Ameliorative inhibition of sirtuin 6 by imidazole derivative triggers oxidative stress-mediated apoptosis associated with Nrf2/Keap1 signaling in non-small cell lung cancer cell lines

Background: Redox homeostasis is the vital regulatory system with respect to antioxidative response and detoxification. The imbalance of redox homeostasis causes oxidative stress. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2, also called Nfe2l2)/Kelchlike ECH-associated protein 1 (Keap1) signaling is the major regulator of redox homeostasis. Nrf2/Keap1 signaling is reported to be involved in cancer cell growth and survival. A high level of Nrf2 in cancers is associated with poor prognosis, resistance to therapeutics, and rapid proliferation, framing Nrf2 as an interesting target in cancer biology. Sirtuins (SIRT1-7) are class III histone deacetylases with NAD + dependent deacetylase activity that have a remarkable impact on antioxidant and redox signaling (ARS) linked with Nrf2 deacetylation thereby increasing its transcription by epigenetic modifications which has been identified as a crucial event in cancer progression under the influence of oxidative stress in various transformed cells. SIRT6 plays an important role in the cytoprotective effect of multiple diseases, including cancer. This study aimed to inhibit SIRT6 using an imidazole derivative, Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl] acetate, to assess its impact on Nrf2/Keap1 signaling in A549 and NCI-H460 cell lines.Method: Half maximal inhibitory concentration (IC50) of Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl] acetate was fixed by cell viability assay. The changes in the gene expression of important regulators involved in this study were examined using quantitative real-time PCR (qRT-PCR) and protein expression changes were confirmed by Western blotting. The changes in the antioxidant molecules are determined by biochemical assays. Further, morphological studies were performed to observe the generation of reactive oxygen species, mitochondrial damage, and apoptosis.Results: We inhibited SIRT6 using Ethyl 2-[5-(4-chlorophenyl)-2-methyl-1-H-Imidazole-4-yl] acetate and demonstrated that SIRT6 inhibition impacts the modulation of antioxidant and redox signaling. The level of antioxidant enzymes and percentage of reactive oxygen species scavenging activity were depleted. The morphological studies showed ROS generation, mitochondrial damage, nuclear damage, and apoptosis. The molecular examination of apoptotic factors confirmed apoptotic cell death. Further, molecular studies confirmed the changes in Nrf2 and Keap1 expression during SIRT6 inhibition.Conclusion: The overall study suggests that SIRT6 inhibition by imidazole derivative disrupts Nrf2/Keap1 signaling leading to oxidative stress and apoptosis induction

Selenium conditioning decreases antioxidant enzyme activity and delays germination potency of Macrotyloma uniflorum and Vigna radiate

Objective: This study focuses on the effect of Selenium (Se) on the germination of Macrotyloma uniflorum and Vigna radiate seeds. Methods: Both the seeds were soaked in solutions containing different concentrations of Se (0 mg/L, 0.5 mg/L, 2.5 mg/L and 5.0 mg/L), for different time intervals (3 h, 6 h, 9 h and 12 h). After soaking, germination efficacy of the seeds was assayed. Total carbohydrate and starch content of the seeds were monitored along with α-amylase activity. The antioxidant activity was also estimated through measuring Catalase, Superoxide dismutase activity and amount of reduced Glutathione as well. Results: The result unveiled that at 0.5 mg/L of Se did not affect the germination at 3 h of soaking, however upon increasing the duration of soaking the germination efficacy is statistically decreased. 3 h soaking of seeds with 2.5 mg/L and 5.0 mg/L of Se reduced the germination efficacy of both the seeds. Further it was observed that increasing the duration of soaking from 3 h to 6hrs, 9 h and 12 h, inhibited the germination potency (P < 0.05). Total carbohydrate and starch content were increased (P < 0.05) in both the seeds soaked in 0.5 mg/L of Se for 3 h, on the other hand there is no statistical difference at 2.5 mg/L and 5.0 mg/L of Se. The α-amylase activities in different experimental samples are in line with carbohydrate and starch levels. Furthermore, it was observed that reduced glutathione and antioxidant enzyme activities were increased (P < 0.05) in both the seeds soaked in 0.5 mg/L of Se for 3 h, however these alterations were statistically reduced (P < 0.05) at 2.5 mg/L and 5.0 mg/L of Se. Conclusion: The present study documents higher concentration of Se could decrease the germination efficacy of M. uniflorum and V. radiate seeds through oxidative stress mediated pathway. On the other hand, lower concentration delays germination. Soaking of M. uniflorum and V. radiate seeds in less concentrated Se solution increases the carbohydrate and starch content compromising germination efficacy

EGFR-Based Targeted Therapy for Colorectal Cancer&mdash;Promises and Challenges

Colorectal carcinoma (CRC) is the most lethal and common form of cancer in the world. It was responsible for almost 881,000 cancer deaths in 2018. Approximately 25% of cases are diagnosed at advanced stages with metastasis&mdash;this poses challenges for effective surgical control and future tumor-related mortality. There are numerous diagnostic methods that can be used to reduce the risk of colorectal carcinoma. Among these, targeted nanotherapy aims to eliminate the tumor and any metastasis. Active targeting can increase the effectiveness and quantity of drugs delivered to the target site. Antibodies that target overexpressed receptors on cell surfaces and indicators are coupled with drug-loaded carriers. The major target receptors of chemotherapeutic drugs delivery include VEGFR, EGFR, FGFR, HER2, and TGF. On account of its major and diverse roles in cancer, it is important to target EGFR in particular for better tumor selection, as EGFR is overexpressed in 25 to 82% of colorectal carcinoma cases. The EGFR monoclonal immunoglobulins cetuximab/panitumumab can thus be used to treat colorectal cancer. This review examines carriers that contain cetuximab-conjugated therapeutic drugs as well as their efficacy in anticancer activities

EGFR-Based Targeted Therapy for Colorectal Cancer—Promises and Challenges

Colorectal carcinoma (CRC) is the most lethal and common form of cancer in the world. It was responsible for almost 881,000 cancer deaths in 2018. Approximately 25% of cases are diagnosed at advanced stages with metastasis—this poses challenges for effective surgical control and future tumor-related mortality. There are numerous diagnostic methods that can be used to reduce the risk of colorectal carcinoma. Among these, targeted nanotherapy aims to eliminate the tumor and any metastasis. Active targeting can increase the effectiveness and quantity of drugs delivered to the target site. Antibodies that target overexpressed receptors on cell surfaces and indicators are coupled with drug-loaded carriers. The major target receptors of chemotherapeutic drugs delivery include VEGFR, EGFR, FGFR, HER2, and TGF. On account of its major and diverse roles in cancer, it is important to target EGFR in particular for better tumor selection, as EGFR is overexpressed in 25 to 82% of colorectal carcinoma cases. The EGFR monoclonal immunoglobulins cetuximab/panitumumab can thus be used to treat colorectal cancer. This review examines carriers that contain cetuximab-conjugated therapeutic drugs as well as their efficacy in anticancer activities