Alternative Approaches for the Management of Huntington's Disease: A Narrative Review.

Huntington's disease (HD) is an autosomal neurodegenerative disease that involves movement disorders, cognitive impairments, and psychiatric symptoms. It is characterized by regionally selective cortical degeneration that proceeds from posterior to anterior cortical region which explains its heterogeneity. At present, the psychiatric symptoms of HD are mostly managed by antidepressant such as selective serotonin reuptake inhibitors or selective nor-epinephrine reuptake inhibitors, and atypical antipsychotics. Currently, there are no efficient pharmacological treatment available for HD. Thus, in order to avoid this void in effective pharmacotherapy, further supplemental and alternative approaches are being explored for the management of problems associated with HD. A literature review was performed using the databases PubMed and Google Scholar identifying clinical studies that were set to ameliorate the symptoms associated with HD. On critical analysis, it was found that alternative treatment modalities like music therapy, video games, Yoga, Physical therapy, and exercise-based programs have a potential and possible role in improving the symptoms of HD at varied degrees.

Combined Administration of Metformin and Vitamin D: A Futuristic Approach for Management of Hyperglycemia.

Diabetes is a series of metabolic disorders that can be categorized into three types depending on different aspects associated with age at onset, intensity of insulin resistance, and beta- cell dysfunction: Type 1 and 2 Diabetes, and Gestational Diabetes Mellitus. Type 2 Diabetes Mellitus (T2DM) has recently been found to account for more than 85% of diabetic cases. The current review intends to raise awareness among clinicians/researchers that combining vitamin D3 with metformin may pave the way for better T2DM treatment and management. An extensive literature survey was performed to analyze vitamin D's role in regulating insulin secretion, their action on the target cells and thus maintaining the normal glucose level. On the other side, the anti-hyperglycemic effect of metformin as well as its detailed mechanism of action was also studied. Interestingly both compounds are known to exhibit the antioxidant effect too. Literature supporting the correlation between diabetic phenotypes and deficiency of vitamin D was also explored further. To thoroughly understand the common/overlapping pathways responsible for the antidiabetic as well as antioxidant nature of metformin and vitamin D3, we compared their antihyperglycemic and antioxidant activities. With this background, we are proposing the hypothesis that it would be of great interest if these two compounds could work in synergy to better manage the condition of T2DM and associated disorders.

Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

Potential of Capric Acid in Neurological Disorders: An Overview.

To solve the restrictions of a classical ketogenic diet, a modified medium-chain triglyceride diet was introduced which required only around 60% of dietary energy. Capric acid (CA), a small molecule, is one of the main components because its metabolic profile offers itself as an alternate source of energy to the brain in the form of ketone bodies. This is possible with the combined capability of CA to cross the blood-brain barrier and achieve a concentration of 50% concentration in the brain more than any other fatty acid in plasma. Natural sources of CA include vegetable oils such as palm oil and coconut oil, mammalian milk and some seeds. Several studies have shown that CA has varied action on targets that include AMPA receptors, PPAR-γ, inflammatory/oxidative stress pathways and gut dysbiosis. Based on these lines of evidence, CA has proved to be effective in the amelioration of neurological diseases such as epilepsy, affective disorders and Alzheimer's disease. But these studies still warrant more pre-clinical and clinical studies that would further prove its efficacy. Hence, to understand the potential of CA in brain disease and associated comorbid conditions, an advance and rigorous molecular mechanistic study, apart from the reported in-vitro/in-vivo studies, is urgently required for the development of this compound through clinical setups.

Neuropharmacological Study on Capsaicin in Scopolamine-injected Mice.

AIM: To evaluate the potential beneficial role of Capsaicin in cognitive dysfunction, mitochondrial impairment, and oxidative damage induced by scopolamine in mice. BACKGROUND: Capsaicin is the chief phenolic component present in red chili and is responsible for its pungent and spicy flavor. It affects TRPV1 channels in nociceptive sensory neurons and is present in the hippocampus, and hypothalamus of the brains of rodents and humans. OBJECTIVE: The main objective is to investigate the effective role of capsaicin in attenuating cognitive dysfunction, mitochondrial impairment, and oxidative damage induced by scopolamine in mice and examine the feasible mechanisms. METHODS: Various doses of capsaicin (5, 10, and 20 mg/kg) were given orally to mice daily for 7 consecutive days after the administration of scopolamine. Various behavioral tests (motor coordination, locomotor counts, hole board test) and biochemical assay (Pro-inflammatory cytokines, catalase, lipid peroxidation, nitrite, reduced glutathione, and superoxide dismutase), mitochondrial complex (I, II, III, and IV) enzyme activities, and mitochondrial permeability transition were evaluated in the distinct regions of the brain. RESULTS: Scopolamine-treated mice showed a considerable reduction in the entries and duration in the light zone as well as in open arms of the elevated plus maze. Interestingly, capsaicin at different doses reversed the anxiety, depressive-like behaviors, and learning and memory impairment effects of scopolamine. Scopolamine-administered mice demonstrated substantially increased pro-inflammatory cytokines levels, impaired mitochondrial enzyme complex activities, and increased oxidative damage compared to the normal control group. Capsaicin treatment reinstated the reduced lipid peroxidation, nitric oxide, catalase, superoxide dismutase, reduced glutathione activity, decreasing pro-inflammatory cytokines and restoring mitochondrial complex enzyme activities (I, II, III, and IV) as well as mitochondrial permeability. Moreover, the IL-1ß level was restored at a dose of capsaicin (10 and 20 mg/kg) only. Capsaicin reduced the scopolamine-induced acetylcholinesterase activity, thereby raising the acetylcholine concentration in the hippocampal tissues of mice. Preservation of neuronal cell morphology was also confirmed by capsaicin in histological studies. From the above experimental results, capsaicin at a dose of 10 mg/kg, p.o. for seven consecutive days was found to be the most effective dose. CONCLUSION: The experiential neuroprotective effect of capsaicin through the restoration of mitochondrial functions, antioxidant effects, and modulation of pro-inflammatory cytokines makes it a promising candidate for further drug development through clinical setup.

Protective Role of Capsaicin in Neurological Disorders: An Overview.

Different pathological conditions that begin with slow and progressive deformations, cause irreversible affliction by producing loss of neurons and synapses. Commonly it is referred to as 'protein misfolding' diseases or proteinopathies and comprises the latest definition of neurological disorders (ND). Protein misfolding dynamics, proteasomal dysfunction, aggregation, defective degradation, oxidative stress, free radical formation, mitochondrial dysfunctions, impaired bioenergetics, DNA damage, neuronal Golgi apparatus fragmentation, axonal transport disruption, Neurotrophins (NTFs) dysfunction, neuroinflammatory or neuroimmune processes, and neurohumoral changes are the several mechanisms that embark the pathogenesis of ND. Capsaicin (8-Methyl-N-vanillyl-6-nonenamide) one of the major phenolic components in chili peppers (Capsicum) distinctively triggers the unmyelinated C-fiber and acts on Transient Receptor Potential Vanilloid-1, which is a Ca2+ permeable, non-selective cation channel. Several studies have shown the neuroprotective role of capsaicin against oxidative damage, behavioral impairment, with 6-hydroxydopamine (6-OHDA) induced Parkinson's disease, pentylenetetrazol-induced seizures, global cerebral ischemia, and streptozotocin-induced Alzheimer's disease. Based on these lines of evidence, capsaicin can be considered as a potential constituent to develop suitable neuro-pharmacotherapeutics for the management and treatment of ND. Furthermore, exploring newer horizons and carrying out proper clinical trials would help to bring out the promising effects of capsaicin to be recommended as a neuroprotectant.

Nanotherapeutic approaches to target mitochondria in cancer.

Treatment of cancer cells exemplifies a difficult test in the light of challenges associated with the nature of cancer cells and the severe side effects too. After making a large number of trials using both traditional and advanced therapies (immunotherapy and hormone therapy), approaches to design new therapies have reached a saturation level. However, nanotechnology-based approaches exhibit higher efficacy and great potential to bypass many of such therapeutic limitations. Because of their higher target specificity, the use of nanoparticles offers incredible potential in cancer therapeutics. Mitochondria, acting as a factory of energy production in cells, reveal an important role in the death as well as the survival of cells. Because of its significant involvement in the proliferation of cancer cells, it is being regarded as an important target for cancer therapeutics. Numerous studies reveal that nanotechnology-based approaches to directly target the mitochondria may help in improving the survival rate of cancer patients. In the current study, we have detailed the significance of mitochondria in the development of cancer phenotype, as well as indicated it as the potential targets for cancer therapy. Our study further highlights the importance of different nanoparticle-based approaches to target mitochondria of cancer cells and the associated outcomes of different studies. Though, nanotechnology-based approaches to target mitochondria of cancer cells demonstrate a potential and efficient way in cancer therapeutics. Yet, further study is needed to overcome the linked limitations.

Targeted Delivery for Neurodegenerative Disorders Using Gene Therapy Vectors: Gene Next Therapeutic Goals.

The technique of gene therapy, ever since its advent nearly fifty years ago, has been utilized by scientists as a potential treatment option for various disorders. This review discusses some of the major neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's Disease (PD), Motor neuron diseases (MND), Spinal Muscular Atrophy (SMA), Huntington's Disease (HD), Multiple Sclerosis (MS), etc. and their underlying genetic mechanisms along with the role that gene therapy can play in combating them. The pathogenesis and the molecular mechanisms specifying the altered gene expression of each of these NDDs have also been discussed in elaboration. The use of gene therapy vectors can prove to be an effective tool in the field of curative modern medicine for the generations to come. Therefore, consistent efforts and progressive research towards its implementation can provide us with powerful treatment options for disease conditions that have so far been considered as incurable.

A Comparative Evaluation of Two Commonly Used GP Solvents on Different Epoxy Resin-based Sealers: An In Vitro Study.

AIM: This study evaluates epoxy resin-based sealers after their final set, immersed in Endosolve-R or xylene for 1-2 minutes, for its easy removal mechanically after softening. MATERIALS AND METHODS: Sixty Teflon molds were grouped with 20 samples in each of the three commercially available sealers, i.e., AH 26, AH Plus, and Adseal. The sealers were put in the specific molds after their manipulation as per the instructions given in the literature by the manufacturer. They were allowed to harden for 2 weeks at 37°C in 100% humidity. Two subgroups, A-Xylene and B-Endosolv-R, of 10 samples each, were formed from 20 set specimens based on solvents to which they were immersed for 1 and 2 minutes, respectively. The data obtained was subjected to the Mauchly's test one-way ANOVA and two-way ANOVA for analysis. RESULTS: It was proved that for all the sealers immersed in solvents, there was a significant reduction in the mean Vickers hardness as the time increases. There was a significant difference in the initial hardness between the mentioned sealers with AH plus showing the highest followed by AH 26 and Adseal showing the lowest. AH Plus and Adseal sealers were softened by xylene after 2 minutes of their initial microhardness (p < 0.001); least effect was seen on AH 26. After 2 minutes, Endosolv-R softened initial microhardness of all the three sealers (p < 0.001). CONCLUSION: It was concluded that Endosolv-R was more effective in softening the epoxy-based resin sealer than xylene, after 2 minutes of exposure. HOW TO CITE THIS ARTICLE: Tyagi S, Choudhary E, Choudhary A, et al. A Comparative Evaluation of Two Commonly Used GP Solvents on Different Epoxy Resin-based Sealers: An In Vitro Study. Int J Clin Pediatr Dent 2020;13(1):35-37.

Investigating the role of acute and repeated stress on remote ischemic preconditioning-induced cardioprotection.

OBJECTIVES: To study the effect of acute and repeated stress on cardioprotection-induced by remote ischemic preconditioning (RIPC). MATERIALS AND METHODS: RIPC was induced by giving 4 short cycles of ischemia and reperfusion, each consisting of five min. The Langendorff's apparatus was used to perfuse the isolated rat hearts by subjecting the hearts to global ischemia of 30 min and reperfusion of 120 min. The coronary effluent was collected to measure the levels of lactate dehydrogenase (LDH) and creatine kinase (CK) for the assessment of injury to the myocardium. Myocardial infarct size was measured by the use of triphenyl tetrazolium chloride. Acute stress was induced by subjecting the animals to cold immersion stress for 5 min. However, in the case of stress adaptation, rats were exposed to a homotypic stressor (cold-water immersion stress) each of 5 min duration for five consecutive days. RESULTS: RIPC demonstrated a significant decrease in ischemia-reperfusion-induced myocardial injury in terms of decrease in LDH, CK, and infarct size. However, acute stress for five minutes prior to RIPC significantly abolished its cardioprotective effects. Exogenous administration of adenosine restored RIPC-induced cardioprotective effects in the presence of acute stress. On repeated stress exposure for 5 days, stress adaptation was noted, and there was no effect of repeated stress exposure on RIPC-induced cardioprotection. However, the cardioprotective effects of adenosine were absent in the case of rats subjected to repeated episodes of stress. CONCLUSION: Acute stress, but not repeated stress exposure, may alter the release of adenosine during RIPC, which may be manifested in the form of reduced cardioprotection during ischemic-reperfusion injury.

Diabetes abolish cardioprotective effects of remote ischemic conditioning: evidences and possible mechanisms.

Diabetes mellitus significantly hampers the development of cardioprotective response to remote pre/post/perconditioning stimuli by impairing the activation of cardioprotective signaling pathways. Among the different pathways, the impairment in O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling and release of cardioprotective humoral factor may contribute in attenuating remote preconditioning-induced cardioprotection. Moreover, the failure to phosphorylate extracellular signal related kinase (ERK), phosphoinositide-3-kinase (PI3K), and AKT along with up-regulation of mechanistic target of rapamycin (mTOR) and decrease in autophagy may also attenuate remote preconditioning-induced cardioprotection. Remote perconditioning stimulus also fails to phosphorylate AKT kinase in diabetic heart. In addition, diabetes may increase the oxidative stress, reactive oxygen species (ROS) production, decrease the beclin expression, and inhibit autophagy to attenuate remote perconditioning-induced cardioprotection. Moreover, diabetes-induced increase in the Rho-associated kinase (ROCK) activity, decrease in the arginase activity, and reduction in nitric oxide (NO) bioavailability may also contribute in decreasing remote perconditioning-induced cardioprotection. Diabetes may reduce the phosphorylation of adenosine 5'-monophosphate activated protein kinase (AMPKα) and increase the phosphorylation of mTOR to attenuate cardioprotection of remote postconditioning. The present review describes the role of diabetes in attenuating remote ischemic conditioning-induced cardioprotection along with the possible mechanisms.