Novel Perspectives of TSLP and RXR Signaling in Corticosteroid-Resistant Asthma: Updates on TSLP Blockers.

Previous studies described that asthma patients who received corticosteroid therapy have been constrained by the corticosteroid resistance subsequently fostered to severe refractory asthma. In this review, we discussed the implications of TSLP, RXR, the role of STAT5-activating cytokines, and IL-33/NH-cell signaling pathways, and recent clinical evidence on TSLP blockers in steroid-resistant asthma. We have searched several public databases such as Pubmed, Scopus, and Relemed and obtained information pertinent to the TSLP, RXR, TSLP blockers, the STAT5-activating cytokines, and IL-33. We discussed the multiple cell signaling mechanisms underlying steroid resistance. Blocking the TSLP and other key signaling molecules like STAT5 can retrieve the sensitivity of natural helper-cells to corticosteroids. RXR derivatives treatment can modulate the activity of TSLP, which further modulates steroid resistance in severe asthmatic patients and in patients with refractory asthma. We discussed the steroid-resistance mediated by the Th2 cells and Th2-driven eosinophilia upon corticosteroid intake. Thus, this review will be beneficial for clinicians and molecular biologists to explore the inflammatory pathways associated with refractory asthma conditions and develop novel therapies against corticosteroid-resistant asthma.

Inflammation and Stem Cell Stochasticity of HPV-induced Cervical Cancer: Epigenetics Based Biomarkers through Microbiome and Metabolome for Personalized Medicine: A Systematic Review.

BACKGROUND: Chemoresistance by stemness in HPV-induced cervical carcinogenesis has significant implications for the overall disease-specific survival of the patients. To date, there are no reports related to the implications of significant aspects of inflammation and microbiome-- mediated epigenetics in cervical cancers. OBJECTIVE: The current systematic review delineates the significant aspects of the inflammation-related pathophysiology, cervical cancer diagnosis based on the HPV-indued stemness, and microbiome- mediated epigenetic markers to develop personalized therapies to target the stemness-acquired indefinitely dividing cancer stem cells. METHODS: We performed a systematic review without a meta- analysis. We searched several public databases, such as Pubmed, ReleMed, National Library of Medicine, and Scopus, related to inflammation, metabolomics, microbiome-mediated epigenetic markers, and HPV-induced stemness. RESULTS AND CONCLUSION: The review significantly described the correlation between microbial inflammation and stem cell stochasticity of HPV-Induced cervical cancer and the expression of epigenetics- based biomarkers through microbiome and metabolome to foster the cervical cancer progression. These are major risk factors that can cause cervical dysplasia with substantial therapy resistance in cervical cancer patients. The qualitative and quantitative examination of the spatial transcriptomic expression of these stemness markers in the dividing cervical cancer stem cells has significant implications in the clinical sector to develop early personalized medicine to prevent cervical precancerous lesions depending on the prognosis of the cervical cancer patients. Mainly, the combinatorial regimen of current therapeutic modalities, along with microbiome-related therapies with future landscape of epigenetics-modulated therapies, may enhance overall disease-specific survival by modulating the stochastic dynamics of basal epithelial cells across the cervical region.

Combinatorial Implications of Nrf2 Inhibitors with FN3K Inhibitor: In vitro Breast Cancer Study.

BACKGROUND: Platinum derivatives are chemotherapeutic agents preferred for the treatment of cancers including breast cancer. Oxaliplatin is an anticancer drug that is in phase II studies to treat metastatic breast cancer. However, its usage is constrained by chemoresistance and dose-related side effects. OBJECTIVE: The objective of this study is to examine the combinatorial efficacy of brusatol, an Nrf2 blocker, with oxaliplatin (a proven FN3K blocker in our study) in mitigating breast cancer growth in vitro. METHODS: We performed cytotoxicity assays, combination index (CI) analysis, colony formation assays, apoptosis assays, and Western blotting. RESULTS: Results of our study described the chemosensitizing efficacy of brusatol in combination with lowdose oxaliplatin against breast cancer through synergistic effects in both BT-474 and T47D cells. A significant mitigation in the migration rate of these cancer cells was observed with the combination regimen, which is equivalent to the IC-50 dose of oxaliplatin (125 µM). Furthermore, ROS-mediated and apoptotic modes of cell death were observed with a combinatorial regimen. Colony formation of breast cancer cell lines was mitigated with a combinatorial regimen of bursatol and oxaliplatin than the individual treatment regimen. FN3K expression downregulated with oxaliplatin in T47D cells. The mitigation of FN3K protein expression with a combination regimen was not observed but the Nrf2 downstream antioxidant signaling proteins were significantly downregulated with a combination regimen similar to individual drug regimens. CONCLUSION: Our study concluded the combination efficacy of phytochemicals like brusatol in combination with low-dose oxaliplatin (FN3K blocker), which could enhance the chemosensitizing effect in breast cancer and minimize the overall dose requirement of oxaliplatin.

Perspectives on the nanocarriers with miRNAs for targeting melanoma stemness through epigenetic regulation.

Several research reports delineated the significant role of miRNAs in cancer proliferation, and their modulatory role in cancer mitigation, and drug resistance. Melanoma cells have been acquiring stemness to several chemotherapeutic agents through drug efflux proteins, epigenetic modulation, and DNA repair. miRNAs could be applied as novel therapeutic modalities for treating several kinds of cancers to modulate these mechanisms involved in stemness. Nanocarriers to carry these tumor-targeting miRNAs to modulate stemness are a prominent strategy to overcome their low penetrability, minimal stability, and nonspecificity. We have searched several public databases such as PubMed, Medline, Google scholar, and NLM and obtained the information pertinent to the miRNA-based nanocarrier systems to target stemness through epigenetic modulation in melanomas. This review delineates that various miRNAs can modulate the stemness in melanomas by specific intricate epigenetic signaling, and other cell-based signaling mechanisms. Specific nanocarrier formulations with specific miRNAs are optimal methods to deliver these miRNAs in order to achieve significant entrapment efficiency, loading efficiency, and stability. Furthermore, the combinatorial regimen of FDA-approved chemotherapeutic molecules with tumor-targeting miRNAs and chemotherapy combined with nanocarriers can efficiently deliver the utmost therapeutic window by targeting tumor matrix, invasion, metastasis, and angiogenesis in melanomas. Substantial research should focus on the clinical application of this gene therapy in melanomas using these low immunogenic, highly degradable, and biocompatible combinatorial nanotherapeutic regimens.

Evaluation of Antioxidant Property of Amla on Bond Strength and Color Stability of Power Bleached Teeth: An In vitro Study.

INTRODUCTION: Objective: To assess the antioxidant property of 10% amla extract in reversing the compromised bond strength and to assess the antioxidant property of 10% amla extract and Elsenz on the color stability of power bleached teeth. MATERIALS AND METHODS: Ninty extracted single-rooted maxillary anterior were collected and divided as follows: The labial surfaces of 30 samples were subjected to power bleaching after which the samples were divided into three groups- Group I (control), Group II (antioxidant amla), and Group III (Elsenz) with n = 10 in each which were then stained with a coffee solution for 10 mins. The color difference was recorded with a colorimeter at baseline, after bleaching, after 7, and after 15 days of staining. sixty specimens were randomly divided into six groups (n = 10) as following: Group I (immediate bonding); Group II (bleaching + immediate bonding); Group III (bleaching + antioxidant and immediate bonding); Group IV (bleaching + 1 week storage + antioxidant + bonding); Group V (bleaching + 2 week storage + antioxidant + bonding); Group VI (bleaching + 2 week storage + bonding). All the specimens were tested for shear bond strength in universal testing machine. Statistical analysis was performed using ANOVA and Scheffe's post hoc test. RESULTS: Significantly higher staining was observed in Group II (amla) and least with Elsenz pasteThe highest mean shear bond strength was found in Group I followed by Group V. CONCLUSION: Elsenz showed the least staining followed by artificial saliva. 10% Amla extract neither was effective in preventing staining of power bleached enamel nor in restoring the poor bond strength of power bleached enamel.