Redox Homeostasis and Nrf2-Regulated Mechanisms Are Relevant to Male Infertility.

Infertility represents a significant global health challenge, affecting more than 12% of couples worldwide, and most cases of infertility are caused by male factors. Several pathological pathways are implicated in male infertility. The main mechanisms involved are driven by the loss of reduction-oxidation (redox) homeostasis and the resulting oxidative damage as well as the chronic inflammatory process. Increased or severe oxidative stress leads to sperm plasma membrane and DNA oxidative damage, dysregulated RNA processing, and telomere destruction. The signaling pathways of these molecular events are also regulated by Nuclear factor-E2-related factor 2 (Nrf2). The causes of male infertility, the role of oxidative stress in male infertility and the Keap1-Nrf2 antioxidant pathway are reviewed. This review highlights the regulatory role of Nrf2 in the balance between oxidants and antioxidants as relevant mechanisms to male fertility. Nrf2 is involved in the regulation of spermatogenesis and sperm quality. Establishing a link between Nrf2 signaling pathways and the regulation of male fertility provides the basis for molecular modulation of inflammatory processes, reactive oxygen species generation, and the antioxidant molecular network, including the Nrf2-regulated antioxidant response, to improve male reproductive outcomes.

Modulation of Nrf2/HO-1 by Natural Compounds in Lung Cancer.

Oxidative stresses (OSs) are considered a pivotal factor in creating various pathophysiological conditions. Cells have been able to move forward by modulating numerous signaling pathways to moderate the defects of these stresses during their evolution. The company of Kelch-like ECH-associated protein 1 (Keap1) as a molecular sensing element of the oxidative and electrophilic stress and nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2) as a master transcriptional regulator of the antioxidant response makes a master cytoprotective antioxidant pathway known as the Keap1/Nrf2 pathway. This pathway is considered a dual-edged sword with beneficial features for both normal and cancer cells by regulating the gene expression of the array of endogenous antioxidant enzymes. Heme oxygenase-1 (HO-1), a critical enzyme in toxic heme removal, is one of the clear state indicators for the duality of this pathway. Therefore, Nrf2/HO-1 axis targeting is known as a novel strategy for cancer treatment. In this review, the molecular mechanism of action of natural antioxidants on lung cancer cells has been investigated by relying on the Nrf2/HO-1 axis.

Bioactive PI3-kinase/Akt/mTOR Inhibitors in Targeted Lung Cancer Therapy.

One of the central signaling pathways with a regulatory effect on cell proliferation and survival is Akt/mTOR. In many human cancer types, for instance, lung cancer, the overexpression of Akt/mTOR has been reported. For this reason, either targeting cancer cells by synthetic or natural products affecting the Akt/mTOR pathway down-regulation is a useful strategy in cancer therapy. Direct inhibition of the signaling pathway or modulation of each related molecule could have significant feedback on the growth and proliferation of cancer cells. A variety of secondary metabolites has been identified to directly inhibit the AKT/mTOR signaling, which is important in the field of drug discovery. Naturally occurring nitrogenous and phenolic compounds can emerge as two pivotal classes of natural products possessing anticancer abilities. Herein, we have summarized the alkaloids and flavonoids for lung cancer treatment together with all the possible mechanisms of action relying on the Akt/mTOR pathway down-regulation. This review suggested that in search of new drugs, phytochemicals could be considered as promising scaffolds to be developed into efficient drugs for the treatment of cancer. In this review, the terms "Akt/mTOR", "Alkaloid", "flavonoid", and "lung cancer" were searched without any limitation in search criteria in Scopus, PubMed, Web of Science, and Google scholar engines.

Nrf2 Modulation in Breast Cancer.

Reactive oxygen species (ROS) are identified to control the expression and activity of various essential signaling intermediates involved in cellular proliferation, apoptosis, and differentiation. Indeed, ROS represents a double-edged sword in supporting cell survival and death. Many common pathological processes, including various cancer types and neurodegenerative diseases, are inflammation and oxidative stress triggers, or even initiate them. Keap1-Nrf2 is a master antioxidant pathway in cytoprotective mechanisms through Nrf2 target gene expression. Activation of the Nfr2 pathway benefits cells in the early stages and reduces the level of ROS. In contrast, hyperactivation of Keap1-Nrf2 creates a context that supports the survival of both healthy and cancerous cells, defending them against oxidative stress, chemotherapeutic drugs, and radiotherapy. Considering the dual role of Nrf2 in suppressing or expanding cancer cells, determining its inhibitory/stimulatory position and targeting can represent an impressive role in cancer treatment. This review focused on Nrf2 modulators and their roles in sensitizing breast cancer cells to chemo/radiotherapy agents.

The Potential Role of Curcumin in Modulating the Master Antioxidant Pathway in Diabetic Hypoxia-Induced Complications.

Oxidative stress is the leading player in the onset and development of various diseases. The Keap1-Nrf2 pathway is a pivotal antioxidant system that preserves the cells' redox balance. It decreases inflammation in which the nuclear trans-localization of Nrf2 as a transcription factor promotes various antioxidant responses in cells. Through some other directions and regulatory proteins, this pathway plays a fundamental role in preventing several diseases and reducing their complications. Regulation of the Nrf2 pathway occurs on transcriptional and post-transcriptional levels, and these regulations play a significant role in its activity. There is a subtle correlation between the Nrf2 pathway and the pivotal signaling pathways, including PI3 kinase/AKT/mTOR, NF-κB and HIF-1 factors. This demonstrates its role in the development of various diseases. Curcumin is a yellow polyphenolic compound from Curcuma longa with multiple bioactivities, including antioxidant, anti-inflammatory, anti-tumor, and anti-viral activities. Since hyperglycemia and increased reactive oxygen species (ROS) are the leading causes of common diabetic complications, reducing the generation of ROS can be a fundamental approach to dealing with these complications. Curcumin can be considered a potential treatment option by creating an efficient therapeutic to counteract ROS and reduce its detrimental effects. This review discusses Nrf2 pathway regulation at different levels and its correlation with other important pathways and proteins in the cell involved in the progression of diabetic complications and targeting these pathways by curcumin.

hTERT-molecular targeted therapy of ovarian cancer cells via folate-functionalized PLGA nanoparticles co-loaded with MNPs/siRNA/wortmannin.

Effective telomerase-molecular targeted cancer therapy might be a promising approach for the efficient treatment of ovarian cancer. Therefore, folate-functionalized PLGA nanoparticles (NPs) were co-loaded with hTERT siRNA, Wortmannin (Wtmn), as a potent PI3K inhibitor, and magnetic nanoparticle (MNPs) as a theranostic agent to gain a multifunctional NPs for targeted drug delivery as well as molecular targeted therapy. 1HNMR, FTIR, DLS, FE-SEM and TEM were applied to characterize the synthesized NPs. In vitro discharge pattern for siRNA and Wtmn from the dual drug-loaded NPs showed an early fast release followed by a constant release up to 200 h. According to the MRI analysis, by increasing the concentration of Fe3O4 in NPs, the weaker T2 signal intensity was enhanced, and a considerable contrast was detected in the MRI images. MTT assay and median-effect analysis showed that the Wtmn/siRNA-loaded MNPs-PLGA-F2 NPs display the most synergistic cytotoxicity on the SKOV-3 ovarian cancer cells. Moreover, the Wtmn/siRNA-loaded MNPs-PLGA-FA NPs could significantly reduce the expression of hTERT, AKT, and p-AKT than the single drug-encapsulated NPs (P < 0.05). Taken together, the findings showed that the multifunctional NPs relying on combinatorial therapy might have considerable potential for effective telomerase-molecular targeted therapy of ovarian cancer.

Fundamental insights into the interaction between telomerase/TERT and intracellular signaling pathways.

Telomerase activity is critical for cancer cells to provide unrestricted proliferation and cellular immortality through maintaining telomeres. Telomerase enzymatic activity is regulatable at the level of DNA, mRNA, post translational modifications, cellular transport and enzyme assembly. More recent studies confirm the interaction of the telomerase with various intracellular signaling pathways including PI3K/AKT/mTOR, NF-κB and Wnt/ß-catenin which mainly participating in inflammation, epithelial to mesenchymal transition (EMT) and tumor cell invasion and metastasis. Furthermore, hTERT protein has been detected in non-nuclear sites such as the mitochondria and cytoplasm in cells. Mitochondrial TERT indicates various non-telomere-related functions such as decreasing reactive oxygen species (ROS) generation, boosting the respiration rate, protecting mtDNA by direct binding, interacting with mitochondrial tRNAs and increasing mitochondrial membrane potential which can lead to higher chemoresistance rate in cancer cells during therapies. Understanding the molecular mechanisms of the TERT function and depended interactions in tumor cells can suggest novel therapeutic approaches. Hence, in this review we will explain the telomerase activity regulation in translational and post translational levels besides the established correlations with various cell signaling pathways with possible pathways for therapeutic targeting.

Fenugreek extract diosgenin and pure diosgenin inhibit the hTERT gene expression in A549 lung cancer cell line.

Trigonella foenum-graecum generally known as fenugreek, has been normally cultivated in Asia and Africa for the edible and medicinal values of its seeds. Fenugreek leaves and seeds have been used widely for therapeutic purposes. Fenugreek seed is recognized to show anti-diabetic and anti-nociceptive properties and other things such as hypocholesterolaemic, and anti-cancer. Diosgenin is a steroidal saponin from therapeutic herbs, fenugreek (T. foenum-graceum L.), has been well-known to have anticancer properties. Telomerase activity is not identified in usual healthy cells, while in carcinogenic cell telomerase expression is reactivated. Therefore telomerase illustrates a promising cancer therapeutic target. We deliberate the inhibitory effect of pure diosgenin and fenugreek extract diosgenin on human telomerase reverse transcriptase gene (hTERT) expression which is critical for telomerase activity. MTT-assay and qRT-PCR analysis were achieved to discover cytotoxicity effects and hTERT gene expression inhibition properties, separately. MTT results exhibited that IC50 for pure diosgenin were 47, 44 and 43 µM and for fenugreek extract diosgenin were 49, 48 and 47 µM for 24, 48 and 72 h after treatment. Culturing cells with pure diosgenin and fenugreek extract diosgenin treatment caused in down regulation of hTERT expression. These results indication that pure and impure diosgenin prevents telomerase activity by down regulation of the hTERT gene expression in A549 lung cancer cell line, with the difference that pure compound is more effective than another.