Effect of naringin on sodium fluoride­induced neurobehavioral deficits in Wistar rats.

There is a lack of treatment for the detrimental effects of fluorosis. Sodium fluoride at a concentration of 10 ppm induces stress, depression and memory impairment in adult Wistar rats. Naringin, a flavanone glycoside isolated from citrus fruits such as lemons and oranges, possesses anti-inflammatory, antioxidant and neuroprotective properties; therefore, it was used for treatment of fluoride induced toxicity in the present study. Adult Wistar rats were divided into eight groups (n=8). The normal control (NOR) group was provided with normal tap water. The sodium fluoride (FLU)10 group received water containing 10 ppm sodium fluoride for 60 days. The treatment groups (FLU10NAR100 and FLU10NAR50) received drinking water with 10 ppm sodium fluoride ad libitum along with Naringin 100 and 50 mg/kg body weight (bw) per oral gavage, respectively. The NAR100 and NAR50 groups received Naringin 100 and 50 mg/kg bw. The PRONAR100 and PRONAR50 groups received Naringin 100 and 50 mg/kg bw for the first 15 days and then subsequently received FLU10 ppm for 60 days (total of 75 days). All animals were subjected to behavioural tests consisting of the open field test (OFT), forced swim test (FST) and novel object recognition test (NORT). After euthanasia, the hippocampus and prefrontal cortex were stained with Cresyl violet. To measure the oxidative stress caused by fluoride and its effect on antioxidant levels, estimation of reduced glutathione (GSH) by Ellman's method, lipid peroxidation (LPO) measured in terms of the MDA:thiobarbituric acid reaction and catalase was performed. To evaluate the effect of fluoride on activity of acetylcholine, estimation of acetylcholinesterase (AChE) by Ellman's method was performed. In NORT and FST, significant changes (P<0.05) were present in the FLU10NAR100 and FLU10NAR50 groups compared with the FLU10 group, showing recovery from memory deficit and depression. The OFT results were insignificant. The LPO was reduced in all the other groups except the FLU10 group, with statistically significant changes. Catalase activity was significantly lower in FLU10 as compared with the NAR100, NAR50, PRONAR100 and PRONAR50 groups. GSH and AChE activities did not show significant changes as compared with the FLU10 group. The CA3 and prefrontal cortex viable and degenerated neuron count in the FLU10 group were insignificant compared with all other groups, except for the NAR100 and NAR50 groups. Thus, Naringin can be a useful drug to avoid the neurological effects of fluoride.

Enhanced tissue distribution of ritonavir-loaded nanostructured lipid carriers-recommending its dose reduction.

Human immunodeficiency virus (HIV) mainly attacks lymphocytes of the human immune system. The untreated infection leads to acquired immune deficiency syndrome (AIDS). Ritonavir (RTV) belongs to protease inhibitors (PIs), the crucial contributors of the combination therapy used in the treatment of HIV that is called highly active antiretroviral therapy (HAART). Formulations targeting the lymphatic system (LS) play a key role in delivering and maintaining therapeutic drug concentrations in HIV reservoirs. In our previous study, we developed RTV-loaded nanostructured lipid carriers (NLCs), which contain the natural antioxidant alpha-tocopherol (AT). In the current study, the cytotoxicity of the formulation was studied in HepG2, MEK293, and H9C2 cell lines. The formulation efficacy to reach the LS was evaluated through a cycloheximide-injected chylomicron flow blockade model in Wistar rats. Biodistribution and toxicity studies were conducted in rodents to understand drug distribution patterns in various organs and to establish the safety profile of the optimized formulation (RTV-NLCs). From the MTT assay, it was found that the cell viability of the formulation is comparable with the pure drug (RTV-API). More than 2.5-folds difference in AUC was observed in animals treated with RTV-NLCs with and without cycloheximide injection. Biodistribution studies revealed higher drug exposure in the lymphoidal organs with the RTV-NLCs. No significant increase in serum biomarkers for hepatotoxicity was observed in rats dosed with the RTV-NLCs. The current study reveals the lymphatic uptake of the RTV-NLCs and their safety in rodents. As the tissue distribution of RTV-NLCs is high, hence re-adjusting the RTV-NLCs dose to get the response equivalent to RTV-API may be more beneficial with respect to its safety and efficacy.

Enhancing temozolomide antiglioma response by inhibiting O6-methylguanine-DNA methyltransferase with selected phytochemicals: in silico and in vitro approach.

The aim of our study was to investigate the potential of rutin, catechin, dehydrozingerone, naringenin, and quercetin, both alone and in combination with temozolomide, to inhibit the expression of O6-methylguanine-DNA methyltransferase (MGMT) in glioma cells. MGMT has been shown to be a major cause of temozolomide resistance in glioma. Our study used both in silico and in vitro methods to assess the inhibitory activity of these phytochemicals on MGMT, with the goal of identifying the most effective combination of compounds for reducing temozolomide resistance. After conducting an initial in silico screening of natural compounds against MGMT protein, five phytochemicals were chosen based on their high docking scores and favorable binding energies. From the molecular docking and simulation studies, we found that quercetin showed a good inhibitory effect of MGMT with its high binding affinity. C6 glioma cells showed increased cytotoxicity when treated with the temozolomide and quercetin combination. It was understood from the isobologram and combination index plot that the drug combination showed a synergistic effect at the lowest dose. Quercetin when combined with temozolomide significantly decreased the MGMT levels in C6 cells in comparison with the other drugs as estimated by ELISA. The percentage of apoptotic cells increased significantly in the temozolomide-quercetin group indicating the potency of quercetin in decreasing the resistance of temozolomide as confirmed by acridine orange/ethidium bromide staining. Our experiment hence suggests that temozolomide resistance can be reduced by combining the drug with quercetin which will serve as an effective therapeutic target for glioblastoma treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03821-7.

Brain-targeted Nano-architectures for Efficient Drug Delivery and Sensitization in Glioblastoma.

Due to ineffective diagnosis and analysis, glioblastoma multiforme (GBM), is still the most aggressive form of all cancers. Standard therapy for GBM comprises resection surgery following chemo and radiotherapy, which offers less efficacious treatment to the malignant nature of glioma. Several treatment strategies involving gene therapy, immunotherapy, and angiogenesis inhibition have been employed recently as alternative therapeutics. The main drawback of chemotherapy is resistance, which is mainly due to the enzymes involved in the therapeutic pathways. Our objective is to provide a clear insight into various nano-architectures used in the sensitization of GBM and their importance in drug delivery and bioavailability. This review includes the overview and summary of articles from Pubmed and Scopus search engines. The present era's synthetic and natural drugs used in the treatment of GBM are facing poor Blood Brain Barrier (BBB) permeability issues due to greater particle size. This problem can be resolved by using the nanostructures that showcase high specificity to cross the BBB with their nano-scale size and broader surface area. Nano-architectures act as promising tools for effective brain-targeted drug delivery at a concentration well below the final dose of free drug, thus resulting in safe therapeutic effects and reversal of chemoresistance. The present review focuses on the mechanisms involved in the resistance of glioma cells to chemotherapeutic agents, nano-pharmacokinetics, diverse types of nano-architectures used for potent delivery of the medicine and sensitization in GBM, their recent clinical advances, potential challenges, and future perspective.

Neuroprotective effect by naringin against fluorosis-induced neurodegeneration in adult Wistar rats.

Fluorosis is widespread in several areas of the world and including India leading to dental and skeletal fluorosis as well as neurological manifestations. With a limited number of treatment options available, we have tried to address the issue with a nutraceutical such as naringin which is an alkaloid derived from the citrus fruit. Naringin is a potent antioxidant and has neuroprotective action which can counteract the redox imbalance induced by sodium fluoride ingestion. Neurological effects of fluorosis were evaluated in Wistar rats by open field test (OFT) and novel object recognition test (NORT) along with lipid peroxidation (LPO) and glutathione estimation in brain homogenate and cresyl violet staining of CA3 neurons in the hippocampus. Animals were divided into groups namely, normal, vehicle, fluoride, naringin 100 mg/kg bd.wt group and fluoride with naringin (FLU-NAR) group. Fluorosis was induced by providing 100 ppm of sodium fluoride ad libitum in drinking water for 30 days and prophylactic treatment of naringin for 15 days per oral. OFT, NORT and forced swim test showed significant (P ≤ 0.05) changes in the FLU-NAR group as compared to the fluoride group indicating behavioral changes in the fluoride group and positive changes in the FLU-NAR group with attenuation of stress, fear, hyperactivity and memory impairment. The decrease in LPO and increase in glutathione levels in the treatment group compared to the fluoride group were supported by histological improvement as compared to the fluoride group. Prophylactic treatment of naringin showed its possible neuroprotective effect, thus giving an alternative treatment strategy to deal with neurological manifestations of fluorosis.

Tumor-associated macrophages employ immunoediting mechanisms in colorectal tumor progression: Current research in Macrophage repolarization immunotherapy.

Tumor-associated macrophages (TAMs) constitute the most prolific resident of the tumor microenvironment (TME) that regulate its TME into tumor suppressive or progressive milieu by utilizing immunoediting machinery. Here, the tumor cells construct an immunosuppressive microenvironment that educates TAMs to polarize from anti-tumor TAM-M1 to pro-tumor TAM-M2 phenotype consequently contributing to tumor progression. In colorectal cancer (CRC), the TME displays a prominent pro-tumorigenic immune profile with elevated expression of immune-checkpoint molecules notably PD-1, CTLA4, etc., in both MSI and ultra-mutated MSS tumors. This authenticated immune-checkpoint inhibition (ICI) immunotherapy as a pre-requisite for clinical benefit in CRC. However, in response to ICI, specifically, the MSIhi tumors evolved to produce novel immune escape variants thus undermining ICI. Lately, TAM-directed therapies extending from macrophage depletion to repolarization have enabled TME alteration. While TAM accrual implicates clinical benefit in CRC, sustained inflammatory insult may program TAMs to shift from M1 to M2 phenotype. Their ability to oscillate on both facets of the spectrum represents macrophage repolarization immunotherapy as an effective approach to treating CRC. In this review, we briefly discuss the differentiation heterogeneity of colonic macrophages that partake in macrophage-directed immunoediting mechanisms in CRC progression and its employment in macrophage re-polarization immunotherapy.

Temozolomide Resistance: A Multifarious Review on Mechanisms Beyond O-6-Methylguanine-DNA Methyltransferase.

BACKGROUND: Chemotherapy with the oral alkylating agent temozolomide still prevails as a linchpin in the therapeutic regimen of glioblastoma alongside radiotherapy. Because of the impoverished prognosis and sparse chemotherapeutic medicaments associated with glioblastoma, the burgeoning resistance to temozolomide has made the whole condition almost irremediable. OBJECTIVE: The present review highlights the possible mechanisms of drug resistance following chemotherapy with temozolomide. METHODS: The review summarizes the recent developments, as published in articles from Scopus, PubMed, and Web of Science search engines. DESCRIPTION: One of the prime resistance mediators, O-6-methylguanine-DNA methyltransferase, upon activation, removes temozolomide-induced methyl adducts bound to DNA and reinstates genomic integrity. In the bargain, neoteric advances in the conception of temozolomide resistance have opened the door to explore several potential mediators like indirect DNA repair systems, efflux mechanisms, epigenetic modulation, microenvironmental influences, and autophagy-apoptosis processes that constantly lead to the failure of chemotherapy. CONCLUSION: This review sheds light on recent discoveries, proposed theories, and clinical developments in the field of temozolomide resistance to summarize the complex and intriguing involvement of oncobiological pathways.

Chemobrain: A review on mechanistic insight, targets and treatments.

Chemo-brain refers to the thinking and memory problems that occur in cancer patients during and after chemotherapy. It is also known as cognitive dysfunction or chemo-fog. Risk factors include brain malignancies, either primary or metastatic, radiotherapy and chemotherapy, either systemic or brain targeted. There are various mechanisms by which chemo-brain occurs in patients post-chemotherapy, including inflammation of neurons, stress due to free radical generation, and alterations in normal neuronal cell process due to biochemical changes. While chemotherapy drugs that are non-brain targeted, usually fail to cross the blood-brain barrier (BBB), this is not the case for inflammatory cytokines that are released, which easily cross the BBB. These inflammatory neurotoxic agents may represent the primary mediators of chemobrain and include the pro-inflammatory cytokines such as interleukins 1 and 6 and tumor necrosis factor. The pronounced rise in oxidative stress due to continuous chemotherapy also leads to a reduction in neurogenesis and gliogenesis, loss of spine and dendritic cells, and a reduction in neurotransmitter release. Based on recent research, potential agents to prevent and treat chemo brain have been identified, which include Lithium, Fluoxetine, Metformin, Rolipram, Astaxanthin, and microglial inhibitors. However, more defined animal models for cognitive dysfunction are required to study in detail the mechanisms involved in chemo-brain; furthermore, well-defined clinical trials are required to identify drug targets and their therapeutic significance. With these focused approaches, the future for improved therapies is promising.

Amelioration of high-fat diet (HFD) + CCl4 induced NASH/NAFLD in CF-1 mice by activation of SIRT-1 using cinnamoyl sulfonamide hydroxamate derivatives: in-silico molecular modelling and in-vivo prediction.

Non-alcoholic fatty liver disease (NAFLD) is one of the major hepatic metabolic disorders that occurs because of the accumulation of lipids in hepatocytes in the form of free fatty acids (FFA) and triglycerides (TG) which become non-alcoholic steatohepatitis (NASH). NOTCH-1 receptors act as novel targets for the development of NAFLD/NASH, where overexpression of NOTCH-1 receptor alters the lipid metabolism in hepatocytes leading to NAFLD. SIRT-1 deacetylates the NOTCH-1 receptor and inhibits NAFLD. Hence, computer-aided drug design (CADD) was used to check the SIRT-1 activation ability of cinnamic sulfonyl hydroxamate derivatives (NMJ 1-8), resveratrol, and vorinostat. SIRT-1 (PDB ID: 5BTR) was docked with eight hydroxamate derivatives and vorinostat using Schrödinger software. Based on binding energy obtained (- 26.31 to - 47.34 kcal/mol), vorinostat, NMJ-2, NMJ-3, NMJ-5 were selected for induced-fit docking (IFD) and results were within - 750.70 to - 753.22 kcal/mol. Qikprop tool was used to analyse the pre pharmacokinetic parameters (ADME analysis) of all hydroxamate compounds. As observed in the molecular dynamic (MD) study, NMJ-2, NMJ-3 were showing acceptable results for activation of SIRT-1. Based on these predictions, in-vivo studies were conducted in CF1 mice, where NMJ-3 showed significant (p < 0.05) changes in lipid profile and anti-oxidant parameters (Catalase, SOD, GSH, nitrite, and LPO) and plasma insulin levels. NMJ-3 treatment also reduced inflammation, fibrosis, and necrosis in liver samples.

Impact of high-intensity interval training on cardio-metabolic health outcomes and mitochondrial function in older adults: a review.

Exercise being a potent stimulator of mitochondrial biogenesis, there is a need to investigate the effects of high-intensity interval training (HIIT) among older adults. This review explores and summarizes the impact of HIIT on mitochondria and various cardio-metabolic health outcomes among older adults, healthy and with comorbid conditions. Electronic databases were scrutinized for literature using permutations of keywords related to (i) Elderly population (ii) HIIT (iii) Mitochondria, cell organelles, and (iv) cardio-metabolic health outcomes. Twenty-one studies that met the inclusion criteria are included in this review. HIIT is an innovative therapeutic modality in preserving mitochondrial quality with age and serves to be a viable, safe, and beneficial exercise alternative in both ill and healthy older adults.

Exercise and Mitochondrial Function: Importance and Inference- A Mini Review.

Skeletal muscles must generate and distribute energy properly in order to function perfectly. Mitochondria in skeletal muscle cells form vast networks to meet this need, and their functions may improve as a result of exercise. In the present review, we discussed exercise-induced mitochondrial adaptations, age-related mitochondrial decline, and a biomarker as a mitochondrial function indicator and exercise interference.

Treatment Approaches for COVID-19: A Critical Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) outbreak was declared as an emerging global public health concern on 30th January 2020. This novel coronavirus (SARS-CoV-2) outbreak was first identified in Wuhan city, China, which soon affected around 185 countries and territories all over the world through various transmission mechanisms. To date, no permanent cure has been found, due to which this pandemic threatens humanity for its very existence. OBJECTIVE: In light of the rising menace, this review aims at providing collective and prominent information on the current outbreak, covering its origin, structure, transmission, clinical features, potential treatment approaches, and clinical trial details. METHODS: The literature published in Scopus and PubMed indexed journals were reviewed, and clinical trial data was retrieved from the ClinicalTrials.gov database. RESULTS: Present review puts forth detailed insights on history, epidemiology, structure, genetic makeup, reservoirs, entry mechanisms, reproduction capacity, pathogenesis, routes of transmission, clinical features, diagnostics, the role of chloroquine in treatment, current promising therapies, and vaccination trials. CONCLUSION: At present, early detection, isolation of infected patients, and supportive care with a few recently USFDA approved alternative medications are being used as per the standard government guidelines. Due to insufficient availability of proof regarding current therapies to produce therapeutic activity against COVID-19, safety precautions, prevention methods, hygiene maintenance and management therapy with intensive care medicine is the only way to fight this current situation.

Dehydrozingerone protects temozolomide-induced cognitive impairment in normal and C6 glioma rats besides enhancing its anticancer potential.

Considering the cognitive impairment induced by temozolomide (TMZ) in glioblastoma survivors, the present study was aimed to evaluate the protective effect of dehydrozingerone (DHZ) against TMZ-induced cognitive impairment (chemobrain) and C6 cell line-induced glioma in male Wistar rats. In both chemobrain and glioma models, TMZ was administered at a dose of 18 mg/kg i.v every 5th day and DHZ at a dose of 100 mg/kg p.o. daily. Additionally, glioma was induced by intracerebral injection of 5 × 104 C6 rat glioma cells in the cortex in the glioma model. Upon disease induction and treatment with TMZ + DHZ, spatial memory was assessed by the Morris water maze (MWM) test and episodic memory by the novel object recognition test (NORT). The induction of glioma was confirmed by histology of the cortex. Hippocampus and frontal cortex were subjected to antioxidant evaluation. Significant loss of spatial and episodic memory was observed with TMZ treatment which was significantly restored by DHZ. DHZ showed significant improvement in oxidative stress markers reversed the histopathological features in the cortex. TMZ-induced elevation of the glutathione level was also reversed by DHZ, indicating the role of DHZ in the reversal of TMZ resistance. In the glioma model, the improvement in cognition by DHZ correlated with the decrease in tumor volume. Altogether, the study results reveal the role of TMZ in worsening the memory and DHZ in reversing it, besides, improving its anticancer potential.