Role of Wnt/ß-catenin pathway in cancer drug resistance: Insights into molecular aspects of major solid tumors.

Adaptive resistance to conventional and targeted therapies remains one of the major obstacles in the effective management of cancer. Aberrant activation of key signaling mechanisms plays a pivotal role in modulating resistance to drugs. An evolutionarily conserved Wnt/ß-catenin pathway is one of the signaling cascades which regulate resistance to drugs. Elevated Wnt signaling confers resistance to anticancer therapies, either through direct activation of its target genes or via indirect mechanisms and crosstalk over other signaling pathways. Involvement of the Wnt/ß-catenin pathway in cancer hallmarks like inhibition of apoptosis, promotion of invasion and metastasis and cancer stem cell maintenance makes this pathway a potential target to exploit for addressing drug resistance. Accumulating evidences suggest a critical role of Wnt/ß-catenin pathway in imparting resistance across multiple cancers including PDAC, NSCLC, TNBC, etc. Here we present a comprehensive assessment of how Wnt/ß-catenin pathway mediates cancer drug resistance in majority of the solid tumors. We take a deep dive into the Wnt/ß-catenin signaling-mediated modulation of cellular and downstream molecular mechanisms and their impact on cancer resistance.

Evaluation of efficacy and safety of glucosamine sulfate, chondroitin sulfate, and their combination regimen in the management of knee osteoarthritis: a systematic review and meta-analysis.

AIM: This study was aimed to assess the efficacy and safety of two oral Symptomatic Slow Acting Drugs for Osteoarthritis (SYSADOAs)-Glucosamine Sulfate, Chondroitin Sulfate, and their combination regimen in the management of knee osteoarthritis (KOA). METHODS: This systematic review was conducted according to PRISMA 2020 guidelines. A detailed literature search was performed from 03/1994 to 31/12/2022 using various electronic databases including PubMed, Embase, Cochrane Library, and Google Scholar, using the search terms-Glucosamine sulfate (GS), Chondroitin sulfate (CS), Knee osteoarthritis, Joint pain, Joint disease, and Joint structure, for literature concerning glucosamine, chondroitin, and their combination in knee osteoarthritis treatment. Cochrane Collaboration's Risk assessment tool (version 5.4.1) was used for assessing the risk of bias and the quality of the literature. The data was extracted from the included studies and subjected to statistical analysis to determine the beneficial effect of Glucosamine Sulfate, Chondroitin Sulfate, and their combination. RESULTS: Twenty-five randomized controlled trials (RCTs) were included in this systematic review. In short, exclusively 9 RCTs for GS, 13 RCTs for CS, and 3 RCTs for the combination of GS and CS. All these studies had their treatment groups compared with placebo. In the meta-analysis, CS showed a significant reduction in pain intensity, and improved physical function compared to the placebo; GS showed a significant reduction in tibiofemoral joint space narrowing. While the combination of GS and CS showed neither a reduction in pain intensity, nor any improvement in the physical function. However, the combination exhibited a non-significant reduction in joint space narrowing. In the safety evaluation, both CS and GS have shown good safety profile and were well tolerated. CONCLUSION: This meta-analysis revealed that the CS (with decreased pain intensity and improvement in the physical function), and GS (with significant reduction in the joint space narrowing) have significant therapeutic benefits. However, their combination did not significantly improve the symptoms or modify the disease. This may be due to the limited trials that are available on the combination of the sulfate forms of the intervention. Hence, there is a scope for conducting multicentric randomised controlled trials to evaluate and conclude the therapeutic role of CS and GS combination in the management of KOA.

A computational study to identify Sesamol derivatives as NRF2 activator for protection against drug-induced liver injury (DILI).

Drug-induced liver injury can be caused by any drugs, their metabolites, or natural products due to the inefficient functioning of drug-metabolizing enzymes, resulting in reactive oxygen species generation and leading to oxidative stress-induced cell death. For protection against oxidative stress, our cell has various defense mechanisms. One of the mechanisms is NRF2 pathway, when activated, protects the cell against oxidative stress. Natural antioxidants such as Sesamol have reported pharmacological activity (hepatoprotective & cardioprotective) and signaling pathways (NRF2 & CREM) altering potential. A Computational analysis was done using molecular docking, IFD, ADMET, MM-GBSA, and Molecular dynamic simulation of the Schrödinger suite. A total of 63,345 Sesamol derivatives were downloaded for the PubChem database. The protein structure of KEAP1-NRF2 (PDB: 4L7D) was downloaded from the RCSB protein database. The molecular docking technique was used to screen compounds that can form an interaction similar to the co-crystalized ligand (1VX). Based on MM-GBSA, docking score, and interactions, ten compounds were selected for ADMET profiling and IFD. After IFD, five compounds (66867225, 46148111, 12444939, 123892179, & 94817569) were selected for molecular dynamics simulation (MDS). Protein-ligand complex stability was assessed during MDS. The selected compounds (66867225, 46148111, 12444939, 123892179, & 94817569) complex with KEAP1 protein shows good stability and bond retentions. In our study, we observed that the selected compounds show good interaction, PCA, Rg, binding free energy, and ADMET profile. We can conclude that the selected compounds can act as NRF2 activators, which should be validated using proper in-vivo/in-vitro models.

A systematic review and meta-analysis on the cardio-protective activity of naringin based on pre-clinical evidences.

The cardioprotective role of naringin has been scientifically well demonstrated in various experimental models such as diabetic cardiomyopathy, ischemic heart diseases, diet-induced cardiac injury, antihypertensive and anti-platelet activities through various mechanisms. However, there is no meta-analysis performed on the cardioprotective activity of naringin. This systematic review and meta-analysis were focused to summarize and conclude the therapeutic benefits of naringin in various cardiovascular disorders using pre-clinical evidence. The online search was performed using electronic databases such as PubMed/Medline, Scopus, ScienceDirect, and Google scholar. The search was mainly focused on the role of naringin in various cardiovascular disorders in experimental animals. Based on the inclusion and exclusion criteria 34 studies were selected. The meta-analysis revealed that naringin could significantly alleviate various physical and chemical stimuli induced cardiovascular disorders such as diabetic cardiomyopathy, ischemic heart diseases, oxidative stress-induced cardiac injury, diet-induced cardiovascular dysfunctions in experimental models involving multiple mechanisms such as antioxidant (ROS/RNS pathways), anti-inflammatory (COX-2, IL-6, TNF-α, NF-κB pathways), enhancing angiogenic factors (VEGF, VCAM, HIF-1α, iNO), suppressing the apoptotic factors (BCL-2, BAX, caspases) and modulation of PCSK-9, PKCα/ß, PPAR-α, JAK/STAT, MAPKs (p38α, ERK1/2, JNK), and PI3K/AKT/mTOR/p70S6K associated pathways. Further, these changes at the cellular and molecular levels were manifested as improvement in the structural, functional, and physiology of the heart upon the naringin treatment. In conclusion, this systematic review and meta-analysis support the available scientific evidence on the therapeutic benefits of naringin in the management of various cardiovascular conditions.

Acteoside isolated from Colebrookea oppositifolia attenuates I/R brain injury in Wistar rats via modulation of HIF-1α, NF-κB, and VEGF pathways.

AIMS: The objective of this study was to assess the anti-stroke activity of acteoside isolated from methanolic root extract of C. oppositifolia METHODS: Ischemia-reperfusion(I/R) brain injury was induced in Wistar rats to assess the anti-stroke activity of acteoside. Rats were pretreated with acteoside (10, 25 & 50 mg/kg, p.o.) before the induction of I/R injury. Parameters such as neurological, motor-cognitive functions were evaluated along with morphological (brain volume, infarct size), biochemical (SOD, Catalase, GSH, lipid peroxidation, TNF-α, IL-6, IL-10, ICAM-1, HIF-1α, VEGF, and NF-κB), histopathological, and gene expression studies (HIF-1α, VEGF) were performed to study the protective effect of acteoside against I/R induced brain injury. RESULTS: I/R injury caused significant deterioration of neurological (p < 0.01), motor (p < 0.01) and cognitive (p < 0.01) functions, associated with increase in the brain volume (p < 0.01), and infarct size (p < 0.01); increase in the levels of MDA, TNF-α, IL-6, ICAM-1, HIF-1α, VEGF, and NF-κB along with significant decrease in SOD, catalase, GSH, and IL-10 (p < 0.01 for all parameters) compared to Sham control group. Histology of brain tissue of disease control group exhibited significant vascular changes, neutrophil infiltration, cerebral oedema, and necrosis of the neuronal cells. Further, the gene-expression studies showed significant increase in the HIF-1α (p < 0.01) and VEGF (p < 0.01) mRNA levels in the I/R control compared to Sham control. Interestingly, the acteoside (10, 25 & 50 mg/kg) has prevented the neurological, motor and cognitive dysfunctions, along with inhibiting the morphological, biochemical, histological and gene expression changes induced by I/R-injury (p < 0.05 for 10 mg; p < 0.01 for 25 & 50 mg/kg of acteoside for all the parameters). CONCLUSION: These findings suggest that acteoside possess potent anti-stroke activity through modulation of HIF-1α, NF-κB, and VEGF pathway along with its potent antioxidant activity.

Biologicals to direct nanotherapeutics towards HER2-positive breast cancers.

HER2-positive breast cancer, an aggressive cancer, is treated with combinations of conventional anticancer drugs viz., cytotoxic drugs, nibs, and mAbs. Major limitations associated with this therapy are patient non-compliance due to the adverse drug reactions and rapid development of resistance by the HER2-positive malignant cells. While the former is addressed by the nano-formulations of the anticancer-drugs to some extent, the latter is still at large. This is because the nanocarriers of the anticancer drugs, by and large, lack the target specificity and selectivity. Thus, nowadays, to overcome these problems, various safe and efficacious biological agents are being used to direct the nanotherapeutics towards the HER2-positive breast cancers. The present review describes the potentials of such biological agents.

Assessment of preclinical effect of (+)-catechin hydrate on sexual function: An in silico and in vivo study.

Considering dopamine-enhancing effect of (+)-catechin, the present study was designed to evaluate dopamine-2 (D2) receptor agonistic and phosphodiesterase-5 (PDE5) enzyme inhibitory effects in in silico and effect on male sexual function of Sprague Dawley rats in vivo. (+)-Catechin and standard (sildenafil and bromocriptine) were docked using Autodock Vina 1.1.2 and visualised by UCSF Chimera 1.14. Significant interactions in terms of binding energies were observed for catechin with both proteins. In in vivo study, the rats were dosed orally for 54 days with (+)-catechin hydrate (50 mg/kg), sildenafil citrate (standard, 4 mg/kg) and carboxymethylcellulose (vehicle, 0.25% w/v). The aphrodisiac effects were evaluated on the day 14, 28, 42 and 54 using the behavioural parameters of mounting and intromission. After the study, animals were sacrificed and testes and spermatozoa were assessed for safety profile. Results showed a significant increase in mount and intromission frequencies and a significant reduction in mount and intromission latencies in the catechin group on all tested days when compared to vehicle control. (+)-Catechin was found to be safe on histology of testes, sperm count, sperm motility and sperm morphology parameters. In conclusion, catechin demonstrated an enhancement in sexual behaviour without eliciting toxicity on the male reproductive system in rats.

Atypical Antidepressant Activity of 3,4-Bis(3,4-Dimethoxyphenyl) Furan-2,5-Dione Isolated from Heart Wood of Cedrus deodara, in Rodents.

Cedrus deodara (Pinaceae) has been used traditionally in Ayurveda for the treatment of central nervous system disorders. 3,4-bis(3,4-dimethoxyphenyl)furan-2,5-dione (BDFD) was isolated from heart wood of Cedrus deodara and was shown to have antiepileptic and anxiolytic activity. Thus, the present study was aimed to explore its anti-depressant effect and to correlate the effect with serotonin and nor adrenaline levels of brain. Albino mice were used as experimental animal. Animals were divided in to three groups; vehicle control, imipramine (30 mg/kg i.p.), BDFD (100 mg/kg i.p.). Tail suspension test (TST) and forced swim test (FST) was performed to evaluate antidepressant effect of BDFD. BDFD (100 mg/kg, i.p.) showed a significant decrease in immobility time when subjected to FST whereas immobility time was not significantly altered in TST. BDFD treatment increased serotonin and noradrenaline levels in the brain which is indicative of BDFD having possible atypical antidepressant action.

Investigation of the cellular and molecular effects of dehydrozingerone formulation on various days of diabetic wound repair.

Cases of diabetes are significantly increasing year by year, attracting the attention of medical professionals and researchers to focus on diabetes and its underlying complications. One among such are diabetic wounds which are difficult to heal, creating severe implications in the day-to-day chores of not only patients, but also family members. Dehydrozingerone (DHZ) is known to possess various effects like anti-inflammatory, anti-microbial, antioxidant, and wound-healing properties. The effect of DHZ on different phases of diabetic wound healing remains untested. Hence, this study was proposed to find out the effect of oral and topical formulation of DHZ on day 5, 10 and 15 of diabetic wound healing. Excisional wounds were created on the dorsal side of animals using punch biopsy to mimic human diabetic wounds. Topical DHZ gel (100 mg in 1 gm of gel) was prepared using 1% Carbopol 934 and was applied twice a day. The treated groups had increased percentage of wound closure; western blotting suggested that DHZ significantly increased ERK and JNK levels and decreased TNF and MMP 2 and 9 levels. From histopathological studies, it was observed that angiogenesis, collagen formation, granulation tissue formation, and fibroblast proliferation were improved on days 5, 10, and 15 of diabetic wound healing. These findings indicate that DHZ (both systemic and topical) are effective during the early phases of wound healing which gets impaired in diabetic wounds. Dehydrozingerone accelerated diabetic wound healing by regulating the various hallmarks of wound healing process.

New Insights on NLRP3 Inflammasome: Mechanisms of Activation, Inhibition, and Epigenetic Regulation.

Inflammasomes are important modulators of inflammation. Dysregulation of inflammasomes can enhance vulnerability to conditions such as neurodegenerative diseases, autoinflammatory diseases, and metabolic disorders. Among various inflammasomes, Nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) is the best-characterized inflammasome related to inflammatory and neurodegenerative diseases. NLRP3 is an intracellular sensor that recognizes pathogen-associated molecular patterns and damage-associated patterns resulting in the assembly and activation of NLRP3 inflammasome. The NLRP3 inflammasome includes sensor NLRP3, adaptor apoptosis-associated speck-like protein (ASC), and effector cysteine protease procaspase-1 that plays an imperative role in caspase-1 stimulation which further initiates a secondary inflammatory response. Regulation of NLRP3 inflammasome ameliorates NLRP3-mediated diseases. Much effort has been invested in studying the activation, and exploration of specific inhibitors and epigenetic mechanisms controlling NLRP3 inflammasome. This review gives an overview of the established NLRP3 inflammasome assembly, its brief molecular mechanistic activations as well as a current update on specific and non-specific NLRP3 inhibitors that could be used in NLRP3-mediated diseases. We also focused on the recently discovered epigenetic mechanisms mediated by DNA methylation, histone alterations, and microRNAs in regulating the activation and expression of NLRP3 inflammasome, which has resulted in a novel method of gaining insight into the mechanisms that modulate NLRP3 inflammasome activity and introducing potential therapeutic strategies for CNS disorders.

Docosahexaenoic Acid and Pregnancy: A Systematic Review and Meta-Analysis of the Association with Improved Maternal and Fetal Health.

This study aimed to investigate the effects of prenatal docosahexaenoic acid (DHA) supplementation on pregnancy outcomes through a systematic review and meta-analysis. We hypothesized that prenatal DHA intake through supplements will improve pregnancy outcomes. Detailed literature search was performed using online databases such as PubMed, EMBASE, and Google Scholar till November 2022, to identify the randomized controlled trials (RCT) with maternal intake of DHA supplementation during the latter half of pregnancy compared to the placebo/control. Based on the inclusion and exclusion criteria, nine RCTs involving 5710 subjects were included. This meta-analysis showed that DHA supplementation (450-800 mg/day) was associated with a significantly higher birth weight of infants (Inverse variance [IV]: 101.71 [57.36-146.06] at 95% CI, P = .00001, I2 = 0%), and fewer low birth weights (LBWs) (Mantel-Haenszel [M-H]: 0.53 [0.33-0.86] at 95% CI, P = .01, I2 = 72%), with lesser but statistically insignificant pre-term births (PTB) (M-H: -0.02 [-0.04 to 0.00] at 95% CI, P = .07, I2 = 0%) compared to the placebo. However, the DHA supplementation has no effect on gestational length (IV: -2.26 [-9.64 to 5.12] at 95% CI, P = .55, I2 = 100%) compared to the placebo. In conclusion, the outcomes of this meta-analysis showed that prenatal DHA supplementation (450-800 mg/day) may reduce the risk of preterm births and increase infant birth weight.

Nose-to-brain Drug Delivery System: An Emerging Approach to Chemotherapy-induced Cognitive Impairment.

The rise in global cancer burden, notably breast cancer, emphasizes the need to address chemotherapy-induced cognitive impairment, also known as chemobrain. Although chemotherapy drugs are effective against cancer, they can trigger cognitive deficits. This has triggered the exploration of preventive strategies and novel therapeutic approaches. Nanomedicine is evolving as a promising tool to be used for the mitigation of chemobrain by overcoming the blood-brain barrier (BBB) with innovative drug delivery systems. Polymer and lipid-based nanoparticles enable targeted drug release, enhancing therapeutic effectiveness. Utilizing the intranasal route of administration may facilitate drug delivery to the central nervous system (CNS) by circumventing first-pass metabolism. Therefore, knowledge of nasal anatomy is critical for optimizing drug delivery via various pathways. Despite challenges, nanoformulations exhibit the potential in enhancing brain drug delivery. Continuous research into formulation techniques and chemobrain mechanisms is vital for developing effective treatments. The intranasal administration of nanoformulations holds promise for improving therapeutic outcomes in chemobrain management. This review offers insights into potential future research directions, such as exploring novel drug combinations, investigating alternative delivery routes, or integrating emerging technologies to enhance the efficacy and safety of nanoformulations for chemobrain management.

Transferrin-conjugated UiO-66 metal organic frameworks loaded with doxorubicin and indocyanine green: A multimodal nanoplatform for chemo-photothermal-photodynamic approach in cancer management.

Stimuli-responsive nanoplatforms have been popular in controlled drug delivery research because of their ability to differentiate the tumor microenvironment from the normal tissue environment in a spatiotemporally controllable manner. The synergistic therapeutic approach of combining cancer chemotherapy with photothermal tumor ablation has improved the therapeutic efficacy of cancer therapeutics. In this study, a UiO-66 metal organic framework (MOF)-based system loaded with doxorubicin (DOX), surface decorated with the photothermal agents indocyanine green (ICG) and polydopamine (PDA), and conjugated with transferrin (TF) was successfully designed to operate as a responsive system to pH changes, featuring photothermal capabilities and target specificity for the purpose of treating breast cancer. The synthesized nanoplatform benefits from its uniform size, excellent DOX encapsulation efficiency (91.66 %), and efficient pH/NIR-mediated controlled release of the drug. In vitro photothermal studies indicate excellent photothermal stability of the formulation even after 6 on-off cycles of NIR irradiation. The in vitro cytotoxicity assessment using an NIR laser (808 nm) revealed that the DOX-loaded functionalized UiO-66 nanocarriers had outstanding inhibitory effects on 4T1 cells because of synergistic chemo-photo therapies, with no substantial toxicity by the carriers. In addition, cellular uptake evaluations revealed that UiO-DOX-ICG@PDA-TF could specifically target 4T1 cells on the basis of receptor-mediated internalization of transferrin receptors. Additionally, in vivo toxicity studies in Wistar rats indicated no signs of significant toxicity. The UiO-based nanoformulations effectively inhibited and destroyed cancer cells under 808 nm laser irradiation because of their minimal toxicity, strong biocompatibility, and outstanding synergistic chemo/photothermal/photodynamic treatment.

Toxicological evaluation of Terminalia paniculata bark extract and its protective effect against CCl4-induced liver injury in rodents.

BACKGROUND: Based on the reported antioxidant and anti-inflammatory potential of Terminalia paniculata, the bark aqueous extract (TPW) was investigated against liver damage. METHODS: Intrinsic cytotoxicity was tested on normal human liver (Chang) cell lines, followed by acute and sub-chronic toxicity studies in mice. TPW was then evaluated against CCl4-induced liver toxicity in rats. Liver enzymes (AST, ALT, and ALP) and antioxidant markers were assessed. The effect of TPW on isolated hepatic cells, post-CCl4 administration, was assessed by isolated mitochondrial membrane staining. The actions of TPW on apoptotic pathway in CCl4-treated Chang cells were also elucidated. RESULTS: TPW was found to be safe at all doses tested in both in vitro and in vivo toxicity studies. TPW (400 mg/kg, p.o.) significantly (*p <0.05) improved liver enzyme activity as compared to CCl4. Also, it improved antioxidant status (GSH, GST, MDA and total thiol) and preserved hepatic cell architecture. TPW pre-treatment significantly attenuated the levels of phospho-p53, p53, cleaved caspase-3, phospho-Bad, Bad and cleaved PARP in CCl4-treated Chang cells, improving the viability considerably. CONCLUSION: The findings support a protective role for Terminalia paniculata in pathologies involving oxidative stress.

Molecular docking and dynamics guided approach to identify potential anti-inflammatory molecules as NRF2 activator to protect against drug-induced liver injury (DILI): a computational study.

Inflammation and oxidative stress can contribute to the etiology of metabolic and chronic illnesses. The ability to prevent oxidative stress induced diseases such as cancer, cardiovascular disease, Alzheimer's disease, and others has been the subject of global research. Drug-induced liver injury (DILI) pathogenesis can be either due to oxidative stress or inflammatory response elicited by the drug, its metabolite, or herbal supplements. Our present research uses computational studies to identify a molecule with anti-inflammatory properties that can operate as an NRF2 activator. Acquiring and preparing the KEAP1-NRF2 Protein (PDB: 4L7D) with Schrodinger Suite was followed by developing a ligand library (Anti-inflammatory library downloaded from ChemDiv database). Molecular docking studies were performed in HTVS, SP, and XP modes, respectively. Based on the docking score, interaction, ADMET and binding free energy, the top ten compounds were selected and subjected to induced-fit docking (IFD) analysis for further study. The top three molecules were chosen for a molecular dynamics (MD) simulation study. Using the Desmond module of the Schrodinger Suite, the stability of the protein-ligand complex and protein-ligand contact throughout 100ns were evaluated during the MD simulation study. In our study, it was observed that three compounds exhibit exceptional stability and retain the essential interaction throughout the studies, and it is anticipated that these compounds may act as effective NRF2 activators. Further in vitro and in vivo assessments can be conducted to determine its potential to prevent DILI via acting as an NRF2 activator for future drug development.

Box-Behnken Design-Aided Validation and Optimization of a Stability-Indicating Reverse Phase-HPLC Method for the Estimation of Tamoxifen Citrate in Lipidic Nano-Vesicles.

Stability indicating a reverse-phase HPLC analytical method for the quantification of tamoxifen citrate (TMX) in the bulk and lipidic nano-vesicles (LNVs) was developed. The optimized method was validated according to the ICH Q2 (R1) guidelines by following a three-factor interaction Box-Behnken design using Design-Expert® software. The responses measured at 236 nm were retention time (Rt), peak area, tailing factor (TF) and the number of theoretical plates. TMX was eluted best using the Luna® C18 LC Column along with a mobile phase of methanol (MeOH) and ammonium acetate buffer (AAB pH 4.5) 80:20 v/v mixture at 25 ± 2°C temperature. The currently developed method was linear in 100-5,000 ng/mL range with a detection limit of 4.55 ng/mL and a quantification limit of 13.78 ng/mL. The optimized method was utilized to evaluate the stability of TMX in different stress conditions by performing forced degradation studies. The results from the degradation study stipulated that on exposure to various stressors namely acid, alkali, oxidative, thermal and UV light, the TMX did not show considerable degradation except for UV light exposure. Further, the method was successfully used for the quantification of TMX in LNVs.

Modulatory role of vitamins A, B3, C, D, and E on skin health, immunity, microbiome, and diseases.

Disruption of the skin barrier and immunity has been associated with several skin diseases, namely atopic dermatitis (AD), psoriasis, and acne. Resident and non-resident immune cells and the barrier system of the skin are integral to innate immunity. Recent advances in understanding skin microbiota have opened the scope of further understanding the various communications between these microbiota and skin immune cells. Vitamins, being one of the important micronutrients, have been reported to exert antioxidant, anti-inflammatory, and anti-microbial effects. The immunomodulatory action of vitamins can halt the progression of skin diseases, and thus, understanding the immuno-pharmacology of these vitamins, especially for skin diseases can pave the way for their therapeutic potential. At the same time, molecular and cellular markers modulated with these vitamins and their derivatives need to be explored. The present review is focused on significant vitamins (vitamins A, B3, C, D, and E) consumed as nutritional supplements to discuss the outcomes and scope of studies related to skin immunity, health, and diseases.

Inhibition of SGK1 potentiates the anticancer activity of PI3K inhibitor in NSCLC cells through modulation of mTORC1, p­ERK and ß­catenin signaling.

Non-small cell lung cancer (NSCLC) is one of the deadliest types of cancer with poor prognosis, accounting for 85% of all lung cancer cases. The phosphoinositide 3-kinase (PI3K) signaling pathway is most frequently altered in NSCLC; nonetheless, targeting this pathway yields limited success primarily because of drug-induced resistance. PI3K-independent activation of serum and glucocorticoid-induced kinase 1 (SGK1) is responsible for development of resistance to PI3K/AKT inhibitors in breast cancer. The present study investigated potential of inhibiting SGK1 activity for the potentiation of PI3K inhibitor activity in NSCLC cell lines using in vitro anti-proliferation assays, protein expression profiling using western blotting and cell cycle analysis. The findings revealed that combined inhibition of PI3K/AKT and SGK1 resulted in synergistic anticancer activity, with increased apoptosis, DNA damage and cell cycle arrest in G1 phase. Furthermore, high SGK1 protein expression in NSCLC cell lines was associated with increased resistance to PI3K inhibitors. Therefore, enhanced SGK1 expression may serve as a marker to predict therapeutic response to PI3K/AKT inhibitors. Profiling of downstream signaling proteins demonstrated that, at the molecular level SGK1-mediated sensitization of NSCLC cell lines to PI3K inhibitors was achieved via inhibition of mTORC1 signaling. Increased sensitivity of NSCLC cell lines was also mediated by other oncogenic pathways, such as Ras/MEK/ERK and Wnt/ß-catenin signaling.

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.

Sesamol combats diabetogenic effects of atorvastatin through GLUT-4 expression and improved pancreatic viability.

Statin-associated diabetes (SAD) is an issue that has come to light after a series of recent clinical trials that has led to the issue of a black box warning for statins by the US FDA. However, the benefit of statin outweighs its risk. Nevertheless, experiments have been conducted to identify the mechanism by which statins aggravate the risk of diabetes only in a select population who bear the risk factors of obesity, sedentary lifestyle, hypertension, and other associated risk factors of lifestyle disorders. In this study, the possibility of utilization of a phyto-molecule, sesamol, for its ability to combat statin-associated diabetes using atorvastatin as the agent of choice has been explored. MMP assay and western blot was conducted to investigate the effects of atorvastatin on apoptotic cascade with sesamol as a protective agent was conducted in MIN-6 cells. Effect of the combination was tested in L6 cells with 2-NBDG uptake assay and as well as western blot for GLUT-4. A diet-induced hypercholesterolemia model was developed in an in vivo model animals and treated with atorvastatin and sesamol with histopathological analysis being carried out to evaluate the apoptotic markers and GLUT-4 presence. It was found that sesamol can combat pancreatic beta cell apoptosis via the internal apoptotic pathway activated by atorvastatin. With regards to muscle cells, sesamol could improve the GLUT-4 vesical production, but not improve glucose uptake which is inhibited by atorvastatin. These findings are further confirmed by animal studies. These findings indicate that sesamol can serve as a prototype molecule for further development and investigation of similar compounds to tackle SAD.