Potential Role of Nrf2, HER2, and ALDH in Cancer Stem Cells: A Narrative Review.

Cancer is one of the main causes of death among humans, second only to cardiovascular diseases. In recent years, numerous studies have been conducted on the pathophysiology of cancer, and it has been established that this disease is developed by a group of stem cells known as cancer stem cells (CSCs). Thus, cancer is considered a stem cell disease; however, there is no comprehensive consensus about the characteristics of these cells. Several different signaling pathways including Notch, Hedgehog, transforming growth factor-ß (TGF-ß), and WNT/ß-catenin pathways cause the self-renewal of CSCs. CSCs change their metabolic pathways in order to access easy energy. Therefore, one of the key objectives of researchers in cancer treatment is to destroy CSCs. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an essential role in the protection of CSCs from reactive oxygen species (ROS) and chemotherapeutic agents by regulating antioxidants and detoxification enzymes. Human epidermal growth factor receptor 2 (HER2) is a member of the tyrosine kinase receptor family, which contributes to the protection of cancer cells against treatment and implicated in the invasion, epithelial-mesenchymal transition (EMT), and tumorigenesis. Aldehyde dehydrogenases (ALDHs) are highly active in CSCs and protect the cells against damage caused by active aldehydes through the regulation of aldehyde metabolism. On the other hand, ALDHs promote the formation and maintenance of tumor cells and lead to drug resistance in tumors through the activation of various signaling pathways, such as the ALDH1A1/HIF-1α/VEGF axis and Wnt/ß-catenin, as well as changing the intracellular pH value. Given the growing body of information in this field, in the present narrative review, we attempted to shed light on the function of Nrf2, HER2, and ALDH in CSCs.

Correlation of PTEN signaling pathway and miRNA in breast cancer.

Breast cancer (BC) is one of the most common cancers among women and can be fatal if not diagnosed and treated on time. Various genetic and environmental factors play a significant role in the development and progression of BC. Within the body, different signaling pathways have been identified that contribute to cancer progression, or conversely, cancer prevention. Phosphatase and tensin homolog (PTEN) is one of the proteins that prevent cancer by inhibiting the oncogenic PI3K/Akt/mTOR signaling pathway. MicroRNAs (miRNAs) are molecules with about 18 to 28 base pairs, which regulate about 30% of human genes after transcription. miRNAs play a key role in the progression or prevention of cancer through different signaling pathway and mechanisms, e.g., apoptosis, angiogenesis, and proliferation. miRNAs, which are upstream mediators of PTEN, can reinforce or suppress the effect of PTEN signaling on BC cells, and suppressing the PTEN signaling, linked to weakness of the cancer cells to chemotherapeutic drugs. However, the precise mechanism and function of miRNAs on PTEN in BC are not yet fully understood. Therefore, in the present study, has been focused on miRNAs regulating PTEN function in BC.

Biomarkers for Diabetic Nephropathy with a Focus on Kidney Injury Molecule-1 (KIM-1).

Diabetic Nephropathy (DN), with an increasing rate of mortality and morbidity, is considered the main cause of End-Stage Renal Disease (ESRD). A wide spectrum of biomarkers exist for early detection of DN, but they suffer from low specificity and sensitivity, indicating the urgent demand for finding more effective biomarkers. Also, the pathophysiology of tubular damage and its relation to DN are not yet completely understood. Kidney Injury Molecule-1 (KIM-1) is a protein that is expressed at substantially low contents in the kidney under physiological conditions. A number of reports have demonstrated the close relationship between urine and tissue KIM-1 levels and kidney disorders. KIM-1 is known as a biomarker for diabetic nephropathy and renal injury. In this study, we aim to review the potential clinical and pathological roles of KIM-1 in diabetic nephropathy.

The nuclear factor erythroid 2-related factor 2/p53 axis in breast cancer.

One of the most important factors involved in the response to oxidative stress (OS) is the nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates the expression of components such as antioxidative stress proteins and enzymes. Under normal conditions, Kelch-like ECH-associated protein 1 (Keap1) keeps Nrf2 in the cytoplasm, thus preventing its translocation to the nucleus and inhibiting its role. It has been established that Nrf2 has a dual function; on the one hand, it promotes angiogenesis and cancer cell metastasis while causing resistance to drugs and chemotherapy. On the other hand, Nrf2 increases expression and proliferation of glutathione to protect cells against OS. p53 is a tumour suppressor that activates the apoptosis pathway in aging and cancer cells in addition to stimulating the glutaminolysis and antioxidant pathways. Cancer cells use the antioxidant ability of p53 against OS. Therefore, in the present study, we discussed function of Nrf2 and p53 in breast cancer (BC) cells to elucidate their role in protection or destruction of cancer cells as well as their drug resistance or antioxidant properties.

Potential roles of the exosome/microRNA axis in breast cancer.

Cancer is one of the most common diseases in the world, and various genetic and environmental factors play a key role in its development. Breast cancer is one of the most common and deadly cancers in women. Exosomes are extracellular vesicles (EVs) with an average size of about 100 nm that contain lipids, proteins, microRNAs (miRNAs), and genetic factors and play a significant role in cell signaling, communication, tumorigenesis, and drug resistance. miRNAs are RNAs with about 22 nucleotides, which are synthesized by RNA polymerase and are involved in regulating gene expression, as well as the prevention or progression of cancer. Many studies have indicated the connection between miRNAs and exosomes. According to their findings, it seems that circulating exosomal miRNAs have not been well evaluated as biomarkers for breast cancer diagnosis or monitoring. Therefore, given the importance of miRNAs in exosomes, the goal of the present study was to clarify the relationship between miRNAs in exosomes and the role they play as biomarkers in breast cancer.

Involvement of antioxidant enzymes in Parkinson's disease.

Similar to many other diseases, the etiology of Parkinson's disease (PD) is multifactorial and includes both genetic and environmental factors. Exposure to pesticides and the production of reactive oxygen species (ROS) in the body, mainly in electron transporter complexes 1 and 2 in the inner mitochondrial membrane, are two primary environmental risk factors for this disease. Increased accumulation of ROS and oxidative stress (OS) trigger a series of reactions that can lead to the aggregation of misfolded proteins, DNA damage, autophagy, and apoptosis, which may adversely affect cell function. These processes cause diseases such as coronary artery disease (CAD), Alzheimer's disease (AD), and PD. As indicated in previous studies, ROS is considered a critical regulator in the progression of PD. The human body contains several antioxidant molecules, such as vitamin A, vitamin C, bilirubin, and uric acid, as well as antioxidant enzymes including paraoxonase (PON), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Therefore, based on the canonical function of the antioxidant enzymes in PD, In the present review, we attempted to examine the function of antioxidant enzymes in PD.

Role of the ER-induced UPR pathway, apoptosis, and autophagy in colorectal cancer.

When large amounts of misfolded or unfolded proteins accumulate in the endoplasmic reticulum (ER) in response to stress, a process called unfolded protein response (UPR) is activated. The disruption of this process leads to many diseases including diabetes, neurodegenerative diseases, and many cancers. In the process of UPR in response to stress and unfolded proteins, specific signaling pathways are induced in the endoplasmic reticulum and subsequently transmitted to the nucleus and cytoplasm, causing homeostasis and restoring the cell's normal condition with reducing protein translation and synthesis. The UPR response followed by stress enhancement balances cell survival with death, therefore in this condition cells decide either to survive or have the path of apoptosis ahead. However, in some cases, this balance is disturbed and the UPR pathway is chronically activated or not activated and the cell conditions lead to cancer. This study aimed to briefly investigate the association between ER stress, UPR, apoptosis, and autophagy in colorectal cancer (CRC). Moreover, in current study, we will try to demonstrate canonical ways and methods for the treatment of CRC cells with attenuated ER stress.

The Function of Autophagy in the Initiation, and Development of Breast Cancer

Autophagy is a significant catabolic procedure that increases in stressful conditions. This mechanism is mostly triggered after damage to the organelles, the presence of unnatural proteins, and nutrient recycling in reaction to these stresses. One of the key points in this article is that cleaning and preserving damaged organelles and accumulated molecules through autophagy in normal cells helps prevent cancer. Since dysfunction of autophagy is associated with various diseases, including cancer, it has a dual function in tumor suppression and expansion. It has newly become clear that the regulation of autophagy can be used for the treatment of breast cancer, which has a promising effect of increasing the efficiency of anticancer treatment in a tissue- and cell-type-specific manner by affecting the fundamental molecular mechanisms. Regulation of autophagy and its function in tumorigenesis is a vital part of modern anticancer techniques. This study discusses the current advances related to the mechanisms that describe essential modulators of autophagy involved in the metastasis of cancers and the development of new breast cancer treatments.

NFR2/ABC transporter axis in drug resistance of breast cancer cells.

Breast cancer is one of the most serious malignancies among women, accounting for about 12% of all cancers. The inherent complexity and heterogeneity of breast cancer results in failure to respond to treatment in the advanced stages of the disease. Breast cancer is caused by several genetic and environmental factors. One of the significant factors involved in the development of breast cancer is oxidative stress, which is generally regulated by nuclear factor erythroid 2-related factor 2 (NRF2). The level of NRF2 expression is low in healthy cells, which maintains the balance of the antioxidant system; however, its expression is higher in cancer cells, which have correlation characteristics such as angiogenesis, stem cell formation, drug resistance, and metastasis. Drug resistance increases with the upregulation of NRF2 expression, which contributes to cell protection. NRF2 controls this mechanism by increasing the expression of ATP-binding cassettes (ABCs). Considering the growing number of studies in this field, we aimed to investigate the relationship between NRF2 and ABCs, as well as their role in the development of drug resistance in breast cancer.

Involvement of heat shock proteins and parkin/α-synuclein axis in Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurological diseases, next only to Alzheimer's disease (AD) in terms of prevalence. It afflicts about 2-3% of individuals over 65 years old. The etiology of PD is unknown and several environmental and genetic factors are involved. From a pathological point of view, PD is characterized by the loss of dopaminergic neurons in the substantia nigra, which causes the abnormal accumulation of α-synuclein (α-syn) (a component of Lewy bodies), which subsequently interact with heat shock proteins (HSPs), leading to apoptosis. Apoptosis is a vital pathway for establishing homeostasis in body tissues, which is regulated by pro-apoptotic and anti-apoptotic factors. Recent findings have shown that HSPs, especially HSP27 and HSP70, play a pivotal role in regulating apoptosis by influencing the factors involved in the apoptosis pathway. Moreover, it has been reported that the expression of these HSPs in the nervous system is high. Apart from this finding, investigations have suggested that HSP27 and HSP70 (related to parkin) show a potent protective and anti-apoptotic impact against the damaging outcomes of mutant α-syn toxicity to nerve cells. Therefore, in this study, we aimed to investigate the relationship between these HSPs and apoptosis in patients with PD.

The potential role of nicotine in breast cancer initiation, development, angiogenesis, invasion, metastasis, and resistance to therapy.

A large body of research studying the relationship between tobacco and cancer has led to the knowledge that smoking cigarettes adversely affects cancer treatment while contributing to the development of various tobacco-related cancers. Nicotine is the main addictive component of tobacco smoke and promotes angiogenesis, proliferation, and epithelial-mesenchymal transition (EMT) while promoting growth and metastasis of tumors. Nicotine generally acts through the induction of the nicotinic acetylcholine receptors (nAChRs), although the contribution of other receptor subunits has also been reported. Nicotine contributes to the pathogenesis of a wide range of cancers including breast cancer through its carcinogens such as (4-methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonornicotine (NNN). Current study aims to review the mechanistic function of nicotine in the initiation, development, angiogenesis, invasion, metastasis, and apoptosis of breast cancer with the main focus on nicotine acetylcholine receptors (nAChRs) and nAChR-mediated signaling pathways as well as on its potential for the development of an effective treatment against breast cancer. Moreover, we will try to demonstrate how nicotine leads to poor treatment response in breast cancer by enhancing the population, proliferation, and self-renewal of cancer stem cells (CSCs) through the activation of α7-nAChR receptors.

Dysregulation of body antioxidant content is related to initiation and progression of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a prevalent neurodegenerative illness. It has been believed that oxidative stress (OS) is an important factor in the advancement of PD. This investigation attempts to evaluate the relations between blood trace elements, ferritin, and transferrin concentrations as well as the levels of protein and gene expression of ceruloplasmin (CP), Nrf-2, and HO-1 in patients suffering PD. METHODS: The serum concentrations of variables were assessed in 110 PD patients group and 110 normal subjects. Furthermore, we applied qRT-PCR as well as western blot (WB) analysis to measure the levels of gene and protein, respectively. RESULTS: Considerable differences were detected in the serum concentrations of copper (Cu), iron (Fe), and zinc (Zn), when healthy and patient groups were compared. Nevertheless, the levels of Se, ferritin, and transferrin were not significantly different between the two groups. qRT-PCR and WB data analysis revealed significant differences of CP, Nrf-2, and HO-1at genes expression and protein levels when comparing the two PD patients and control groups. CONCLUSION: The results of the current work revealed that blood levels of Cu, Fe, and Zn were significantly higher in subjects who had PD. In addition, it was found that the levels of protein and gene expression CP, Nrf-2, and HO-1 were markedly higher in PD group than in non-PD subjects. Indeed, in this study, the results showed that the antioxidant content of the body can be linked to PD.

Oxidative stress and Parkinson's disease: conflict of oxidant-antioxidant systems.

Parkinson's disease (PD) is defined as a chronic neurodegenerative disorder which is diagnosed mostly by its clinical manifestations. Reactive oxygen species (ROS) are considered as key modulators in the development of PD. Despite the intensive investigations, antioxidant-dependent molecular mechanisms of initiation and development of PD are controversial. Free radicals cause serious damage and death of dopamine producing cells when antioxidant capacity of the cells is reduced against oxidative stress (OxS). Many intracellular reactions create ROS, including activation of NADPH oxidase (NOX), mitochondrial dysfunction, and hydrogen peroxide (H2O2) decomposition. On the contrary, natural antioxidants, vitamins, proteins, and antioxidant signaling pathways are major factors to neutralize ROS and its destructive effects. The functional role of nuclear factor E2-related factor 2, Heme oxygenase-1, and selenium against ROS-dependent initiation and progression of PD is elucidated. In this review, we collected multiple factors that play the main role in the initiation, development, and pathogenesis of PD and we discussed their function in the PD.

Association of Paraoxonse1 (PON1) Genotypes with the Activity of PON1 in Patients with Parkinson's Disease.

OBJECTIVE: Various numbers of factors such as oxidative stress, neurotoxins, and pesticides have been implicated in its pathophysiology of Parkinson's disease (PD). Paraoxonas1 (PON1) metabolizes xenobiotics, including pesticides. Therefore, we surveyed the relationship between PON1 polymorphisms with its activities in the pathogenesis of Parkinson's disease.. METHODS: We investigated polymorphisms of the PON1 (L55M and Q192R) by PCR-RFLP assays; we also measure the levels of PON1, TAC (total antioxidant capacity) and TOS (total oxidant status) with ELISA (Enzyme-linked immunosorbent assay) and spectrophotometric method for their activities. RESULTS: Paraoxonase and arylesterase activity of PON1 as well as their concentrations were lower in patients with PD compared with control group, but from the view of the specific activity, it was not significant between two groups. In the compare of TAC, TOS, and OSI, the TOS and OSI were higher in the patients than controls, while patients had lower levels of TAC compared with controls. Serum PON1 concentrations and activities were higher in LL (comparison with LM and MM) and RR (comparison with QR and QQ) genotypes while we did not observe any significant differences in arylesterase levels among mentioned polymorphisms. CONCLUSION: In the current study, we reported associations between PON1 polymorphisms (55, 192) and enzyme activities in Parkinson's disease as there was a significant reduction in PON1 levels in patients with Parkinson compared with healthy. Taken together, paraoxonase enzyme in subjects with different genotypes could be a potential biomarker for determining the severity and prognosis of Parkinson. However, more studies are needed to clarify its clinical values. Key words: Parkinson's disease; paraoxonase1; Polymorphism.

FGF-23, Klotho and Vitamin D Levels in Scleroderma.

BACKGROUND: Scleroderma is a chronic connective tissue disease of unknown etiology. Vitamin D and parathyroid hormone (PTH) that play particular functions in calcium and phosphate homeostasis may be involved in the etiology of this disorder. Klotho, the co-receptor of the fibroblast growth factor 23 (FGF-23), can interfere with calcium and phosphate metabolism. The purpose of this study was to evaluate serum Klotho, FGF-23, intact PTH (iPTH) and vitamin D levels in scleroderma patients compared with the healthy controls. METHODS: The study was performed in Biotechnology Research Center, Tabriz University of Medical Sciences (TUMS) from 2014-2015. Sixty scleroderma patients based on the classification criteria of systemic sclerosis and 30 age- and sex-matched healthy controls were included in this study. Serum Klotho, FGF-23, 25-hydroxy vitamin D (25-OH Vit D), and iPTH levels were analyzed using ELISA. RESULTS: Serum levels of Klotho and 25-OH Vit D in the scleroderma patients were lower than those in the healthy controls (P<0.001). In addition, scleroderma patients had higher serum iPTH levels than the controls (P<0.001). There was no significant difference in serum FGF-23 levels between the patients and controls (P=0.202). CONCLUSION: The decreased serum Klotho, 25-OH Vit D, and increased iPTH levels in the scleroderma patients may be associated with the pathogenesis of this disease and could be considered a future therapeutic target.