Nicotine-induced survival signaling in lung cancer cells is dependent on their p53 status while its down-regulation by curcumin is independent

<p>Abstract</p> <p>Background</p> <p>Lung cancer is the most lethal cancer and almost 90% of lung cancer is due to cigarette smoking. Even though nicotine, one of the major ingredients of cigarette smoke and the causative agent for addiction, is not a carcinogen by itself, several investigators have shown that nicotine can induce cell proliferation and angiogenesis. We observed that the proliferative index of nicotine is different in the lung cancer cell lines H1299 (p53-/-) and A549 (p53+/+) which indicates that the mode of up-regulation of survival signals by nicotine might be different in cells with and without p53.</p> <p>Results</p> <p>While low concentrations of nicotine induced activation of NF-κB, Akt, Bcl2, MAPKs, AP1 and IAPs in H1299, it failed to induce NF-κB in A549, and compared to H1299, almost 100 times higher concentration of nicotine was required to induce all other survival signals in A549. Transfection of WT-p53 and DN-p53 in H1299 and A549 respectively, reversed the mode of activation of survival signals. Curcumin down-regulated all the survival signals induced by nicotine in both the cells, irrespective of their p53 status. The hypothesis was confirmed when lower concentrations of nicotine induced NF-κB in two more lung cancer cells, Hop-92 and NCI-H522 with mutant p53 status. Silencing of p53 in A549 using siRNA made the cells susceptible to nicotine-induced NF-κB nuclear translocation as in A549 DN-p53 cells.</p> <p>Conclusions</p> <p>The present study reveals a detrimental role of nicotine especially in lung cancer patients with impaired p53 status and identifies curcumin as a potential chemopreventive.</p

Nations within a nation: variations in epidemiological transition across the states of India, 1990–2016 in the Global Burden of Disease Study

18% of the world's population lives in India, and many states of India have populations similar to those of large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state of India as part of the Global Burden of Disease (GBD) Study 2016

The Taming of Nuclear Factor Erythroid-2-Related Factor-2 (Nrf2) Deglycation by Fructosamine-3-Kinase (FN3K)-Inhibitors-A Novel Strategy to Combat Cancers

Glycated stress is mediated by the advanced glycation end products (AGE) and the binding of AGEs to the receptors for advanced glycation end products (RAGEs) in cancer cells. RAGEs are involved in mediating tumorigenesis of multiple cancers through the modulation of several downstream signaling cascades. Glycated stress modulates various signaling pathways that include p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa&ndash;B (NF-&kappa;B), tumor necrosis factor (TNF)-&alpha;, etc., which further foster the uncontrolled proliferation, growth, metastasis, angiogenesis, drug resistance, and evasion of apoptosis in several cancers. In this review, a balanced overview on the role of glycation and deglycation in modulating several signaling cascades that are involved in the progression of cancers was discussed. Further, we have highlighted the functional role of deglycating enzyme fructosamine-3-kinase (FN3K) on Nrf2-driven cancers. The activity of FN3K is attributed to its ability to deglycate Nrf2, a master regulator of oxidative stress in cells. FN3K is a unique protein that mediates deglycation by phosphorylating basic amino acids lysine and arginine in various proteins such as Nrf2. Deglycated Nrf2 is stable and binds to small musculoaponeurotic fibrosarcoma (sMAF) proteins, thereby activating cellular antioxidant mechanisms to protect cells from oxidative stress. This cellular protection offered by Nrf2 activation, in one way, prevents the transformation of a normal cell into a cancer cell; however, in the other way, it helps a cancer cell not only to survive under hypoxic conditions but also, to stay protected from various chemo- and radio-therapeutic treatments. Therefore, the activation of Nrf2 is similar to a double-edged sword and, if not controlled properly, can lead to the development of many solid tumors. Hence, there is a need to develop novel small molecule modulators/phytochemicals that can regulate FN3K activity, thereby maintaining Nrf2 in a controlled activation state

VagiBIOM Lactobacillus suppository improves vaginal health index in perimenopausal women with bacterial vaginosis: a randomized control trial

Abstract Bacterial vaginosis (BV) can cause vaginal dysbiosis that may influence general vaginal health and pregnancy complications. Balancing vaginal microbiome using Lactobacillus spp. may be a new way to prevent and treat mild BV. We conducted a randomized, double-blind, placebo-controlled pilot study aimed at evaluating the effect of the product VagiBIOM, a multi-Lactobacillus vaginal suppository, on peri- and premenopausal women with BV in restoring vaginal pH and overall vaginal health by resetting the vaginal microbiome composition. Sixty-six peri- and premenopausal women with BV symptoms were randomized with a 2:1 ratio to be treated with VagiBIOM or placebo suppositories. Vaginal pH, VAS itching score, total Nugent score, and vaginal health index (VHI) were measured. Vaginal microbiome changes before and after the treatment were analyzed by 16S rRNA sequencing and bioinformatics analysis. After 4 weeks of intervention with VagiBIOM or a placebo, the mean score for vaginal pH, VAS itching, and total Nugent score was significantly decreased from the baseline. Compared to the baseline scores, the VHI scores improved significantly following 28-day intervention (p < 0.001). Our results revealed two Lactobacillus species, L. hamsteri, and L. helveticus, as indicator species occurring differentially in the VagiBIOM-treated group. Furthermore, the regression and species network analyses revealed significant bacterial associations after VagiBIOM treatment. Lactobacillus hamsteri was positively associated with the Nugent score and negatively associated with vaginal pH. L. iners and L. salivarius were positively and inversely associated with VHI. As is typical, Bacteroides fragilis was positively associated with vaginal pH and negatively associated with the Nugent score. Interestingly, the Lactobacillus spp. diversity improved after VagiBIOM treatment. The VagiBIOM suppository treatment for peri- and premenopausal women with BV significantly relieved vaginal itching by decreasing vaginal pH and Nugent scores and improving the overall VHI after 4 weeks’ intervention. This effect was primarily the result of VagiBIOM improving vaginal Lactobacillus diversity. Trial Registration ClinicalTrials.gov registration: NCT05060029, first registration 09/28/2021: Title: A Pilot Study to Evaluate the Efficacy and Safety of Lactobacillus Species Suppositories on Vaginal Health and pH

Anti-EGFR anchored paclitaxel loaded PLGA nanoparticles for the treatment of triple negative breast cancer. In-vitro and in-vivo anticancer activities

The aim of the present study is to analyze the viability of anti-EGFR anchored immunonanoparticle (INP) bearing Paclitaxel (PTX) to specifically bind the EGFR protein on the TNBC cells. The NP was prepared by nanoprecipitation and characterized the particle size, charge, entrapment of drug and release of it. The anti-EGFR anchored and the integrity was confirmed by SDS-PAGE. Cytotoxicity and NPs cellular uptake was analyzed with MDA-MB-468 type cancer cells and the EGFR expression was confirmed by PCR, qualitatively and quantitatively. The in-vivo antitumor activity of INP was determined by using athymic mice model and targeting efficiency was measured by calculating the PTX accumulation in the tumor plasma. The prepared INP with the size of 336.3 nm and the charge of -3.48 mV showed sustained drug release upto 48 h. The INP showed significant reduction of cancer cell viability of 10.6% for 48 h with 93 fold higher PTX accumulation in the tumor plasma compared with NPs. Based on these reports, we recommend that anti-EGFR anchored PTX loaded NP may have the ability to target the TNBC cells and improve the therapeutic action and subsidize the side effects of PTX for the treatment of TNBC