Modulatory role of BV6 and chloroquine on the regulation of apoptosis and autophagy in non-small cell lung cancer cells.

Aims: Non-small cell lung cancer (NSCLC) is one of the aggressive tumors mostly diagnosed in the advanced stage. Therapeutic failure and drug resistance pose a major problem in NSCLC treatment primarily due to alterations in autophagy and loss of apoptosis. Therefore, the present study aimed to investigate the importance of the second mitochondria-derived activator of caspase mimetic BV6 and autophagy inhibitor chloroquine (CQ) on the regulation of apoptosis and autophagy, respectively. Subjects and Methods: Study was conducted on NCI-H23 and NCI-H522 cell lines to evaluate the effect of BV6 and CQ on the transcription and translation level of LC3-II, caspase-3, and caspase-9 genes by quantitative real-time-polymerase chain reaction and western blotting techniques. Results: In NCI-H23 cell line, BV6 and CQ treatments showed increased mRNA and protein expression of caspase-3, and caspase-9 compared to its untreated counterpart. BV6 and CQ treatments also caused downregulation of LC3-II protein expression compared to its counterpart. In NCI-H522 cell line, BV6 treatment showed a significantly increased expression of caspase-3 and caspase-9 mRNA and protein expression levels whereas BV6 treatment downregulated the expression level of LC3-II protein. A similar pattern was also observed in CQ treatment when compared with the respective controls. Both BV6 and CQ modulated in vitro expression of caspases and LC3-II which have critical regulatory roles in apoptosis and autophagy, respectively. Conclusions: Our findings suggest that BV6 and CQ could be promising candidates in NSCLC treatment and there is a need to explore them in vivo and in clinical applications.

NLRP3 inflammasome in rosmarinic acid-afforded attenuation of acute kidney injury in mice.

Cisplatin (CP) is a well-known anticancer drug used to effectively treat various kinds of solid tumors. CP causes acute kidney injury (AKI) and unfortunately, there is no therapeutic approach in hand to prevent AKI. Several signaling pathways are responsible for inducing AKI which leads to inflammation in proximal convoluted tubule cells in the kidney. Furthermore, the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome is involved in the CP-induced AKI. In this study, we investigated therapeutic effects of rosmarinic acid (RA) against inflammation-induced AKI. RA was orally administered at the dose of 100 mg/kg for two consecutive days after 24 h of a single injection of CP at the dose of 20 mg/kg administered intraperitoneally in Swiss albino male mice. Treatment of RA inhibited the activation of NLRP3 signaling pathway by blocking the activated caspase-1 and downstream signal molecules such as IL-1ß and IL18. CP activated HMGB1-TLR4/MyD88 axis was also found to be downregulated with the RA treatment. Activation of nuclear factor-κB and elevated protein expression of cyclooxygenase-2 (COX-2) were also found to be downregulated in RA-treated animals. Alteration of early tubular injury biomarker, kidney injury molecule-1 (KIM-1), was found to be subsided in RA-treated mice. RA has been earlier reported for antioxidant and anti-inflammatory properties. Our findings show that blocking a critical step of inflammasome signaling pathway by RA treatment can be a novel and beneficial approach to prevent the CP-induced AKI.

mRNA expression and protein-protein interaction (PPI) network analysis of adrenal steroidogenesis in response to exposure to phthalates in rats.

Phthalate esters such as di-butyl phthalate (DBP) and di-ethyl hexyl phthalate (DEHP) used in personal care and consumer products and medical devices have potential to affect human health. We studied the effect of DBP and DEHP on critical enzymes of glucocorticoid biosynthesis pathway in the adrenal gland and pro-inflammatory cytokines in the serum in male Wistar rats. DEHP and DBP treatment altered the mRNA expression of enzymes of glucocorticoid biosynthesis pathway accompanied by a reduction in glucocorticoid production and elevation in the level of glucocorticoid regulated pro-inflammatory cytokines indicating a cascading effect of phthalates. The analysis of PPI (protein - protein interaction) network involving Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) of enzymes through STRING database revealed that all the proteins have the maximum level of interaction with the selected number of proteins. The STRING database analysis together with in vivo data indicates the potential effects of phthalates on various targets of steroidogenesis pathway with a global biological impact.

Molecular interactions of vinclozolin metabolites with human estrogen receptors 1GWR-α and 1QKM and androgen receptor 2AM9-ß: Implication for endocrine disruption.

Background: Vinclozolin (VCZ) is a widely used antifungal agent with capability to enter into the human food chain. VCZ metabolizes into seven metabolites M1-M7. Several studies have shown its effects on reprotoxicity. However, there is limited information available on the interaction of VCZ metabolites with nuclear receptors. In silico studies aimed at identifying interaction of endocrine disruptor with nuclear receptors serve a prescreening framework in risk assessment.Methods: We studied interactive potential of VCZ and its metabolites with human estrogen (ER) and androgen receptor (AR) using molecular docking method. Binding potential of VCZ and its metabolites with estrogen receptors 1GWR-α, 1QKM and androgen receptor 2AM9-ß was checked by using Schrodinger Maestro 10.5. Estradiol (E2), a natural ligand of ER and AR was taken as a reference.Results: VCZ and its metabolites showed higher or similar binding efficiency on interaction with target proteins when compared with E2. VCZ and its metabolites also exhibited agonistic effect against 1GWR-α, 1QKM and 2AM9-ß with strong binding potential to them.Conclusion: Some VCZ metabolites such as M4 and M5 showed higher binding potencies with 1GWR-α, 1QKM and 2AM9-ß than E2. Toxicity data of VCZ is well endowed. However, endocrine disrupting potential of VCZ via nuclear receptor mediated pathway is less understood. This in silico study revealing that not only VCZ but its metabolites have potential to interact with 1GWR-α, 1QKM and 2AM9-ß offers a platform for further exploration of VCZ in this direction.

Dichotomy of bisphenol A-induced expression of peroxisome proliferator-activated receptors in hepatic and testicular tissues in mice.

Environmental and dietary exposure to bisphenol A (BPA) and its toxicological consequences are extensively reported. BPA has multiple cellular targets. One of the mechanisms of action of BPA involves interaction with and activation of nuclear receptors (NRs) including peroxisome proliferator activated-receptors (PPARs). PPARs regulate genes involved in adipogenesis, and metabolism of glucose, lipid and cholesterol. Study of tissue and dose specific PPAR expression may decipher the toxicity outcome of BPA exposure. We studied expression of three forms of PPARs in mouse liver and testes exposed to BPA for 14 days. mRNA and protein expression of all forms of PPAR increased linearly (monotonic) with the dose in the liver while non-monotonic but dose specific effects were observed in the testes showing a differential pattern of expression. However, histopathological study showed a dose-dependent pattern of changes in liver as well as testes demonstrating a monotonic effect. These findings imply that other PPAR-independent mechanisms may play a role in BPA-induced pathological changes. The present study warrants exploration of the role of PPARs in BPA-induced effects on male reproductive functions and offers an insight into the peculiar response of BPA at low subchronic levels which may be helpful in designing appropriate risk assessment framework.

Nanoencapsulation of betamethasone valerate using high pressure homogenization-solvent evaporation technique: optimization of formulation and process parameters for efficient dermal targeting.

Betamethsone valerate (BMV), a medium potency topical corticosteroid, is one of the most commonly employed pharmacological agents for the management of atopic dermatitis in both adults and children. Despite having remarkable pharmacological efficacy, these agents have limited clinical implication due to poor penetration across the startum cornum (SC). To mitigate issues related to targeted delivery, stability, and solubility as well as to potentiate therapeutic and clinical implication, the nanodelivery systems have gained remarkable recognition. Therefore, this study was aimed to encapsulate BMV into the chitosan nanoparticles (CS-NPs) for optimum dermal targeting and improved penetration across the SC. The prepared NPs were characterized for particle size, zeta potential, polydispersity index, entrapment efficiency, loading capacity, crystallinity, thermal behavior, morphology, in vitro release kinetics, drug permeation across the SC, and percentage of drug retained into various skin layers. Results showed that optimized BMV-CS-NPs exhibited optimum physicochemical characteristics including small particle size (< 250 ± 28 nm), higher zeta potential (+58 ± 8 mV), and high entrapment efficiency (86 ± 5.6%) and loading capacity (34 ± 7.2%). The in vitro release study revealed that BMV-CS-NPs displayed Fickian-diffusion type mechanism of release in simulated skin surface (pH 5.5). Drug permeation efficiency and the amount of BMV retained into the epidermis and the dermis were comparatively higher in case of BMV-CS-NPs compared to BMV solution. Conclusively, we anticipated that BMV-CS-NPs could be a promising nanodelivery system for efficient dermal targeting of BMV and improved anti-AD efficacy.

Hyaluronic acid, a promising skin rejuvenating biomedicine: A review of recent updates and pre-clinical and clinical investigations on cosmetic and nutricosmetic effects.

Hyaluronic acid (HA) plays multifaceted role in regulating the various biological processes such as skin repairmen, diagnosis of cancer, wound healing, tissue regeneration, anti-inflammatory, and immunomodulation. Owing to its remarkable biomedical and tissue regeneration potential, HA has been numerously employed as one of the imperative components of the cosmetic and nutricosmetic products. The present review aims to summarize and critically appraise recent developments and clinical investigations on cosmetic and nutricosmetic efficacy of HA for skin rejuvenation. A thorough analysis of the literature revealed that HA based formulations (i.e., gels, creams, intra-dermal filler injections, dermal fillers, facial fillers, autologous fat gels, lotion, serum, and implants, etc.) exhibit remarkable anti-wrinkle, anti-nasolabial fold, anti-aging, space-filling, and face rejuvenating properties. This has been achieved via soft tissue augmentation, improved skin hydration, collagen and elastin stimulation, and face volume restoration. HA, alone or in combination with lidocaine and other co-agents, showed promising efficacy in skin tightness and elasticity, face rejuvenation, improving aesthetic scores, reducing the wrinkle scars, longevity, and tear trough rejuvenation. Our critical analysis evidenced that application/administration of HA exhibits outstanding nutricosmetic efficacy and thus is warranted to be used as a prime component of cosmetic products.