Tumor histoculture captures the dynamic interactions between tumor and immune components in response to anti-PD1 in head and neck cancer.

Dynamic interactions within the tumor micro-environment drive patient response to immune checkpoint inhibitors. Existing preclinical models lack true representation of this complexity. Using a Head and Neck cancer patient derived TruTumor histoculture platform, the response spectrum of 70 patients to anti-PD1 treatment is investigated in this study. With a subset of 55 patient samples, multiple assays to characterize T-cell reinvigoration and tumor cytotoxicity are performed. Based on levels of these two response parameters, patients are stratified into five sub-cohorts, with the best responder and non-responder sub-cohorts falling at extreme ends of the spectrum. The responder sub-cohort exhibits high T-cell reinvigoration, high tumor cytotoxicity with T-cells homing into the tumor upon treatment whereas immune suppression and tumor progression pathways are pre-dominant in the non-responders. Some moderate responders benefit from combination of anti-CTLA4 with anti-PD1, which is evident from better cytotoxic T-cell: T-regulatory cell ratio and enhancement of tumor cytotoxicity. Baseline and on-treatment gene expression signatures from this study stratify responders and non-responders in unrelated clinical datasets.

Protective Effects of Pelargonidin against DMBA-Induced Mammary Tumorigenesis in BALB/c Mice through Reduced Oxidative Stress and Lipid Anomalies.

Among luminal types of breast cancers, ER + breast cancer is the most frequently diagnosed cancer globally. ER + breast cancer is commonly treated with SERM drugs that block ER to prevent ER-mediated cancerous growth. Our previous computational screening found pelargonidin (PG) can inhibit ER-signaling with potent bioactivity and satisfactory toxicological features. The present study explored the anti-tumoral prospect of PG against DMBA-induced ER + murine mammary carcinogenesis. The female BALB/c mice were divided into control (A) and DMBA-exposed groups. Following tumor appearance, the DMBA-exposed group was divided into five groups: tumor control, PG-treated (Groups P25, P50, and P100), and tamoxifen-treated (TAM). The results indicated that PG-treatment dose-dependently reduced the mean tumor volume, reinstated body weight loss, and enhanced the percentage survival of tumor-bearing mice. In addition, we recorded a significant reduction in LPO, total cholesterol, and triglycerides and a surge in the activity of antioxidases and phase II detoxifying enzymes in PG-treated animals. PG also dose-dependently increased the serum level of unbound estradiol, an indicator of competitive ER binding by an ER agonist/antagonist. These data suggest that pelargonidin has potent anticancer potential against the animal model of ER + breast cancer that matches the efficiency of tamoxifen with conceivably fewer side effects.

Therapeutic role of traditionally used Indian medicinal plants and spices in combating COVID-19 pandemic situation.

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is a big challenge and burning issue to the scientific community and doctors worldwide. Globally, COVID-19 has created a health disaster and adversely affects the economic growth. Although some vaccines have already emerged, no therapeutic medication has yet been approved by FDA for the treatment of COVID-19 patients. Traditionally, we have been using different medicinal plants like neem, tulsi, tea, and many spices like garlic, ginger, turmeric, black seed, onion, etc. for the treatment of flu-like diseases. In this paper, we are highlighting the recent research progress in the identification of natural products from the Indian medicinal plants and spices that have potential inhibition properties against SARS-CoV-2. This study will provide an initiative to stimulate further research by providing useful guidance to the medicinal chemists for designing new protease inhibitors effective against SARS-CoV-2 in future.Communicated by Ramaswamy H. Sarma.

The antidiabetic drug pioglitazone ameliorates betel-nut-induced carcinogenesis in mice by restoring normal lipid metabolism, reducing oxidative stress, and inducing apoptosis.

CONTEXT: Oral administration (2 mg mL-1) of aqueous extract of betel nut (AEBN) for 24 weeks induced oncogenic alterations in the liver of female Swiss Albino mice concomitant with aberrant lipid metabolism, overactivation of Akt/mTOR signaling, and loss of apoptosis. AIM: This study was designed to investigate the potential of repurposing the antidiabetic drug pioglitazone for alleviating AEBN-induced carcinogenesis. METHODS: Sera of animals were evaluated for lipid profile and free fatty acid levels. Liver tissues were investigated for oxidative stress, histopathology, and expression of proteins involved in lipid metabolism and oncogenesis by western blotting. Apoptosis was determined using TUNEL assay. RESULTS: Coadministration of pioglitazone (10 mg kg-1 b.w) with AEBN for 8 weeks restored normal lipid profile and AMPK/ACC signaling, reduced FASN and HMGCR expressions and oxidative stress, and actively induced Akt/mTOR-mediated apoptosis in the liver. CONCLUSIONS: Pioglitazone can effectively alleviate AEBN-induced carcinogenesis in mice.

Phytochemical characterization of Styrax benzoin resin extract, molecular docking, ADME, and antibacterial activity study.

Styrax benzoin fumes have a spiritual aspect from ancient times, magical essence like a pleasant perfume, and are employed in religious ceremonies in India. This study aims to identify the volatile compounds in S. benzoin extract, their binding affinity to the bacterial target proteins, and study the antibacterial activity of the potential extract. The compounds obtained from GC-MS analysis of S. benzoin extract were subjected to molecular docking studies against DHFR of Staphylococcus aureus, tRNA synthetase of Escherichia coli, DHPS of Mycobacterium tuberculosis. Molecular docking studies revealed that seventeen compounds out of 20 compounds exhibited higher binding affinity than co-ligand (-7.00 kcal/mol) against the Staphylococcus aureus enzyme DHFR. Consequently, the crude extracts were evaluated for antibacterial activity against S. aureus, and the acetone extract showed promising findings. S. benzoin fumes might replace synthetic room fresheners, and promising compounds could be exploited in the cosmetics industry.

Circular RNAs are Potential Prognostic Markers of Head and Neck Squamous Cell Carcinoma: Findings of a Meta-Analysis Study.

Background: Several studies have reported the role of circRNAs in the pathogenesis, diagnosis and prognosis of different cancers. This meta-analysis study aimed to evaluate the potential of using circRNAs as prognostic biomarkers of head and neck squamous cell carcinoma (HNSCC). Methods: 816 relevant articles were retrieved from PubMed and Science Direct databases, out of which 17 met the inclusion criteria. These 17 studies were assessed for quality by the Newcastle-Ottawa Scale (NOS) system, and 9 high quality studies (NOS>7) were included in the meta-analysis. Cochran Q test and the I square (I 2) metric were calculated to detect potential heterogeneity among studies. Sensitivity analysis was performed to validate the credibility of outcomes, and publication bias was determined using Begg's funnel plot and Egger's test. Hazard ratio (HR) and 95% Confidence Intervals (CIs) were used to evaluate overall survival (OS) of HNSCC patients by univariate and multivariate analyses. Results: The dysregulated levels of 9 circRNAs (circPVT1, circCORO1C, circ_0000199, circCUX1, circPARD3, circMYC, circ_0102272, circ_0092125 and circ_00072387) were inversely related to OS of HNSCC patients [upregulated circRNA (univariate analysis: HR = 3.40, 95% CI: 2.66-4.36, p < 0.0001, I 2 = 0%; multivariate analysis: HR = 3.33, 95% CI: 2.54-4.38, p < 0.0001, I 2 = 0%), downregulated circRNA (univariate analysis: HR = 2.83, 95% CI: 1.73-4.65, p < 0.0001, I2 = 57.8%; multivariate analysis: HR = 2.35, 95% CI: 1.42-3.89, p = 0.0009, I2 = 0%)]. The individual HR for these 9 circRNAs indicated inverse relation to OS, validating the overall HR. The dyregulated levels of these circRNAs were also associated with poor clinicopathological outcomes such as primary tumor size, lymph node metastasis, distant metastasis and poor tumor (T), nodes (N), metastases (M); i.e TNM staging, and six of these circRNAs regulated diverse micro RNAs, revealing their role in tumorigenesis and cancer progression. Conclusion: Nine different circRNAs dysregulated in HNSCC tumors may serve as potential prognostic markers of HNSCC. These markers are associated with reduced OS and poor clinicopathological outcomes of HNSCC patients. They are also involved in the pathogenesis and progression of HNSCC through diverse mechanisms.

Lead and cadmium exposure network in children in a periurban area in India: susceptibility and health risk.

To investigate the complex Pb-Cd exposure network in school-going children, a thorough investigation of the probable exposure means (diet, water, and school micro-environments such as paint dust and school courtyard soil) and exposure route (ingestion, inhalation and dermal) was carried out in a periurban area spanning three districts in southern Assam, India. Multivariate statistical analysis was carried out to understand the complex data matrices, and the health risk assessments (carcinogenic and non-carcinogenic) based on US EPA Risk Assessment models were also made. We found the median values to be 0.9-4.0 mg Pb/kg and 0.21-6.2 mg Cd/kg in various food items. Groundwater also had Pb (0.13-0.48 mg/L) and Cd (0.11-0.29 mg/L). Pb levels in paint dust were within the permissible limits, but 50% of the samples had higher than permissible levels of Cd. Approximately 23% of the school courtyard soil had Pb above the global background levels, but all the samples had 4-27 times elevated levels of Cd in them. School micro-environment contributed significantly to the metal load in children due to their typical hand-to-mouth behavior and dietary intake (food and water) via ingestion was the most prominent route of exposure in children. The evaluation of the estimated chronic daily intake and the hazard quotient indicated hazardous exposure over a lifetime to both Pb and Cd, but only Cd posed a prominent cancer risk. It could be concluded that chronic insidious effects of metals would be a noteworthy toxicological threat to children when exposed early on.

Vildagliptin, a dipeptidyl peptidase-4 inhibitor, reduces betel-nut induced carcinogenesis in female mice.

AIM: Betel-nut, a popular masticatory among Southeast Asian populations is a class I carcinogen, previously associated with dyslipidemia and aberrant lipid metabolism, and is reported to be used more frequently by females, than males. This study investigates the potential of repurposing the anti-diabetic drug, vildagliptin, a dipeptidyl peptidase-4 inhibitor, for alleviating the oncogenic condition in female Swiss Albino mice administered an aqueous extract of betel-nut (AEBN) orally (2 mg ml-1) for 24 weeks. MAIN METHODS: Tissues were investigated by histopathological, immunohistochemical and apoptosis assays. Biochemical analyses of oxidative stress markers and lipid profile were performed using different tissues and sera. The expressions of different proteins involved in lipid metabolism and oncogenic pathways were evaluated by Western blotting. KEY FINDINGS: AEBN induced carcinogenesis primarily in the liver by significantly impairing AMPK signaling, inducing oxidative stress, activating Akt/mTOR signaling, increasing Ki-67 immunoreactivity and cyclin D1 expression, and significantly diminishing apoptosis. Co-administration of AEBN with vildagliptin (10 mg kg-1 body weight) for 8 weeks reduced liver dysplasia, and significantly decreased free palmitic acid, increased free oleic acid, normalized lipid profile, decreased oxidative stress, cyclin D1 expression, Ki-67 immunoreactivity, and Bcl2 expression, and increased the ratio of apoptotic/non-apoptotic cells. Mechanistically, vildagliptin elicited these physiological and molecular alterations by restoring normal AMPK signaling and reducing the cellular expressions of FASN and HMGCR, restoring AMPK-dependent phosphorylation of p53 at Ser-15 and reducing Akt/mTOR signaling. SIGNIFICANCE: These results indicate that vildagliptin may alleviate betel-nut induced carcinogenesis in the liver of female mice.

Pleiotropic effects of anti-diabetic drugs: A comprehensive review.

Diabetes mellitus characterized by hyperglycaemia presents an array of comorbidities such as cardiovascular and renal failure, dyslipidemia, and cognitive impairments. Populations above the age of 60 are in an urgent need of effective therapies to deal with the complications associated with diabetes mellitus. Widely used anti-diabetic drugs have good safety profiles and multiple reports indicate their pleiotropic effects in diabetic patients or models. This review has been written with the objective of identifying the widely-marketed anti-diabetic drugs which can be efficiently repurposed for the treatment of other diseases or disorders. It is an updated, comprehensive review, describing the protective role of various classes of anti-diabetic drugs in mitigating the macro and micro vascular complications of diabetes mellitus, and differentiating these drugs on the basis of their mode of action. Notably, metformin, the anti-diabetic drug most commonly explored for cancer therapy, has also exhibited some antimicrobial effects. Unlike class specific effects, few instances of drug specific effects in managing cardiovascular complications have also been reported. A major drawback is that the pleiotropic effects of anti-diabetic drugs have been mostly investigated only in diabetic patients. Thus, for effective repurposing, more clinical trials devoted to analyse the effects of anti-diabetic drugs in patients irrespective of their diabetic condition, are required.