Suppression of Experimental Autoimmune Encephalomyelitis in Mice by ß-Hydroxy ß-Methylbutyrate, a Body-Building Supplement in Humans.

Although several immunomodulatory drugs are available for multiple sclerosis (MS), most present significant side effects with long-term use. Therefore, delineation of nontoxic drugs for MS is an important area of research. ß-Hydroxy ß-methylbutyrate (HMB) is accessible in local GNC stores as a muscle-building supplement in humans. This study underlines the importance of HMB in suppressing clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of MS. Dose-dependent study shows that oral HMB at a dose of 1 mg/kg body weight/d or higher significantly suppresses clinical symptoms of EAE in mice. Accordingly, orally administered HMB attenuated perivascular cuffing, preserved the integrity of the blood-brain barrier and blood-spinal cord barrier, inhibited inflammation, maintained the expression of myelin genes, and blocked demyelination in the spinal cord of EAE mice. From the immunomodulatory side, HMB protected regulatory T cells and suppressed Th1 and Th17 biasness. Using peroxisome proliferator-activated receptor (PPAR)α-/- and PPARß-/- mice, we observed that HMB required PPARß, but not PPARα, to exhibit immunomodulation and suppress EAE. Interestingly, HMB reduced the production of NO via PPARß to protect regulatory T cells. These results describe a novel anti-autoimmune property of HMB that may be beneficial in the treatment of MS and other autoimmune disorders.

Activation of PPARα Exhibits Therapeutic Efficacy in a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis.

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal inherited neurodegenerative disease of children that occurs because of defective function of the lysosomal membrane glycoprotein CLN3. JNCL features glial activation and accumulation of autofluorescent storage material containing subunit c of mitochondrial ATP synthase (SCMAS), ultimately resulting into neuronal loss. Until now, no effective therapy is available for JNCL. This study underlines the possible therapeutic importance of gemfibrozil, an activator of peroxisome proliferator-activated receptor α (PPARα) and a lipid-lowering drug approved by the Food and Drug Administration in an animal model of JNCL. Oral gemfibrozil treatment reduced microglial and astroglial activation, attenuated neuroinflammation, restored the level of transcription factor EB (TFEB; the master regulator of lysosomal biogenesis), and decreased the accumulation of storage material SCMAS in somatosensory barrel field (SBF) cortex of Cln3Δex7/8 (Cln3ΔJNCL) mice of both sexes. Accordingly, gemfibrozil treatment also improved locomotor activities of Cln3ΔJNCL mice. While investigating the mechanism, we found marked loss of PPARα in the SBF cortex of Cln3ΔJNCL mice, which increased after gemfibrozil treatment. Oral gemfibrozil also stimulated the recruitment of PPARα to the Tfeb gene promoter in vivo in the SBF cortex of Cln3ΔJNCL mice, indicating increased transcription of Tfeb in the CNS by gemfibrozil treatment via PPARα. Moreover, disease pathologies aggravated in Cln3ΔJNCL mice lacking PPARα (Cln3ΔJNCLΔPPARα) and gemfibrozil remained unable to decrease SCMAS accumulation, reduce glial activation, and improve locomotor performance of Cln3ΔJNCLΔPPARα mice. These results suggest that activation of PPARα may be beneficial for JNCL and that gemfibrozil may be repurposed for the treatment of this incurable disease.SIGNIFICANCE STATEMENT Despite intense investigations, no effective therapy is available for JNCL, an incurable inherited lysosomal storage disorder. Here, we delineate that oral administration of gemfibrozil, a lipid-lowering drug, decreases glial inflammation, normalizes and/or upregulates TFEB, and reduces accumulation of autofluorescent storage material in SBF cortex to improve locomotor activities in Cln3Δex7/8 (Cln3ΔJNCL) mice. Aggravation of disease pathology in Cln3ΔJNCL mice lacking PPARα (Cln3ΔJNCLΔPPARα) and inability of gemfibrozil to decrease SCMAS accumulation, reduce glial activation, and improve locomotor performance of Cln3ΔJNCLΔPPARα mice delineates an important role of PPARα in this process. These studies highlight a new property of gemfibrozil and indicate its possible therapeutic use in JNCL patients.

Protection of Mice from Controlled Cortical Impact Injury by Food Additive Glyceryl Tribenzoate.

Despite intense investigations, no effective therapy is available to halt the pathogenesis of traumatic brain injury (TBI), a major health concern, which sometimes leads to long-term neurological disability, especially in war veterans and young adults. This study highlights the use of glyceryl tribenzoate (GTB), a flavoring ingredient, in ameliorating the disease process of controlled cortical impact (CCI)-induced TBI in mice. Oral administration of GTB decreased the activation of microglia and astrocytes to inhibit the expression of inducible nitric oxide synthase (iNOS) in hippocampus and cortex of TBI mice. Accordingly, GTB treatment protected and/or restored synaptic maturation in the hippocampus of TBI mice as revealed by the status of PSD-95, NR-2A and GluR1. Furthermore, oral GTB also reduced the size of lesion cavity in the brain of TBI mice. Finally, GTB treatment improved locomotor functions and protected spatial learning and memory in TBI mice. These results outline a novel neuroprotective property of GTB which may be beneficial in treatment of TBI.

Therapeutic efficacy of cinnamein, a component of balsam of Tolu/Peru, in controlled cortical impact mouse model of TBI.

Traumatic brain injury (TBI) remains a major health concern which causes long-term neurological disability particularly in war veterans, athletes and young adults. In spite of intense clinical and research investigations, there is no effective therapy to cease the pathogenesis of the disease. It is believed that axonal injury during TBI is potentiated by neuroinflammation and demyelination and/or failure to remyelination. This study highlights the use of naturally available cinnamein, also chemically known as benzyl cinnamate, in inhibiting neuroinflammation, promoting remyelination and combating the disease process of controlled cortical impact (CCI)-induced TBI in mice. Oral delivery of cinnamein through gavage brought down the activation of microglia and astrocytes to decrease the expression of inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) in hippocampus and cortex of TBI mice. Cinnamein treatment also stimulated remyelination in TBI mice as revealed by PLP and A2B5 double-labeling, luxol fast blue (LFB) staining and axonal double-labeling for neurofilament and MBP. Furthermore, oral cinnamein reduced the size of lesion cavity in the brain, improved locomotor functions and restored memory and learning in TBI mice. These results suggest a new neuroprotective property of cinnamein that may be valuable in the treatment of TBI.

Flavonoids, alkaloids and terpenoids: a new hope for the treatment of diabetes mellitus.

Diabetes mellitus is a metabolic syndrome characterized by a hyperglycemic state and multi-organ failure. Millions of people worldwide are suffering from this deadly disease taking a hit on their pocket and mental health in the name of its treatment. Modern medical practices with new technological advancements and discoveries have made revolutionary changes in the treatment. But, unfortunately, Glucose-lowering drugs used have many accompanying effects such as chronic vascular disease, renal malfunction, liver disease and, many skin problems. These complications have made us think about alternative treatments for diabetes with minimum or no side effects. Nowadays, in addition to modern medicine, herbal treatment has been suggested to treat diabetes mellitus. These herbal medicines contain biological macromolecules such as flavonoids, Terpenoids, glycosides, and alkaloids, which show versatile anti-diabetic effects. These phytochemicals are generally considered safe, and naturally occurring compounds have a potential role in preventing or controlling diabetes mellitus. The underlying mechanism of their anti-diabetic effects includes improvement in insulin secretion, decrease in insulin resistance, enhanced liver glycogen synthesis, antioxidant and anti-inflammatory activities. In this review, we have focused on the mechanism of various phytochemicals targeting hyperglycemia and its underlying pathogenesis.

Physiological Relevance of Angiotensin Converting Enzyme 2 As a Metabolic Linker and Therapeutic Implication of Mesenchymal Stem Cells in COVID-19 and Hypertension.

Severe acute respiratory syndrome corona virus - 2 (SARS-CoV-2) is a single stranded RNA virus and responsible for infecting human being. In many cases the individual may remain asymptomatic. Some recently reported studies revealed that individuals of elderly age group and with pre-existing medical conditions such as hypertension, diabetes mellitus had severe consequences, even may lead to death. However, it is not clearly delineated whether hypertension itself or associated comorbidities or antihypertensive therapy contributes to the grave prognosis of COVID-19 infections. This review is aimed to decipher the exact mechanisms involved at molecular level from existing evidence and as reported. It has been reported that SARS-CoV-2 enters into the host cell through interaction between conserved residues of viral spike protein and angiotensin converting enzyme 2 (ACE2) receptor which is highly expressed in host's cardiac and pulmonary cells and finally transmembrane protease, serine-2 (TMPRSS2), helps in priming of the surface protein. Subsequently, symptom related to multi organ involvement is primarily contributed by cytokine storm. Although various clinical trials are being conducted on renin- angiotensin- system inhibitor, till to date there is no standard treatment protocol approved for critically ill COVID-19 positive cases with pre-existing hypertension. Recently, several studies are carried out to document the safety and efficacy outcome of mesenchymal stem cell transplantation based on its immunomodulatory and regenerative properties. Therefore, identification of future novel therapeutics in the form of mesenchymal stem cell either alone or in combination with pharmacological approach could be recommended for combating SARS-CoV-2 which might be dreadful to debilitating elderly people. Graphical Abstract.

Repurposing of SARS-CoV nucleocapsid protein specific nuclease resistant RNA aptamer for therapeutics against SARS-CoV-2.

COVID-19 pandemic is rapidly advancing among human population. Development of new interventions including therapeutics and vaccines against SARS-CoV-2 will require time and validation before it could be made available for public use. Keeping in view of the emergent and evolving situation the motive is to repurpose and test the immediate efficacy of available drugs and therapeutics against COVID-19. Through this article we propose and discuss the possibility of repurposing the available nuclease resistant RNA aptamer against the nucleocapsid protein of SARS-CoV as a potential therapeutic agent for COVID-19.

Inhibition of complex I-III activity of brain mitochondria after intracerebroventricular administration of streptozotocin in rats is possibly related to loss of body weight.

The effects of streptozotocin (STZ) on the brain after intracerebroventricular (ICV) administration in rodents have been suggested to mimic the pathogenesis of sporadic Alzheimer's disease (AD). Oxidative damage, decreased glucose utilization, mitochondrial bioenergetic changes, neuroinflammation and behavioral impairment have been reported in rodents after ICV-STZ administration. However, the molecular mechanisms of STZ effects on brain after ICV administration remain highly controversial. In this study we re-examined several bioenergetic parameters of rat brain mitochondria on day 15 following ICV-STZ treatment. We observed only a moderate but statistically significant decrease in complex I-III activity in brain mitochondria from streptozotocin-treated rats. There were no changes in complex II-III activity or phosphorylation capacity of brain mitochondria after streptozotocin treatment. More importantly, it was observed that ICV-STZ treatment caused variable degrees of body-weight loss in rats, and complex I-III activity was decreased only in those rats showing a significant (more than 10%-35%) loss in body-weights.

Biochemical deficits and cognitive decline in brain aging: Intervention by dietary supplements.

The aging of brain in the absence of neurodegenerative diseases, usually called non-pathological brain aging or normal cognitive aging, is characterized by an impairment of memory and cognitive functions. The underlying cellular and molecular changes in the aging brain that include oxidative damage, mitochondrial impairment, changes in glucose-energy metabolism and neuroinflammation have been reported widely from animal experiments and human studies. The cognitive deficit of non-pathological brain aging is the resultant of such inter-dependent and reinforcing molecular pathologies which have striking similarities with those operating in Alzheimer's disease which causes progressive, irreversible and a devastating form of dementia and cognitive decline in the elderly people. Further, this article has described elaborately how nutraceuticals present in a wide variety of plants, fruits and seeds, natural vitamins or their analogues, synthetic antioxidants and other compounds taken with the diet can ameliorate the cognitive decline of brain aging by correcting the biochemical alterations at multiple levels. The clinical usefulness of such dietary supplements should be examined both for normal brain aging and Alzheimer's disease through randomized controlled trials.

Role of Serum Adiponectin and Vitamin D in Prediabetes and Diabetes Mellitus.

OBJECTIVES: The roles of deficient or deranged insulin, adiponectin and 25 hydroxy vitamin D (25[OH]D) levels regulating food intake, energy metabolism, glucose and lipid metabolism and body weight have been reported in the pathogenesis of prediabetes and type 2 diabetes mellitus. However, their congruity in the etiology of diabetes mellitus is unknown. Thus, the aim of the study was to investigate the roles of these parameters together and to establish their interrelationship in patients with prediabetes and diabetes. METHODS: The preliminary cross-sectional study included 77 persons with type 2 diabetes who were matched for age, sex and body mass index (BMI); 73 persons with prediabetes; and 52 healthy control subjects. Fasting serum levels of adiponectin, insulin and 25(OH)D were measured by commercially available immune assay kits, and routine biochemical parameters were analyzed in all study groups. RESULTS: The results show statistically significant lower levels of serum adiponectin and serum 25(OH)D and higher serum insulin levels in persons with prediabetes or type 2 diabetes with respect to controls. The changes in the serum adiponectin or serum 25(OH)D in persons with prediabetes and type 2 diabetes were found to be inversely correlated with the serum levels of insulin. Moreover, multiple linear regression analysis, with 25(OH)D, insulin and homeostatic model assessment-insulin resistance (HOMA-IR) as the variables, revealed that serum adiponectin levels might be an independent risk factor for the progression of prediabetes and type 2 diabetes in subjects. CONCLUSIONS: The association of these hormones might act as a significant predictor of progression of prediabetes to type 2 diabetes. Decreased serum adiponectin levels might be an independent risk factor for progression to prediabetes and type 2 diabetes, which may help in developing experimental models of the disease or in identifying biomarkers or disease-modifying drugs.

Ceramide and Sphingosine-1-Phosphate in Cell Death Pathways : Relevance to the Pathogenesis of Alzheimer's Disease.

The metabolic turnover of sphingolipids produces several signaling molecules that profoundly affect the proliferation, differentiation and death of cells. In particular, an enormous body of information is available that defines the varied role of ceramide and sphingosine-1-phosphate in cell death and survival. This review specifically examines the role of ceramide and sphingosine-1- phosphate in triggering neuronal death in Alzheimer's disease by analyzing the data from post-mortem studies and experimental research. There is compelling evidence that ceramide plays a key role in the neurodegeneration and amyloidogenesis occurring in the brain in Alzheimer's disease. Further, it appears that ceramide and amyloid beta protein orchestrate an attack on mitochondria to set in the pathways of cell death. However, the complexity of metabolic and signaling pathways of sphingolipid derivatives precludes an immediate identification of effective drug targets for the therapy of Alzheimer's disease.