Current Molecular Medicine - Volume 23, Issue 1, 2023

According to the GLOBOCAN 2020 data, colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related death. The risk factors for colorectal cancer include a diet abundant with fat, refined carbohydrates, animal protein, low fiber content, alcoholism, obesity, long-term cigarette smoking, low physical activity, and aging. Colorectal carcinomas are classified as adenocarcinoma, neuroendocrine, squamous cell, adenosquamous, spindle cell, and undifferentiated carcinomas. In addition, many variants of colorectal carcinomas have been recently distinguished based on histological, immunological, and molecular characteristics. Recently developed targeted molecules in conjunction with standard chemotherapeutics or immune checkpoint inhibitors provide promising treatment protocols for colorectal cancer. However, the benefit of targeted therapies is strictly dependent on the mutational status of signaling molecules (e.g., KRAS) or mismatch repair systems. Here it is aimed to provide a comprehensive view of colorectal cancer types, molecular pathways associated, recently developed targeted therapies, as well as proteomic investigations applied to colorectal cancer for the discovery of novel biomarkers and new targets for treatment protocols.

Free radicals contain one or more unpaired electrons in their valence shell, thus making them unstable, short-lived, and highly reactive species. Excessive generation of these free radicals ultimately leads to oxidative stress causing oxidation and damage to significant macromolecules in the living system and essentially disrupting signal transduction pathways and antioxidants equilibrium. At lower concentrations, ROS serves as “second messengers,” influencing many physiological processes in the cell. However, higher concentrations beyond cell capacity cause oxidative stress, contributing to human pathologies such as diabetes, cancer, Parkinson’s disease, cardiovascular diseases, cataract, asthma, hypertension, atherosclerosis, arthritis, and Alzheimer’s disease. Signaling pathways such as NF-ΚB, MAPKs, PI3K/Akt/ mTOR, and Keap1-Nrf2- ARE modulate the detrimental effects of oxidative stress by increasing the expression of cellular antioxidant defenses, phase II detoxification enzymes, and decreased production of ROS. Free radicals such as H2O2 are indeed needed for the advancement of the cell cycle as these molecules influence DNA, proteins, and enzymes in the cell cycle pathway. In the course of cell cycle progression, the cellular redox environment becomes more oxidized, moving from the G1 phase, becoming higher in G2/M and moderate in the S phase. Signals in the form of an increase in cellular pro-oxidant levels are required, and these signals are often terminated by a rise in the amount of antioxidants and MnSOD with a decrease in the level of cyclin D1 proteins. Therefore, understanding the mechanism of cell cycle redox regulation will help in the therapy of many diseases.

Retinopathy of prematurity (ROP) is a neonatal disease corresponding to vision impairment and blindness. Utilizing the pathogenesis of ROP and the risk factors affecting its progression can help prevent and reduce its incidence and lead to the emergence and development of new treatment strategies. Factors influencing retinopathy include growth and inflammatory factors that play an essential role in the pathogenesis of the ROP. This review summarizes the most critical factors in the pathogenesis of ROP.

Deregulation of ubiquitin-mediated degradation of oncogene products or tumor suppressors appears to be implicated in the genesis of carcinomas, according to new clinical findings. Conferring to recent research, some members of the tripartite motif (TRIM) proteins (a subfamily of the RING type E3 ubiquitin ligases) act as significant carcinogenesis regulators. Intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis are all regulated by TRIM family proteins, the majority of which have E3 ubiquitin ligase activity. The expression of TRIMs in tumors is likely to be related to the formation and/or progression of the disease, and TRIM expression could be used to predict cancer prognosis. Breast cancer is the most common malignancy in women and also the leading cause of death. TRIM family proteins have unique, vital activities, and their dysregulation, such as TRIM 21, promotes breast cancer, according to growing evidence. Many TRIM proteins have been identified as important cancer biomarkers, with decreased or elevated levels of expression. TRIM29 functions as a hypoxia-induced tumor suppressor gene, revealing a new molecular mechanism for ATM-dependent breast cancer suppression. In breast cancer cells, the TRIM28-TWIST1-EMT axis exists, and TRIM28 enhances breast cancer metastasis by stabilizing TWIST1, and thereby increasing epithelial-tomesenchymal transition. Interestingly, many TRIM proteins are involved in the control of p53, and many TRIM proteins are likewise regulated by p53, according to current research. Furthermore, TRIMs linked to specific tumors may aid in the creation of innovative TRIM-targeted cancer treatments. This review focuses on TRIM proteins that are involved in tumor development, progression, and are of clinical significance in breast cancer.

Heart failure (HF) is a serious clinical syndrome, usually occurs at the advanced stage of various cardiovascular diseases, featured by high mortality and rehospitalization rate. According to left ventricular (LV) ejection fraction (LVEF), HF has been categorized as HF with reduced EF (HFrEF; LVEF<40%), HF with mid-range EF (HFmrEF; LVEF 40-49%), and HF with preserved EF (HFpEF; LVEF ≥50%). HFpEF accounts for about 50% of cases of heart failure and has become the dominant form of heart failure. The mortality of HFpEF is similar to that of HFrEF. There are no welldocumented treatment options that can reduce the morbidity and mortality of HFpEF now. Understanding the underlying pathological mechanisms is essential for the development of novel effective therapy options for HFpEF. In recent years, significant research progress has been achieved on the pathophysiological mechanism of HFpEF. This review aimed to update the research progress on the pathophysiological mechanism of HFpEF.

Parkinson’s disease (PD) is one of the most common progressive neurodegenerative disorders affecting approximately 1% of the world’s population at the age of 50 and above. Majority of PD cases are sporadic and show symptoms after the age of 60 and above. At that time, most of the dopaminergic neurons in the region of substantia nigra pars compacta have been degenerated. Although in past decades, discoveries of genetic mutations linked to PD have significantly impacted our current understanding of the pathogenesis of this devastating disorder, it is likely that the environment also plays a critical role in the etiology of sporadic PD. Recent epidemiological and experimental studies indicate that exposure to environmental agents, including a number of agricultural and industrial chemicals, may contribute to the pathogenesis of several neurodegenerative disorders, including PD. Furthermore, there is a strong correlation between mitochondrial dysfunction and several forms of neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and PD. Interestingly, substantia nigra of patients with PD has been shown to have a mild deficiency in mitochondrial respiratory electron transport chain NADH dehydrogenase (Complex I) activity. This review discusses the role of mitochondrial toxicants in the selective degeneration of dopaminergic neurons targeting the electron transport system that leads to Parkinsonism.

Aims: This study aimed to clarify that breviscapine combined with bone marrow mesenchymal stem cells (BMSCs) treatment can reduce Aβ deposition in Alzheimer's disease (AD) patients. Background: AD is a common degenerative disease of the central nervous system. Aβ protein deposition in the cerebral cortex and hippocampus causes neuronal peroxidation damage, synaptic dysfunction, neuroinflammation, and nerve cell apoptosis, and ultimately leads to AD. Objective: To investigate whether breviscapine combined with BMSCs treatment can reduce Aβ deposition in AD. Methods: The AD rat model was successfully induced by Aβ1-42. The expression of protein and mRNA was detected by western blot and reverse transcription-quantitative PCR (RT-qPCR), respectively. Results: In AD rat brain tissue, the expression of circular RNA ciRS-7 (ciRS-7), ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), and NF-kappaB p65 was significantly downregulated, and the expression of β-amyloid precursor protein (APP), β-site APPcleaving enzyme 1 (BAEC1), and Aβ was upregulated. The expression of ciRS-7, UCHL1, and p65 was significantly upregulated after breviscapine or BMSCs treatment, and there was increased APP and BAEC1 degradation. Notably, breviscapine combined with BMSCs treatment was more effective than either treatment alone. In SH-SY5Y cells, overexpression of ciRS-7 reduced Aβ deposition by upregulating UCHL1 to degrade APP and BAEC1, but these effects were reversed with inhibition of NF-kB signaling. Finally, knockdown of ciRS-7 elevated Aβ, APP, and BAEC1 expression in each group of rats compared with the control. Conclusion: Breviscapine combined with BMSCs treatment can reduce Aβ deposition in AD rats and promote the degradation of APP and BAEC1 by activating NF-kB to promote UCHL1 expression.

Background: Autoimmune hepatitis (AIH) is an inflammatory liver disease that is characterized histologically by interface hepatitis, biochemically by elevated transaminase levels, and serologically by the presence of autoantibodies. Toll-like receptor (TLR)-4 is a TLR family member that, upon activation in hepatocytes, initiates a cascade of events. Interleukin-2 (IL-2) and tumour necrosis factor α (TNF-α) are potent inflammatory cytokines secreted in AIH, playing an important role in the early development of inflammation and hepatocyte damage. Objectives: This study examined the role of cyclosporine in AIH and illustrated its actions on altered hepatic function in the silica-induced AIH model. Methods: AIH was induced in Wistar rats using sodium silicate. The rats were divided into four groups: the control group, silica-AIH group, cyclosporine-treated group, and prevention group. TLR-4 and IL-2 mRNA expressions in liver tissues were tested by RTPCR. Results: AIH was associated with up-regulation of liver enzymes, IL-2 and TLR-4 gene expression, while cyclosporine significantly down-regulated the expression of both. The relative quantity of TLR-4 mRNA was 1±0, 13.57±1.91, 4±0.38, and 2±0 in control, AIH, cyclosporine, and prevention groups, respectively (p<0.001). Also, the relative quantity of IL-2 mRNA was 1±0, 14.79±1.42, 7.07±0.96, and 3.4±0.55 in control, AIH, cyclosporine, and prevention groups, respectively (p<0.001). Additionally, immunohistochemical staining for TNF-α in liver sections was increased in the silica-AIH group but was found to decrease in the cyclosporine-treated and prevention groups. Conclusion: This study advocates the therapeutic role of cyclosporine in treating immune-mediated hepatic diseases. Cyclosporine improves histological alterations in the liver and inhibits the production of proinflammatory cytokines.