Stilbenes: a journey from folklore to pharmaceutical innovation.

In modern times, medicine is predominantly based on evidence-based practices, whereas in ancient times, indigenous people relied on plant-based medicines with factual evidence documented in ancient books or folklore that demonstrated their effectiveness against specific infections. Plants and microbes account for 70% of drugs approved by the USFDA (U.S. Food and Drug Administration). Stilbenes, polyphenolic compounds synthesized by plants under stress conditions, have garnered significant attention for their therapeutic potential, bridging ancient wisdom with modern healthcare. Resveratrol, the most studied stilbene, initially discovered in grapes, red wine, peanuts, and blueberries, exhibits diverse pharmacological properties, including cardiovascular protection, antioxidant effects, anticancer activity, and neuroprotection. Traditional remedies, documented in ancient texts like the Ayurvedic Charak Samhita, foreshadowed the medicinal properties of stilbenes long before their modern scientific validation. Today, stilbenes are integral to the booming wellness and health supplement market, with resveratrol alone projected to reach a market value of 90 million US$ by 2025. However, challenges in stilbene production persist due to limited natural sources and costly extraction methods. Bioprospecting efforts reveal promising candidates for stilbene production, particularly endophytic fungi, which demonstrate high-yield capabilities and genetic modifiability. However, the identification of optimal strains and fermentation processes remains a critical consideration. The current review emphasizes the knowledge of the medicinal properties of Stilbenes (i.e., cardiovascular, antioxidant, anticancer, anti-inflammatory, etc.) isolated from plant and microbial sources, while also discussing strategies for their commercial production and future research directions. This also includes examples of novel stilbenes compounds reported from plant and endophytic fungi.

Immunotherapy in Small Cell Lung Cancer Treatment: a Promising Headway for Future Perspective.

OPINION STATEMENT: Despite advancements in clinical research, both prognosis and treatment for SCLC patients are still in the nascent stage. SCLC is a fatal disease with high tumor mutational burden and is strongly associated with exposure to tobacco. This leads to the development of potential neo-antigens, inhibition of immune responses, and development of paraneoplastic disorders. Surgery, radiation, and chemotherapy are widely accepted treatments for cancer globally, and most recently, immunotherapy has now become the "fourth pillar" of SCLC treatment. Various immune checkpoint pathways regulate the activation of T cells at multiple stages during an immune response. T cell checkpoint inhibitors such as anti-PD1 (pembrolizumab, nivolumab), anti-PDL1, and anti-CTLA-4 (tremelimumab, ipilimumab) have potential to show anti-cancer activity along with the promise to prolong survival in patients with SCLC. Treatment with the CTLA-4-specific antibodies can restore the immune response by increasing the accumulation and survival of T-cells whereas monoclonal antibodies block either PD-1 or its ligands that prevent downregulation of effector T-cell, which enables the T-cells to mediate the death of tumor cells. Furthermore, monoclonal antibody in combination with chemotherapy has attained quite a focus to enhance the survival of SCLC patients. Apart from this, various immunotherapeutic approaches have been evaluated in the clinical trials for SCLC patients such as TLR9 agonist, anti-CD47, anti-ganglioside therapy, and anti-Notch signaling. The current review focuses on the rationale as well as on the clinical studies of immunotherapy in SCLC along with the clinical end results of certain immunotherapeutic agents and novel therapeutic combinations in SCLC patients.

Synergistic polymorphic interactions of phase II metabolizing genes and their association toward lung cancer susceptibility in North Indians.

Lung cancer is a multifactorial carcinoma with diverse heterogeneity. Genetic variations in drug-metabolizing enzymes may lead to defective detoxification and clearance of carcinogenic compounds. The high-order gene-gene interaction has been carried out between different genotypes of Phase II detoxification genes (NQO1, SULT1A1, NAT2, and EPHX1). Our results depict the genetic combination of SULT1A1 R213H with NAT2 × 5B L161L, SULT1A1 R213H with NAT2 × 5C K268R, EPHX1 H139R and NAT2 × 5B L161L exhibit a protective effect towards lung cancer risk. Further, the triple combinations of NQO1 P187S, EPHX1 Y113H, and EPHX1 H139R; NQO1 P187S, EPHX1 Y113H, and NAT2 × 6 R197Q; NQO1 P187S, EPHX1 Y113H, and NAT2 × 7 G286E; SULT1A1 R213H, EPHX1 H139R, and NAT2 × 7 G286E suggested a two-fold increased risk of lung cancer for subjects. Genetic polymorphisms of phase II detoxifying genes (NAT2, NQO1, EPHX1, SULT1A1) are prognostic markers for lung cancer.

Genetic polymorphisms in the mEH gene in relation to tobacco smoking: role in lung cancer susceptibility and survival in north Indian patients with lung cancer undergoing platinum-based chemotherapy.

Aim: Epoxide hydrolase is involved in oxidative defenses and is responsible for the activation of carcinogens. The relationship between EPHX1 polymorphisms (Tyr113His and His139Arg) and overall survival (OS) and lung cancer (LC) risk was investigated. Methods: The study comprised 550 cases and 550 controls. Genotyping and statistical analysis were applied. Results: The variant genotypes of EPHX1 polymorphisms exhibited no association with LC risk. The Tyr113His polymorphism exhibited twofold increased odds of lymph node invasion (p = 0.04). The Tyr/His genotype is a risk factor for smokers. Subjects carrying the combined genotype for His139Arg showed better median survival time (MST) and the heterozygous genotype revealed better MST in the case of small-cell lung cancer (SCLC; 11.30 vs 6.73 months; log-rank test: p = 0.02). The heterozygous genotype (His139Arg) had longer MST in patients receiving cisplatin/carboplatin and irinotecan (11.30 vs 7.23; log-rank test: p = 0.007) Conclusion: The Tyr113His polymorphism is associated with LC risk in smokers and is a potential prognostic factor for OS in patients with SCLC after irinotecan.

Lay abstract Microsomal epoxide hydrolase (mEH) is an enzyme that plays a defensive role against chemicals. In this study, the relationship between the variation of the epoxide hydrolase and the risk of lung cancer was investigated and its role in the survival of patients with lung cancer was evaluated. The study comprised 550 cases and 550 controls. Genotyping was carried out using molecular biology tools and was followed by statistical analysis. The variant genotype of the EPHX1 gene was not associated with the risk of lung cancer, even based on histology. The variant form of the EPHX1 gene was found to be a risk factor for smokers. The Tyr/His genotype was associated with the risk of lung cancer in male subjects. Patients carrying the variant form of the EPHX1 gene (His¹³⁹Arg) experienced better survival. The heterozygous genotype of the EPHX1Tyr¹¹³His gene was related to longer survival time in patients who received cisplatin/carboplatin along with irinotecan. The EPHX1 Tyr¹¹³His polymorphism is associated with LC risk in smokers and is a potential prognostic factor for OS of patients with small-cell lung cancer (SCLC) after irinotecan therapy and might increase the likelihood of lymph node metastasis; EPHX1His¹³⁹Arg exhibited better survival, especially in patients with SCLC.

Genetic polymorphism of Arg213His variant in the SULT1A1 gene is associated with reduced susceptibility to lung cancer in North Indian population.

Sulfotransferases (SULTs) are phase II detoxification enzymes that is involved in the biotransformation of many compounds including tobacco carcinogens. A polymorphism in the SULT1A1 (Arg213His) gene results in reduced enzyme activity.We investigated the association between the SULT1A1 (Arg213/His) genotype and lung cancer (LC). This case-control study comprised of 550 cases and controls, matched on age, gender and smoking status.The variant genotype exhibited no association with LC risk, even after stratification on basis of histological subtypes. Male LC patients carrying the variant His213 allele (p = 0.02) did not exhibit an increased risk towards LC. Smokers harbouring the Arg/His genotype did demonstrate a reduced risk towards LC (AOR = 0.70; p = 0.019). Furthermore, the LC subjects who were heavy smokers and harbouring the Arg/His genotype (AOR = 0.28; p = 0.019) did not show a genetic predisposition towards LC susceptibility. The subjects who smoked pack years of above 40 and carrying the His/His (AOR = 0.28; p = 0.036) genotype were found to have a reduced risk for LC. Furthermore, 473 subjects were analysed in regards to overall survival, wherein the His/His genotype exhibited better OS than Arg/Arg genotype (11.30 vs. 8.07 months).This study provides evidence of no genetic predisposition towards LC risk associated with SULT1A1 Arg213His polymorphism in relation to tobacco smoking.

Association of NAT-2 gene polymorphisms toward lung cancer susceptibility and prognosis in North Indian patients treated with platinum-based chemotherapy.

Aim: The present study has been carried out to evaluate the association of the N-acetyl transferase 2 (NAT2) variants in North Indian lung cancer patients and healthy controls. Furthermore, we have also determined the effect of the polymorphic variants of the NAT2 gene on the clinical outcomes and overall survival among lung cancer (LC) subjects treated with platinum-based doublet chemotherapy. Methods: This case-control study comprised a total of 550 cases and 550 healthy controls. The genotyping was carried out using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and the statistical analysis was carried out using MedCalc. Results: There was a lack of any significant association for both 590G>A and 803A>G polymorphisms toward risk for LC, but 857G>A polymorphism exhibited a risk toward LC (p = 0.005). Whereas, variant alleles for the 481C>T polymorphism had a decreased risk for LC (p = 0.0003). Further, 857G>A polymorphism conferred a positive association between genotype and ADCC (p = 0.001) and 481C>T polymorphism had a decreased risk for SQCC (OR = 0.39, p = 0.0006) and SCLC (p = 0.001) subjects. The smokers carrying mutant genotype for the 481C>T polymorphism had a decreased risk toward LC (p < 0.0001) even in light (p = 0.002) as well as heavy smokers (p = 0.001). In case of females, 2.59-fold and 3.66-fold increased risk of LC development was observed in subjects with intermediate and slow acetylator for the 857G>A polymorphism. Whereas, in case of males this polymorphism depicts a reduced risk for LC. On the other hand, 803A>G depicted a 2.82-fold risk of LC in case of female subjects who were slow acetylators. Our study exhibits a significant difference in the overall haplotype distribution between cases and controls. In our study overall, (857G>A, 481C>T, 803A>G) was found to be best model, but was not significant using MDR. Considering the CART results 481C>T polymorphism came out to be the most significant factor in determining the LC risk. For the 803A>G polymorphism, a threefold odds of lymph node invasion were observed for mutant genotype, the recessive model exhibited an odds ratio of 2.8. 590G>A appears to be a potential prognostic factor for OS of SCLC patients after irinotecan therapy as the survival time for such patients was better. Conclusion: These results suggest that NAT2 variant genotype for 590G>A and 803A>G was not found to modulate risk toward LC, but 857G>A polymorphism exhibited a risk toward LC and 481C>T polymorphism had a decreased risk for LC. NAT2 590G>A appears to be a potential prognostic factor for OS of SCLC patients after irinotecan therapy and 481C>T came out to be significant factor using CART.

MTHFR polymorphism as a predictive biomarker for gastrointestinal and hematological toxicity in North Indian adenocarcinoma patients.

In the present study, we investigated the relationship between the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and overall survival, toxicity and treatment response for North Indian adenocarcinoma patients. The polymorphisms of MTHFR gene in north Indian adenocarcinoma patients were assessed by PCR-RFLP. Our data observed that patients with mutant genotype (C/C) for 1298 A>C) polymorphism showed higher trend of median survival time compared to patients bearing the wild type genotype (A/A) (MST= 13.93 vs. 7.97, p=0.12). Further, we observed patients with the heterozygous genotype for A1298C polymorphism had 12-fold risk of diarrhea (AOR =12.54, 95% CI = 1.54-101.86, p=0.018). The patients with heterozygous genotype (CT) of the C677T polymorphism had 5.34-fold increased risk of developing neutropenia (AOR=5.34, 95% CI=1.49-19.06, p=0.009). Our results suggest that MTHFR polymorphisms are associated with hematological toxicity. MTHFR polymorphism might impact the development of pemetrexed and platinum-related toxicities but not as a clinical predictor of efficiency.

Association of NQO1Pro187Ser polymorphism with clinical outcomes and survival of lung cancer patients treated with platinum chemotherapy.

Background: The study was carried out to evaluate the association of NQO1 P187S polymorphism in North Indian lung cancer (LC) patients. We determined the effect of this polymorphic variant on the survival of LC patients. Patients & methods/results: This case-control study comprised a total of 1100 subjects. The genotyping was carried out using PCR-RFLP and statistical analysis was carried out. The variant TT genotype exhibited 3.5-fold higher odds in subjects with stage III (p = 0.0006), fivefold higher odds of lymph-node invasion (p = 0.007) and an odd of <1 in case of metastasis (p = 0.0028). Patients possessing TT genotype and administered with paclitaxel, exhibited a poor survival (3.57 vs 12.20 months; hazard ratio = 7.95; p = 0.0098). Conclusion: These results suggest that NQO1 variant genotype was not found to modulate risk toward LC. However, the variant genotype was found to be strongly correlated with stage III LC, lymph node invasion and was found to be positively correlating with metastasis.

GSTP1 Ile105Val polymorphism among North Indian lung cancer patients treated using monotherapy and poly-pharmacy.

BACKGROUND: Genetic polymorphism within the P1 isoenzyme of the Glutathione-S-Transferase (GST) family is found to modulate and alter the enzyme activity of GSTP1 protein and thus may result in a change of sensitivity to platinum-based chemotherapy. We investigated the relationship between GSTP1 Ile105Val polymorphisms and overall survival, treatment response, and for both hematological and non-hematological toxicity of advanced North Indian lung cancer patients undergoing platinum-based double chemotherapy. METHODS: The polymorphism of GSTP1 Ile105Val in North Indian lung cancer patients was assessed by polymerase chain reaction-restriction fragment length polymorphism. A total of 682 lung cancer patients were enrolled in the study, and it was observed that patients who were carrying both the mutant alleles (Val/Val) for the GSTP1 polymorphism showed a higher trend of median survival time (MST) as compared to the patients bearing the wild type of genotype (Ile/Ile) (MST = 8.30 vs. 7.47, p = 0.56). Based on toxicity profiling, we observed that lung cancer patients with the mutant genotype of GSTP1 (Val/Val) had an increased risk of leukopenia (OR = 2.41; 95% CI = 1.39-4.18, p = 0.001) as compared to subjects carrying both copies of the wild alleles (Ile/Ile). Our data suggested that patients with heterozygous genotype (Ile/Val) had a 2.14-fold increased risk of developing severe anemia (OR = 2.14, 95% CI = 0.97-4.62, p = 0.03). Our data also showed that in small cell lung carcinoma (SCLC) patients' polymorphism of GSTP1 was associated with thrombocytopenia (χ2 test = 7.32, p = 0.02). CONCLUSIONS: Our results suggest that GSTP1 Ile105Val polymorphism could be a predictive biomarker for hematological toxicity, like leukopenia and anemia, but not thrombocytopenia or neutropenia.