Targeting Ras-ERK cascade by bioactive natural products for potential treatment of cancer: an updated overview.

MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) pathway is an important link in the transition from extracellular signals to intracellular responses. Because of genetic and epigenetic changes, signaling cascades are altered in a variety of diseases, including cancer. Extant studies on the homeostatic and pathologic behavior of MAPK signaling have been conducted; however, much remains to be explored in preclinical and clinical research in terms of regulation and action models. MAPK has implications for cancer therapy response, more specifically in response to experimental MAPK suppression, compensatory mechanisms are activated. The current study investigates MAPK as a very complex cell signaling pathway that plays roles in cancer treatment response, cellular normal conduit maintenance, and compensatory pathway activation. Most MAPK inhibitors, unfortunately, cause resistance by activating compensatory feedback loops in tumor cells and tumor microenvironment components. As a result, innovative combinatorial treatments for cancer management must be applied to limit the likelihood of alternate pathway initiation as a possibility for generating novel therapeutics based on incorporation in translational research. We summarize current knowledge about the implications of ERK (MAPK) in cancer, as well as bioactive products from plants, microbial organisms or marine organisms, as well as the correlation with their chemical structures, which modulate this pathway for the treatment of different types of cancer.

The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling.

The endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.

Chalcone suppresses tumor growth through NOX4-IRE1α sulfonation-RIDD-miR-23b axis.

Chalcone is a polyphenolic compound found abundantly in natural plant components. They have been acclaimed as potential antitumor compounds in multiple tumor cells. However, not much attention has been paid to elucidate its antitumor mechanism of action. Here, chalcone was demonstrated to trigger endoplasmic reticulum (ER) stress-induced apoptosis through sulfonation of IRE1α by ER-localized NADPH oxidase 4 (NOX4). IRE1α-sulfonation at a cysteine residue was shown to induce "regulated IRE1α-dependent decay" (RIDD) of mRNA rather than specific splicing of XBP1. The IRE1α sulfonation-induced RIDD degraded miR-23b, enhancing the expression of NOX4. The expression of NOX4 was also upregulated in breast, and prostate cancer tissue. In chalcone-administered mice in vivo, tumor growth was regressed by the consistent mechanisms "NOX4-IRE1α sulfonation-RIDD". Similarly, NOX4 activation and IRE1α sulfonation were also highly increased under severe ER stress conditions. Together, these findings suggest chalcone as a lead anticancer compound where it acts through NOX4-IRE1α-RIDD-miR-23b axis providing a promising vision of chalcone derivatives' anticancer mechanism.

Role of Endoplasmic Reticulum Stress Sensor IRE1α in Cellular Physiology, Calcium, ROS Signaling, and Metaflammation.

Inositol-requiring transmembrane kinase endoribonuclease-1α (IRE1α) is the most prominent and evolutionarily conserved unfolded protein response (UPR) signal transducer during endoplasmic reticulum functional upset (ER stress). A IRE1α signal pathway arbitrates yin and yang of cellular fate in objectionable conditions. It plays several roles in fundamental cellular physiology as well as in several pathological conditions such as diabetes, obesity, inflammation, cancer, neurodegeneration, and in many other diseases. Thus, further understanding of its molecular structure and mechanism of action during different cell insults helps in designing and developing better therapeutic strategies for the above-mentioned chronic diseases. In this review, recent insights into structure and mechanism of activation of IRE1α along with its complex regulating network were discussed in relation to their basic cellular physiological function. Addressing different binding partners that can modulate IRE1α function, UPRosome triggers different downstream pathways depending on the cellular backdrop. Furthermore, IRE1α are in normal cell activities outside the dominion of ER stress and activities under the weather of inflammation, diabetes, and obesity-related metaflammation. Thus, IRE1 as an ER stress sensor needs to be understood from a wider perspective for comprehensive functional meaning, which facilitates us with assembling future needs and therapeutic benefits.

Antioxidant, antibacterial, antidiarrheal and antipyretic activities of organic crude fractions of Commelina paludosa.

BACKGROUND: The herb, Commelina paludosa (CP) Blume (Family-Commelinaceae) is medicinally used by the traditional practitioners in Bangladesh. However, there is a lack of scientific evidence on this medicinal herb. AIM AND OBJECTIVES: This study aimed to evaluate the phytochemical and pharmacological activities of CP (ethanol [ECP], chloroform [CCP] and n-hexane [NHCP] of whole-plant extracts). MATERIALS AND METHODS: For this antioxidant, antimicrobial, antidiarrheal and antipyretic activities of crude extracts of CP were conducted by 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging, disc diffusion and serial dilution, castor oil-induced diarrhea and yeast powder-induced pyrexia methods respectively. RESULTS AND OBSERVATION: The results suggest that all the fractions significantly scavenged DPPH radicals. In the disc diffusion test, the zones of inhibition were observed within the range of 7 mm to 30.67 mm at 500 mg/disc. The highest zones of inhibition were observed by ECP, CCP and NHCP against Bacillus azotoformans, Lactobacillus coryifomis and Salmonella typhi respectively. NHCP was found to exert stronger antibacterial effect than the ECP and CCP. CONCLUSION: Minimum inhibitory concentrations were detected within the range of 31.25 and 250 µg/ml. Moreover, the crude fractions also showed significant (P < 0.05) antidiarrheal and antipyretic activities in Swiss mice. CP may be a good source of therapeutic components.