epigenetic dysregulation and its involvement in disrupting the synaptic exactitude in the hippocampus of diabetic mice model, providing an insight into the pathophysiology of diabetes-induced neuroepigenetic changes.

Necrostatin-1S mitigates type-2 diabetes-associated cognitive decrement and lipotoxicity-induced neuro-microglia changes through p-RIPK-RIPK3-p-MLKL axis.

Type-2 diabetes mellitus (T2DM) is associated with neuroinflammation and cognitive decrement. Necroptosis programmed necrosis is emerging as the major contributing factor to central changes. It is best characterized by the upregulation of p-RIPK(Receptor Interacting Kinase), p-RIPK3, and the phosphorylated-MLKL (mixed-lineage kinase domain-like protein). The present study aims to evaluate the neuroprotective effect of Necrostatin (Nec-1S), a p-RIPK inhibitor, on cognitive changes in the experimental T2DM model in C57BL/6 mice and lipotoxicity-induced neuro-microglia changes in neuro2A and BV2 cells. Further, the study also explores whether Nec-1S would restore mitochondrial and autophago-lysosomal function.T2DM was developed in mice by feeding them a high-fat diet (HFD) for 16 weeks and injecting a single dose of streptozotocin (100 mg/kg, i.p) on the 12th week. Nec-1S was administered for 3 weeks at (10 mg/kg, i.p) once every 3 days. Lipotoxicity was induced in neuro2A, and BV2 cells using 200 µM palmitate/bovine serum albumin conjugate. Nec-1S (50 µM), and GSK-872(10 µM) were further used to explore their relative effect. The neurobehavioral performance was assessed using mazes and task-assisted performance tests. To decipher the hypothesis plasma parameters, western blot, immunofluorescence, microscopy, and quantitative reverse transcription-PCR studies were carried out. The Nec-1S treatment restored cognitive performance and reduced the p-RIPK-p-RIPK3-p-MLKL mediated neuro-microglia changes in the brain and in cells as well, under lipotoxic stress. Nec-1S reduced tau, and amyloid oligomer load. Moreover, Nec-1S restored mitochondrial function and autophago-lysosome clearance. The findings highlight the central impact of metabolic syndrome and how Nes-1S, by acting as a multifaceted agent, improved central functioning.

Antiplatelet Effect of Daphnetin Is Regulated by cPLA2-Mediated Thromboxane A2 Generation in Mice.

Coumarin derivatives have been recognized for their antithrombotic, anti-inflammatory, and antioxidant properties, and daphnetin is one of the natural coumarin derivatives isolated from Daphne Koreana Nakai. Although the pharmacological value of daphnetin is well documented in diverse biological activities, its antithrombotic effect has not been studied to date. Here, we characterized the role and underlying mechanism of daphnetin in the regulation of platelet activation using murine platelets. In order to check the effect of daphnetin on platelet function, we first measured the effect of daphnetin on platelet aggregation and secretion. Collagen-induced platelet aggregation and dense granule secretion were partially inhibited by daphnetin. Interestingly, 2-MeSADP-induced secondary waves of aggregation and secretion were completely inhibited by daphnetin. It is known that 2-MeSADP-induced secretion and the resultant secondary wave of aggregation are mediated by the positive feedback effect of thromboxane A2 (TxA2) generation, suggesting the important role of daphnetin on TxA2 generation in platelets. Consistently, daphnetin did not affect the 2-MeSADP-induced platelet aggregation in aspirinated platelets where the contribution of TxA2 generation was blocked. Additionally, platelet aggregation and secretion induced by a low concentration of thrombin, which is affected by the positive feedback effect of TxA2 generation, were partially inhibited in the presence of daphnetin. Importantly, 2-MeSADP- and thrombin-induced TxA2 generation was significantly inhibited in the presence of daphnetin, confirming the role of daphnetin on TxA2 generation. Finally, daphnetin significantly inhibited 2-MeSADP-induced cytosolic phospholipase A2 (cPLA2) and ERK phosphorylation in non-aspirinated platelets. Only cPLA2 phosphorylation, not ERK phosphorylation, was significantly inhibited by daphnetin in aspirinated platelets. In conclusion, daphnetin plays a critical role in platelet function by inhibiting TxA2 generation through the regulation of cPLA2 phosphorylation.

Metabolic Regulation of Glia and Their Neuroinflammatory Role in Alzheimer's Disease.

Alzheimer's disease (AD) is an aging-related neurodegenerative disorder. It is characterized clinically by progressive memory loss and impaired cognitive function. Its progression occurs from neuronal synapse loss to amyloid pathology and Tau deposit which eventually leads to the compromised neuronal function. Neurons in central nervous tissue work in a composite and intricate network with the glia and vascular cells. Microglia and astrocytes are becoming the prime focus due to their involvement in various aspects of neurophysiology, such as trophic support to neurons, synaptic modulation, and brain surveillance. AD is also often considered as the sequela of prolonged metabolic dyshomeostasis. The neuron and glia have different metabolic profiles as cytosolic glycolysis and mitochondrial-dependent oxidative phosphorylation (OXPHOS), especially under dyshomeostasis or with aging pertaining to their unique genetic built-up. Various efforts are being put in to decipher the role of mitochondrial dynamics regarding their trafficking, fission/fusion imbalance, and mitophagy spanning over both neurons and glia to improve aging-related brain health. The mitochondrial dysfunction may lead to activation in various signaling mechanisms causing metabolic reprogramming in glia cells, further accelerating AD-related pathogenic events. The glycolytic-dominant astrocytes switch to the neurotoxic phenotype, i.e., disease-associated astrocyte under metabolic stress. The microglia also transform from resting to reactive phenotype, i.e., disease-associated microglia. It may also exist in otherwise a misconception an M1, glycolytic, or M2, an OXPHOS-dependent phenotype. Further, glial transformation plays a vital role in regulating hallmarks of AD pathologies like synapse maintenance, amyloid, and Tau clearance. In this updated review, we have tried to emphasize the metabolic regulation of glial reactivity, mitochondrial quality control mechanisms, and their neuroinflammatory response in Alzheimer's progression.

Role of MicroRNAs, Aptamers in Neuroinflammation and Neurodegenerative Disorders.

Exploring the microRNAs and aptamers for their therapeutic role as biological drugs has expanded the horizon of its applicability against various human diseases, explicitly targeting the genetic materials. RNA-based therapeutics are widely being explored for the treatment and diagnosis of multiple diseases, including neurodegenerative disorders (NDD). Latter includes microRNA, aptamers, ribozymes, and small interfering RNAs (siRNAs), which control the gene expression mainly at the transcriptional strata. One RNA transcript translates into different protein types; hence, therapies targeted at the transcriptional sphere may have prominent and more extensive effects than alternative therapeutics. Unlike conventional gene therapy, RNAs, upon delivery, can either altogether abolish or alter the synthesis of the protein of interest, therefore, regulating their activities in a controlled and diverse manner. NDDs like Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, Prion disease, and others are characterized by deposition of misfolded protein such as amyloid-ß, tau, α-synuclein, huntingtin and prion proteins. Neuroinflammation, one of the perquisites for neurodegeneration, is induced during neurodegenerative pathogenesis. In this review, we discuss microRNAs and aptamers' role as two different RNA-based approaches for their unique ability to regulate protein production at the transcription level, hence offering many advantages over other biologicals. The microRNA acts either by alleviating the malfunctioning RNA expression or by working as a replacement to lost microRNA. On the contrary, aptamer act as a chemical antibody and forms an aptamer-target complex.

Neuroepigenetic alterations in the prefrontal cortex of type 2 diabetic mice through DNA hypermethylation.

BACKGROUND: DNA methylation changes have known to downregulate several regulatory proteins epigenetically during various neurodegenerative disorders. Our study aims to understand the effect of this global DNA methylation on the cerebral complications of type 2 diabetes mice, and its notable effect on maintaining the synaptic fidelity. METHODS AND RESULTS: Chronic high fat diet and streptozotocin-induced diabetic mice were studied for the neurobehavioral and neuroanatomic parameters pertaining to prefrontal cortex, subsequently elucidating the associated changes in DNA methylation within these diabetic brains. Further, the impact of this epigenetic dysregulation on HSF1, BDNF and PSD95 were studied by assessing the binding affinity and level of % methylation within the promoter site of their respective genes. Our study suggest increased DNMT aberrations within the prefrontal cortex, with increased MeCP2 levels, confirming DNA hypermethylation. This was in accordance with the altered neurobehavioral changes. Further, the hypermethylation was found to participate in gene silencing of HSF1, BDNF and PSD95 proteins, responsible for maintaining the synaptic fidelity. CONCLUSION: Overall, our study concludes the plausible involvement of neuroepigenetic alterations in the prefrontal cortex (PFC) of the type 2 diabetes mice, specifically DNA hypermethylation. PFC plays a central role in modulating cognitive and other executive functions through its connection with several brain regions, and thus therapeutic strategies targeting epigenetic modulations in it, can pave a way in controlling several neurological alterations in the brain.

An Insight into Recent Advances on Platelet Function in Health and Disease.

Platelets play a variety of roles in vascular biology and are best recognized as primary hemostasis and thrombosis mediators. Platelets have a large number of receptors and secretory molecules that are required for platelet functionality. Upon activation, platelets release multiple substances that have the ability to influence both physiological and pathophysiological processes including inflammation, tissue regeneration and repair, cancer progression, and spreading. The involvement of platelets in the progression and seriousness of a variety of disorders other than thrombosis is still being discovered, especially in the areas of inflammation and the immunological response. This review represents an integrated summary of recent advances on the function of platelets in pathophysiology that connects hemostasis, inflammation, and immunological response in health and disease and suggests that antiplatelet treatment might be used for more than only thrombosis.

Glia: A major player in glutamate-GABA dysregulation-mediated neurodegeneration.

The imbalance between glutamate and γ-aminobutyric acid (GABA) results in the loss of synaptic strength leading to neurodegeneration. The dogma on the field considered neurons as the main players in this excitation-inhibition (E/I) balance. However, current strategies focusing only on neurons have failed to completely understand this condition, bringing up the importance of glia as an alternative modulator for neuroinflammation as glia alter the activity of neurons and is a source of both neurotrophic and neurotoxic factors. This review's primary goal is to illustrate the role of glia over E/I balance in the central nervous system and its interaction with neurons. Rather than focusing only on the neuronal targets, we take a deeper look at glial receptors and proteins that could also be explored as drug targets, as they are early responders to neurotoxic insults. This review summarizes the neuron-glia interaction concerning GABA and glutamate, possible targets, and its involvement in the E/I imbalance in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis.

The GRKs Reactome: Role in Cell Biology and Pathology.

G protein-coupled receptor kinases (GRKs) are protein kinases that function in concert with arrestins in the regulation of a diverse class of G protein-coupled receptors (GPCRs) signaling. Although GRKs and arrestins are key participants in the regulation of GPCR cascades, the complex regulatory mechanisms of GRK expression, its alternation, and their function are not thoroughly understood. Several studies together with the work from our lab in recent years have revealed the critical role of these kinases in various physiological and pathophysiological processes, including cardiovascular biology, inflammation and immunity, neurodegeneration, thrombosis, and hemostasis. A comprehensive understanding of the mechanisms underlying functional interactions with multiple receptor proteins and how these interactions take part in the development of various pathobiological processes may give rise to novel diagnostic and therapeutic strategies. In this review, we summarize the current research linking the role of GRKs to various aspects of cell biology, pathology, and therapeutics, with a particular focus on thrombosis and hemostasis.

Pyk2 downstream of G12/13 pathways regulates platelet shape change through RhoA/p160ROCK.

Rho/Rho-kinase downstream of G12/13 plays an important role in the regulation of calcium-independent platelet shape change. We have previously shown that proline-rich tyrosine kinase 2 (Pyk2) is activated downstream of G12/13 pathways. In this study, we evaluated the role of Pyk2 in G12/13-induced platelet shape change. We used low concentrations of YFLLRNP, a heptapeptide binding to protease-activated receptor 1 (PAR1), or PAR4-activating peptide AYPGKF in the presence of Gαq inhibitor YM254890 to selectively stimulate G12/13 pathways. We found that G12/13-induced platelet shape change was completely inhibited in the presence of Pyk2 inhibitors AG17 and TAT-Pyk2-CT, suggesting an important role of Pyk2 in platelet shape change. In addition, AYPGKF-induced shape change in Gq -/- platelets was completely inhibited in the presence of AG17 or RhoA/p160ROCK inhibitor Y27632, confirming the role of Pyk2 in RhoA-dependent shape change. Furthermore, AYPGKF-induced platelet aggregation and dense granule secretion were inhibited by blocking Pyk2 or RhoA. Finally, G12/13-induced myosin phosphatase target subunit 1 (MYPT1) phosphorylation was inhibited by AG17, confirming that Pyk2 regulates RhoA/p160ROCK activation in platelets. These results demonstrate that Pyk2 downstream of G12/13 pathways regulates platelet shape change as well as platelet aggregation and dense granule secretion through the regulation of RhoA/p160ROCK.

Characterization of Integrin αIIbß3-Mediated Outside-in Signaling by Protein Kinase Cδ in Platelets.

Engagement of integrin αIIbß3 promotes platelet-platelet interaction and stimulates outside-in signaling that amplifies activation. Protein kinase Cδ (PKCδ) is known to play an important role in platelet activation, but its role in outside-in signaling has not been established. In the present study, we determined the role of PKCδ and its signaling pathways in integrin αIIbß3-mediated outside-in signaling in platelets using PKCδ-deficient platelets. Platelet spreading to immobilized fibrinogen resulted in PKCδ phosphorylation, suggesting that αIIbß3 activation caused PKCδ activation. αIIbß3-mediated phosphorylation of Akt was significantly inhibited in PKCδ -/- platelets, indicating a role of PKCδ in outside-in signaling. αIIbß3-mediated PKCδ phosphorylation was inhibited by proline-rich tyrosine kinase 2 (Pyk2) selective inhibitor, suggesting that Pyk2 contributes to the regulation of PKCδ phosphorylation in outside-in signaling. Additionally, Src-family kinase inhibitor PP2 inhibited integrin-mediated Pyk2 and PKCδ phosphorylation. Lastly, platelet spreading was inhibited in PKCδ -/- platelets compared to the wild-type (WT) platelets, and clot retraction from PKCδ -/- platelets was markedly delayed, indicating that PKCδ is involved in the regulation of αIIbß3-dependent interactivities with cytoskeleton elements. Together, these results provide evidence that PKCδ plays an important role in outside-in signaling, which is regulated by Pyk2 in platelets.

Role of GRK6 in the Regulation of Platelet Activation through Selective G Protein-Coupled Receptor (GPCR) Desensitization.

Platelet G protein-coupled receptors (GPCRs) regulate platelet function by mediating the response to various agonists, including adenosine diphosphate (ADP), thromboxane A2, and thrombin. Although GPCR kinases (GRKs) are considered to have the crucial roles in most GPCR functions, little is known regarding the regulation of GPCR signaling and mechanisms of GPCR desensitization by GRKs in platelets. In this study, we investigated the functional role of GRK6 and the molecular basis for regulation of specific GPCR desensitization by GRK6 in platelets. We used GRK6 knockout mice to evaluate the functional role of GRK6 in platelet activation. Platelet aggregation, dense- and -granule secretion, and fibrinogen receptor activation induced by 2-MeSADP, U46619, thrombin, and AYPGKF were significantly potentiated in GRK6-/- platelets compared to the wild-type (WT) platelets. However, collagen-related peptide (CRP)-induced platelet aggregation and secretion were not affected in GRK6-/- platelets. Interestingly, platelet aggregation induced by co-stimulation of serotonin and epinephrine which activate Gq-coupled 5HT2A and Gz-coupled 2A adrenergic receptors, respectively, was not affected in GRK6-/- platelets, suggesting that GRK6 was involved in specific GPCR regulation. In addition, platelet aggregation in response to the second challenge of ADP and AYPGKF was restored in GRK6-/- platelets whereas re-stimulation of the agonist failed to induce aggregation in WT platelets, indicating that GRK6 contributed to P2Y1, P2Y12, and PAR4 receptor desensitization. Furthermore, 2-MeSADP-induced Akt phosphorylation and AYPGKF-induced Akt, extracellular signal-related kinase (ERK), and protein kinase Cδ (PKC) phosphorylation were significantly potentiated in GRK6-/- platelets. Finally, GRK6-/- mice exhibited an enhanced and stable thrombus formation after FeCl3 injury to the carotid artery and shorter tail bleeding times, indicating that GRK6-/- mice were more susceptible to thrombosis and hemostasis. We conclude that GRK6 plays an important role in regulating platelet functional responses and thrombus formation through selective GPCR desensitization.

S1PR2 inhibition mitigates cognitive deficit in diabetic mice by modulating microglial activation via Akt-p53-TIGAR pathway.

Cognitive deficit is one of the challenging complications of type 2 diabetes. Sphingosine 1- phosphate receptors (S1PRs) have been implicated in various neurodegenerative and metabolic disorders. The association of S1PRs and cognition in type 2 diabetes remains elusive. Microglia-mediated neuronal damage could be the thread propagating cognitive deficit. The effects of S1PR2 inhibition on cognition in high-fat diet and streptozotocin-induced diabetic mice were examined in this work. We further assessed microglial activation and putative microglial polarisation routes. Cognitive function loss was observed after four months of diabetes induction in Type 2 diabetes animal model. JTE013, an S1PR2 inhibitor, was used to assess neuroprotection against cognitive decline and neuroinflammation in vitro and in vivo diabetes model. JTE013 (10 mg/kg) improved synaptic plasticity by upregulating psd95 and synaptophysin while reducing cognitive decline and neuroinflammation. It further enhanced anti-inflammatory microglia in the hippocampus and prefrontal cortex (PFC), as evidenced by increased Arg-1, CD206, and YM-1 levels and decreased iNOS, CD16, and MHCII levels. TIGAR, TP53-induced glycolysis and apoptosis regulator, might facilitate the anti-inflammatory microglial phenotype by promoting oxidative phosphorylation and decreasing apoptosis. However, since p53 is a TIGAR suppressor, inhibiting p53 could be beneficial. S1PR2 inhibition increased p-Akt and TIGAR levels and reduced the levels of p53 in the PFC and hippocampus of type 2 diabetic mice, thereby decreasing apoptosis. In vitro, palmitate was used to imitate sphingolipid dysregulation in BV2 cells, followed by conditioned media exposure to Neuro2A cells. JTE013 rescued the palmitate-induced neuronal apoptosis by promoting the anti-inflammatory microglia. In the present study, we demonstrate that the inhibition of S1PR2 improves cognitive function and skews microglia toward anti-inflammatory phenotype in type 2 diabetic mice, thereby promising to be a potential therapy for neuroinflammation.

Experimental Type 2 diabetes and lipotoxicity-associated neuroinflammation involve mitochondrial DNA-mediated cGAS/STING axis: implication of Type-1 interferon response in cognitive impairment.

Type-1 IFN (interferon)-associated innate immune response is increasingly getting attention in neurodegenerative and metabolic diseases like type 2 diabetes (T2DM). However, its significance in T2DM/lipotoxicity-induced neuroglia changes and cognitive impairment is missing. The present study aims to evaluate the involvement of cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon gene), IRF3 (interferon regulatory factor-3), TBK (TANK binding kinase)-mediated Type-1 IFN response in the diabetic brain, and lipotoxicity (palmitate-bovine serum albumin conjugate/PA-BSA)-induced changes in cells (neuro2a and BV2). T2DM was induced in C57/BL6 mice by feeding on a high-fat diet (HFD, 60% Kcal) for 16 weeks and injecting a single dose of streptozotocin (100 mg/kg, i.p) in the 12th week. Plasma biochemical parameter analysis, neurobehavioral assessment, protein expression, and quantitative polymerase chain reaction study were carried out to decipher the hypothesis. T2DM-associated metabolic and lipotoxic stress led to mitochondrial impairment causing leakage of mtDNA to the cytoplasm further commencing cGAS activation and its downstream signaling. The diseased hippocampus and cortex showed decreased expression of synaptophysin (p < 0.01) and PSD-95 (p < 0.01, p < 0.05) with increased expression of cGAS (p < 0.001), p-STING (p < 0.001), p-STAT1 (signal transducer and activator of transcription) (p < 0.01), and IFN-ß (p < 0.001) compared to normal control. The IFN-ß/p-STAT1-mediated microglia activation was executed employing a conditioned media approach. C-176, a selective STING inhibitor, alleviated cGAS/p-STING/IFN-ß expression and proinflammatory microglia/M1-associated markers (CD16 expression, CXCL10, TNF-α, IL-1ß mRNA fold change) in the diabetic brain. The present study suggests Type-1IFN response may result in neuroglia dyshomeostasis affecting normal brain function. Alleviating STING signaling has the potential to protect T2DM-associated central ailment.

The Perspectives of Platelet Proteomics in Health and Disease.

Cardiovascular thromboembolic diseases and cancer continue to be a leading cause of death and disability worldwide. Therefore, it is crucial to advance their diagnoses and treatment in the context of individualized medicine. However, the disease specificity of the currently available markers is limited. Based on analyses of a subset of peptides and matching proteins in disease vs. healthy platelets, scientists have recently shown that focused platelet proteomics enables the quantification of disease-specific biomarkers in humans. In this review, we explored the potential of accurate platelet proteomic research, which is required to identify novel diagnostic and pharmaceutical targets by comprehending the proteome variety of healthy individuals and patients for personalized and precision medicine.

Histopathological and Immunohistochemical Characterization of Sebaceous Adenoma and Epithelioma in Dogs.

Sebaceous gland tumors are neoplasms originating from the sebaceous gland and are the third most common type of skin tumor, accounting for 21-35% of all cutaneous neoplasms in dogs. According to their histopathological characteristics, sebaceous gland tumors can be classified into adenoma as a benign tumor and epithelioma as a malignant tumor. Sebaceous epithelioma is distinguished from sebaceous adenoma by containing 90% or more reserve cells. However, this simple numerical criterion is insufficient to histologically distinguish between epitheliomas and adenomas. In addition, sebaceoma in humans, a similar tumor to sebaceous epithelioma, is a term used for tumors with more than 50% of reserve cells, unlike epithelioma. Therefore, we aimed to compare and characterize the histological and immunohistochemical profiles of comprehensive sebaceous adenoma, epithelioma, and borderline tumors that have more than 50% but less than 90% of reserve cells. A total of 14 canine sebaceous tumors were diagnosed as seven adenomas, four borderline tumors, and three epitheliomas. Histologically, the sebaceous adenomas showed nodules consisting of mature sebocytes surrounded by monolayer basaloid cells. In contrast, the portion of the reserve cells was increased, the portion of lipidized cells was decreased, and the majority of lipidized cells were found to be immature in sebaceous epithelioma. In the sebaceous adenomas, necrosis was not observed and mitotic figures were rarely seen. However, necrosis and mitotic figures were highly frequent in both borderline tumor and sebaceous epithelioma. Immunohistochemistry revealed that borderline tumor and sebaceous epithelioma showed significantly higher expression against Ki-67 than sebaceous adenoma. We conclude that it is more accurate to employ the cut-off value of 50% reserve cells in humans rather than the current 90% reserve cells for classifying sebaceous gland tumors in dogs, thereby providing new insight into the characterization of the sebaceous gland tumors.

A rare case of chikungunya encephalitis and its management: A case report and literature review.

Key Clinical Message: Chikungunya encephalitis, though rare, warrants clinical attention due to its severe complications. Early identification and appropriate management are crucial for improved outcomes in patients with this rare manifestation of chikungunya virus (CHIKV) infection. Abstract: CHIKV infection is commonly associated with fever and joint pains, but neurological complications such as encephalitis are rare. Here, we present a unique case of confirmed chikungunya encephalitis in a 12-year-old male exhibiting atypical neurological symptoms. The diagnostic journey involved comprehensive neuroimaging and serological investigations, revealing intriguing findings on magnetic resonance imaging and positive CHIKV RNA in serum and cerebrospinal fluid. We discuss the clinical presentation, radiological characteristics, and management strategies, emphasizing the importance of recognizing this uncommon neurological manifestation of CHIKV infection.

Piceatannol promotes neuroprotection by inducing mitophagy and mitobiogenesis in the experimental diabetic peripheral neuropathy and hyperglycemia-induced neurotoxicity.

Piceatannol (PCN), a SIRT1 activator, regulates multiple oxidative stress mechanism and has anti-inflammatory potential in various inflammatory conditions. However, its role in Diabetic insulted peripheral neuropathy (DN) remains unknown. Oxidative stress and mitochondrial dysfunction are major contributing factors to DN. Myriad studies have proven that sirtuin1 (SIRT1) stimulation convalesce nerve functions by activating mitochondrial functions like mitochondrial biogenesis and mitophagy. Diabetic neuropathy (DN) was provoked by injecting streptozotocin (STZ) at a dose of 55 mg/kg, i.p to male Sprague Dawley (SD) rats. Mechanical, thermal hyperalgesia was evaluated by using water immersion, Vonfrey Aesthesiometer, and Randall Sellito Calipers. Motor, sensory nerve conduction velocity was measured using Power Lab 4sp system whereas The Laser Doppler system was used to evaluate nerve blood flow. To induce hyperglycemia for the in vitro investigations, high glucose (HG) (30 mM) conditions were applied to Neuro2a cells. At doses of 5 and 10 µM, PCN was examined for its role in SIRT1 and Nrf2 activation. HG-induced N2A cells, reactive oxygen exposure, mitochondrial superoxides and mitochondrial membrane potentials were restored by PCN exposure, and their neurite outgrowth was enhanced. Peroxisome proliferator activated receptor-gamma coactivator-1α (PGC-1α) directed mitochondrial biogenesis was induced by increased SIRT1 activation by piceatannol. SIRT1 activation also enhanced Nrf2-mediated antioxidant signalling. Our study results inferred that PCN administration can counteract the decline in mitochondrial function and antioxidant activity in diabetic rats and HG-exposed N2A cells by increasing the SIRT1 and Nrf2 activities.

Sphingosine 1 phosphate lyase inhibition rescues cognition in diabetic mice by promoting anti-inflammatory microglia.

Sphingosine-1-phosphate (S1P) is emerging as a crucial sphingolipid modulating neuroinflammation and cognition. S1P levels in the brain have been found to be decreased in cognitive impairment. S1P lyase (S1PL) is the key enzyme in metabolizing S1P and has been implicated in neuroinflammation. This study evaluated the effect of S1PL inhibition on cognition in type 2 diabetic mice. Fingolimod (0.5 mg/kg and 1 mg/kg) rescued cognition in high-fat diet and streptozotocin-induced diabetic mice, as evident in the Y maze and passive avoidance test. We further evaluated the effect of fingolimod on the activation of microglia in the pre-frontal cortex (PFC) and hippocampus of diabetic mice. Our study revealed that fingolimod inhibited S1PL and promoted anti-inflammatory microglia in both PFC and hippocampus of diabetic mice as it increased Ym-1 and arginase-1. The levels of p53 and apoptotic proteins (Bax and caspase-3) were elevated in the PFC and hippocampus of type 2 diabetic mice which fingolimod reversed. The underlying mechanism promoting anti-inflammatory microglial phenotype was also explored in this study. TIGAR, TP53-associated glycolysis and apoptosis regulator, is known to foster anti-inflammatory microglia and was found to be downregulated in the brain of type 2 diabetic mice. S1PL inhibition decreased the levels of p53 and promoted TIGAR, thereby increasing anti-inflammatory microglial phenotype and inhibiting apoptosis in the brain of diabetic mice. Our study reveals that S1PL inhibition could be beneficial in mitigating cognitive deficits in diabetic mice.