Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers.

Cancer is a borderless global health challenge that continues to threaten human health. Studies have found that oxidative stress (OS) is often associated with the etiology of many diseases, especially the aging process and cancer. Involved in the OS reaction as a key transcription factor, Nrf2 is a pivotal regulator of cellular redox state and detoxification. Nrf2 can prevent oxidative damage by regulating gene expression with antioxidant response elements (ARE) to promote the antioxidant response process. OS is generated with an imbalance in the redox state and promotes the accumulation of mutations and genome instability, thus associated with the establishment and development of different cancers. Nrf2 activation regulates a plethora of processes inducing cellular proliferation, differentiation and death, and is strongly associated with OS-mediated cancer. What's more, Nrf2 activation is also involved in anti-inflammatory effects and metabolic disorders, neurodegenerative diseases, and multidrug resistance. Nrf2 is highly expressed in multiple human body parts of digestive system, respiratory system, reproductive system and nervous system. In oncology research, Nrf2 has emerged as a promising therapeutic target. Therefore, certain natural compounds and drugs can exert anti-cancer effects through the Nrf2 signaling pathway, and blocking the Nrf2 signaling pathway can reduce some types of tumor recurrence rates and increase sensitivity to chemotherapy. However, Nrf2's dual role and controversial impact in cancer are inevitable consideration factors when treating Nrf2 as a therapeutic target. In this review, we summarized the current state of biological characteristics of Nrf2 and its dual role and development mechanism in different tumor cells, discussed Keap1/Nrf2/ARE signaling pathway and its downstream genes, elaborated the expression of related signaling pathways such as AMPK/mTOR and NF-κB. Besides, the main mechanism of Nrf2 as a cancer therapeutic target and the therapeutic strategies using Nrf2 inhibitors or activators, as well as the possible positive and negative effects of Nrf2 activation were also reviewed. It can be concluded that Nrf2 is related to OS and serves as an important factor in cancer formation and development, thus provides a basis for targeted therapy in human cancers.

ALDH1: A potential therapeutic target for cancer stem cells in solid tumors.

Solid tumors can be divided into benign solid tumors and solid malignant tumors in the academic community, among which malignant solid tumors are called cancers. Cancer is the second leading cause of death in the world, and the global incidence of cancer is increasing yearly New cancer patients in China are always the first. After the concept of stem cells was introduced in the tumor community, the CSC markers represented by ALDH1 have been widely studied due to their strong CSC cell characteristics and potential to be the driving force of tumor metastasis. In the research results in the past five years, it has been found that ALDH1 is highly expressed in various solid cancers such as breast cancer, lung cancer, colorectal cancer, liver cancer, gastric cancer, cervical cancer, esophageal cancer, ovarian cancer, head,and neck cancer. ALDH1 can activate and transform various pathways (such as the USP28/MYC signaling pathway, ALDH1A1/HIF-1α/VEGF axis, wnt/ß-catenin signaling pathway), as well as change the intracellular pH value to promote formation and maintenance, resulting in drug resistance in tumors. By targeting and inhibiting ALDH1 in tumor stem cells, it can enhance the sensitivity of drugs and inhibit the proliferation, differentiation, and metastasis of solid tumor stem cells to some extent. This review discusses the relationship and pathway of ALDH1 with various solid tumors. It proposes that ALDH1 may serve as a diagnosis and therapeutic target for CSC, providing new insights and new strategies for reliable tumor treatment.

Metformin: A promising drug for human cancers.

Small-molecule chemical drugs are of great significance for tumor-targeted and individualized therapies. However, the development of new small-molecule drugs, from basic experimental research and clinical trials to final application in clinical practice, is a long process that has a high cost. It takes at least 5 years for most drugs to be developed in the laboratory to prove their effectiveness and safety. Compared with the development of new drugs, repurposing traditional non-tumor drugs can be a shortcut. Metformin is a good model for a new use of an old drug. In recent years, the antitumor efficacy of metformin has attracted much attention. Epidemiological data and in vivo, and in vitro experiments have shown that metformin can reduce the incidence of cancer in patients with diabetes and has a strong antagonistic effect on metabolism-related tumors. Recent studies have shown that metformin can induce autophagy in esophageal cancer cells, mainly by inhibiting inflammatory signaling pathways. In recent years, studies have shown that the antitumor functions and mechanisms of metformin are multifaceted. The present study aims to review the application of metformin in tumor prevention and treatment.

Effects of silencing RIP1 with siRNA on the biological behavior of the LoVo human colon cancer cell line.

The present study aimed to investigate the effects of silencing RIP1 by small interfering RNA (siRNA) on the biological behavior of the LoVo human colorectal carcinoma cell line and to provide evidence for the feasibility of colorectal cancer gene therapy. LoVo cells were divided into the RIP1 siRNA group, the blank control group and the negative control group. Chemically synthesized siRNA targeting RIP1 (RIP1 siRNA) was transfected into LoVo cells. Following transfection of the RIP1-targeted siRNA into the LoVo cells, the expression of the RIP1 gene was effectively inhibited. The results demonstrated that RIP1 effectively regulated the malignant biological behavior of the LoVo colon cancer cell line. Furthermore, the proliferation, motility and invasiveness of LoVo cells were inhibited by siRNA knockdown of RIP1. The results revealed that the RIP1 gene has an important role in the regulation of proliferation and apoptosis in colorectal carcinoma cells.

Bone mesenchymal stem cells contributed to the neointimal formation after arterial injury.

OBJECTIVES: Recent findings suggest that in response to repair-to-injury bone marrow mesenchymal stem cells (BMSCs) participate in the process of angiogenesis. It is unclear what role BMSCs play in the structure of the vessel wall. In present study, we aimed to determine whether BMSCs had the capacity of endothelial cells (ECs). METHODS: BMSCs were separated and cultured. FACS and RT-PCR analysis confirmed the gene expression phenotype. The capacity of migration and adhesion and the ultrastructure of BMSCs were examined. The effect of BMSCs transplantation on the vascular repair was investigated in a murine carotid artery-injured model. RESULTS: BMSCs could express some markers and form the tube-like structure. The migration and adhesion capacity of BMSCs increased significantly after stimulated. In addition, BMSCs had the intact cell junction. In vivo the local transfer of BMSCs differentiated into neo-endothelial cells in the injury model for carotid artery and contributed to the vascular remodeling. CONCLUSION: These results showed that BMSCs could contribute to neointimal formation for vascular lesion and might be associated with the differentiation into ECs, which indicated the important therapeutic implications for vascular diseases.

Tetramethylpyrazine inhibits angiotensin II-induced cardiomyocyte hypertrophy and tumor necrosis factor-α secretion through an NF-κB-dependent mechanism.

Tetramethylpyrazine (TMP), a bioactive compound isolated from the Chinese herb, Ligusticum wallichii Franchat, has been reported to play a protective role in cardiac diseases. However, the cellular and molecular mechanisms behind the protective effects of TMP on the heart remain to be elucidated. In this study, we aimed to determine the effects of TMP on angiotensin II (Ang II)-induced hypertrophy in neonatal rat cardiomyocytes and its possible mechanisms of action. In addition, we investigated whether TMP regulates tumor necrosis factor-α (TNF-α) secretion and expression. We found that TMP significantly inhibited the Ang II-induced hypertrophic growth of neonatal cardiomyocytes, as evidenced by the decrease in [3H]leucine incorporation and ß-myosin heavy chain (ß-MHC) mRNA expression. TMP inhibited Ang II-stimulated TNF-α protein secretion and mRNA expression in the cardiomyocytes. Further experiments revealed that Ang II increased the level of the phosphorylated form of the transcription factor, nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), as well as NF-κB-DNA binding activity in the cardiomyocytes; treatment with TMP significantly inhibited the Ang II-induced activation of NF-κB. Furthermore, the inhibition of NF-κB by the specific inhibitor, pyrrolidine dithiocarbamate (PDTC), markedly attenuated the Ang II-induced increase in [3H]leucine incorporation, ß-MHC mRNA expression and TNF-α protein secretion. Our findings suggest that TMP inhibits Ang II-induced cardiomyocyte hypertrophy and TNF-α production through the suppression of the NF-κB pathway, which may provide new insight into the mechanisms underlying the protective effects of TMP in heart diseases.

Endothelin-1 stimulates the expression of L-type Ca2+ channels in neonatal rat cardiomyocytes via the extracellular signal-regulated kinase 1/2 pathway.

The cardiac L-type Ca(2+) channel current (I(Ca,L)) plays an important role in controlling both cardiac excitability and excitation-contraction coupling and is involved in the electrical remodeling during postnatal heart development and cardiac hypertrophy. However, the possible role of endothelin-1 (ET-1) in the electrical remodeling of postnatal and diseased hearts remains unclear. Therefore, the present study was designed to investigate the transcriptional regulation of I(Ca,L) mediated by ET-1 in neonatal rat ventricular myocytes using the whole-cell patch-clamp technique, quantitative RT-PCR and Western blotting. Furthermore, we determined whether the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway is involved. ET-1 increased I(Ca,L) density without altering its voltage dependence of activation and inactivation. In line with the absence of functional changes, ET-1 increased L-type Ca(2+) channel pore-forming α1C-subunit mRNA and protein levels without affecting the mRNA expression of auxiliary ß- and α2/δ-subunits. Furthermore, an actinomycin D chase experiment revealed that ET-1 did not alter α1C-subunit mRNA stability. These effects of ET-1 were inhibited by the ETA receptor antagonist BQ-123 but not the ETB receptor antagonist BQ-788. Moreover, the effects of ET-1 on I(Ca,L) and α1C-subunit expression were abolished by the ERK1/2 inhibitor (PD98059) but not by the p38 MAPK inhibitor (SB203580) or the c-Jun N-terminal kinase inhibitor (SP600125). These findings indicate that ET-1 increased the transcription of L-type Ca(2+) channel in cardiomyocytes via activation of ERK1/2 through the ETA receptor, which may contribute to the electrical remodeling of heart during postnatal development and cardiac hypertrophy.

Astragaloside IV attenuates Toll-like receptor 4 expression via NF-κB pathway under high glucose condition in mesenchymal stem cells.

Diabetic hyperglycemia causes a variety of pathological changes. Astragaloside IV (AS-IV) was widely used for the treatment of cardiovascular diseases in China. The aim of this study was to determine the effect of AS-IV on bone marrow mesenchymal stem cells (MSCs) and the underlying mechanism in diabetes. We used reverse transcription polymerase chain reaction and western blotting to determine the expression of Toll-like receptor 4 (TLR4), matrix metalloproteinase-2 (MMP-2) and NF-κB p65 in MSCs under high glucose (HG) with or without pretreatment with AS-IV. The surface expression of TLR4 was checked by flow cytometry and the expression of TNF-α and MCP-1 were detected by ELISA in diabetes patients treated with AS-IV. AS-IV promoted the proliferation of MSCs and attenuated the increased expression of TLR4 induced by HG. In addition, AS-IV decreased the HG-induced translocation of NF-κB p65 and increased the MMP-2 expression in MSCs. AS-IV decreased the TLR4, TNF-α and MCP-1 expression in patients. Collectively,our data revealed that AS-IV attenuated TLR4 expression through the NF-κB signaling pathway in MSCs.

[Endothelin-1 stimulates the expression of pacemaker channel I(f) in cardiomyocytes through a p38 MAPK-independent signaling pathway].

OBJECTIVE: To investigate the transcriptional regulation of pacemaker channel I(f) mediated by vasoactive peptide endothelin-1 (ET-1) in neonatal rat ventricular myocytes and its mechanism. METHODS: Neonatal rat ventricular myocytes were enzymatically isolated. I(f) current was recorded using the whole-cell patch-clamp technique. The expression of hyperpolarization-activated cyclic nucleotide-gated channel (HCN) isoforms HCN2 and HCN4 were measured by quantitative RT-PCR. RESULTS: ET-1 increased the expression of HCN2 and HCN4 mRNA in a dose- and time-dependent manner. These effects were blocked by specific ETA receptor antagonist BQ-123 but not the ETB receptor antagonist BQ-788. The effects of ET-1 on HCN2 and HCN4 mRNA expression were not affected by the p38 mitogen-activated protein kinase (MAPK) inhibitor (SB-203580). CONCLUSION: These findings indicate that ET-1 stimulates the expression of pacemaker channel I(f) in cardiomyocytes via ETA receptor through a p38 MAPK-independent signaling pathway, which might be linked to the intrinsic arrhythmogenic potential of ET-1.

Hyperglycemia suppresses cardiac stem cell homing to peri-infarcted myocardium via regulation of ERK1/2 and p38 MAPK activities.

Hyperglycemia in the acute phase of myocardial infarction (MI) is a marker of worse prognosis in both diabetic and non-diabetic patients; however, the role of hyperglycemia in the homing of cardiac stem cells (CSCs) to damaged myocardium post-MI and the possible mechanisms involved are not well understood. In this study, an MI model was induced in normoglycemic and hyperglycemic rats by left coronary artery ligation. Immunofluorescence was used to examine the migration of CSCs in vivo by injecting BrdU-labeled CSCs into the atrium-ventricle groove (AV-groove). Immunohistochemistry, western blot analysis and ELISA were carried out to detect the expression of stem cell factor (SCF) protein and RT-PCR was conducted for the expression of SCF mRNA. Phosphorylation of ERK1/2 and p38 MAPK was detected by western blot analysis. Afterwards, cardiac function was evaluated by hemodynamic measurement. On Day 5 post-MI, the accumulation of CSCs significantly increased in the peri-infarcted myocardium in normoglycemic rats, which led to an improvement in cardiac function 3 weeks after MI. However, the accumulation of CSCs markedly decreased in hyperglycemic rats, followed by the decline of cardiac function. SCF expression, followed with phosphorylation of ERK1/2 and p38 MAPK, were also significantly downregulated in the peri-infarcted myocardium in hyperglycemic rats compared to normoglycemic rats. Moreover, SCF expression and the migration of CSCs were blocked by either the MEK-specific inhibitor PD98059 or the p38 MAPK-selective inhibitor SB203580. The experiments in vitro confirmed that hyperglycemia decreased SCF expression via reduction in ERK1/2 and p38 MAPK activities and further inhibited the migration of CSCs. The results suggest that hyperglycemia suppresses CSC migration towards the ischemic area post-MI. This is possibly due to decreased myocardial SCF expression via reduction of ERK1/2 and p38 MAPK activities in hyperglycemic rats.