STAT3 as a newly emerging target in colorectal cancer therapy: Tumorigenesis, therapy response, and pharmacological/nanoplatform strategies.

Colorectal cancer (CRC) ranks as the third most aggressive tumor globally, and it can be categorized into two forms: colitis-mediated CRC and sporadic CRC. The therapeutic approaches for CRC encompass surgical intervention, chemotherapy, and radiotherapy. However, even with the implementation of these techniques, the 5-year survival rate for metastatic CRC remains at a mere 12-14%. In the realm of CRC treatment, gene therapy has emerged as a novel therapeutic approach. Among the crucial molecular pathways that govern tumorigenesis, STAT3 plays a significant role. This pathway is subject to regulation by cytokines and growth factors. Once translocated into the nucleus, STAT3 influences the expression levels of factors associated with cell proliferation and metastasis. Literature suggests that the upregulation of STAT3 expression is observed as CRC cells progress towards metastatic stages. Consequently, elevated STAT3 levels serve as a significant determinant of poor prognosis and can be utilized as a diagnostic factor for cancer patients. The biological and malignant characteristics of CRC cells contribute to low survival rates in patients, as the upregulation of STAT3 prevents apoptosis and promotes pro-survival autophagy, thereby accelerating tumorigenesis. Furthermore, STAT3 plays a role in facilitating the proliferation of CRC cells through the stimulation of glycolysis and promoting metastasis via the induction of epithelial-mesenchymal transition (EMT). Notably, an intriguing observation is that the upregulation of STAT3 can mediate resistance to 5-fluorouracil, oxaliplatin, and other anti-cancer drugs. Moreover, the radio-sensitivity of CRC diminishes with increased STAT3 expression. Compounds such as curcumin, epigallocatechin gallate, and other anti-tumor agents exhibit the ability to suppress STAT3 and its associated pathways, thereby impeding tumorigenesis in CRC. Furthermore, it is worth noting that nanostructures have demonstrated anti-proliferative and anti-metastatic properties in CRC.

Targeting Nrf2 in ischemia-reperfusion alleviation: From signaling networks to therapeutic targeting.

The nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of redox balance and it responds to various cell stresses that oxidative stress is the most well-known one. The Nrf2 should undergo nuclear translocation to exert its protective impacts and decrease ROS production. On the other hand, ischemic/reperfusion (I/R) injury is a pathological event resulting from low blood flow to an organ and followed by reperfusion. The I/R induces cell injury and organ dysfunction. The present review focuses on Nrf2 function in alleviation of I/R injury. Stimulating of Nrf2 signaling ameliorates I/R injury in various organs including lung, liver, brain, testis and heart. The Nrf2 enhances activity of antioxidant enzymes to reduce ROS production and prevent oxidative stress-mediated cell death. Besides, Nrf2 reduces inflammation via decreasing levels of pro-inflammatory factors including IL-6, IL-1ß and TNF-α. Nrf2 signaling is beneficial in preventing apoptosis and increasing cell viability. Nrf2 induces autophagy to prevent apoptosis during I/R injury. Furthermore, it can interact with other molecular pathways including PI3K/Akt, NF-κB, miRNAs, lncRNAs and GSK-3ß among others, to ameliorate I/R injury. The therapeutic agents, most of them are phytochemicals such as resveratrol, berberine and curcumin, induce Nrf2 signaling in I/R injury alleviation.