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A predominant challenge in the discovery approach to curative leukemia is investigating the effect of mesenchymal stem cells (MSCs) on leukemic cells. We aimed to investigate the role of MSCs in targeting telomerase enzyme and consequently telomere length of leukemic cells. For this purpose, the KG1 cell as leukemia cell line was co-cultured with MSCs in the trans-well system. After seven days of co-culture, KG1 cells were collected, and telomerase activity, telomere length, and hTERT gene expression were analyzed by PCR-ELISA TRAP assay and real-time PCR, respectively. Also, the potentially involved ERK pathway was analyzed at gene and protein levels by real time PCR and flow cytometry, respectively. It was found that MSCs caused a significant decrease in telomerase activity, telomere length, and hTERT gene expression. The following results showed that MSCs resulted in a significant decrease in the ERK expression levels. It can be concluded that the co-culture of MSCs with KG1 cells be involved in the telomerase targeting via ERK signaling pathways. This study concluded that the co-culture of MSCs with AML leukemic cells could secrete a significant amount of cytokines that cause to inhibit the proliferation of AML cell lines via ERK signaling pathway. The recognition of cytokines as well as growth factors involved in the anti-proliferative effect of MSCs requires further investigation. This effect as a therapeutic strategy could be considered in the basic experimental studies.

Microinjury can trigger in situ tissue repair. Bone transport consists of continuous microinjuries/microfracture and induces bone formation and angiogenesis. Tibial cortex transverse transport (TTT) was found to promote angiogenesis at the foot and the healing of diabetic foot ulcers (DFUs). However, the underlying mechanism remains largely unknown. We divided 72 Sprague-Dawley rats with DFUs into the control, sham, and TTT groups. Wound measurement and histology were performed to evaluate the wound healing processes. Enzyme-linked immunosorbent assay, flow cytometry, immunohistochemistry, and Western Blot were used to assess angiogenesis and the activity of endothelial progenitor cells (EPCs) and the Ras/Raf/MEK/ERK signaling pathway. We found accelerated wound healing, improved epidermal continuity, and increased dermal thickness in the TTT group than the control and the sham groups. Higher levels of serum TGF-β1, PDGF-BB, and VEGF were detected in the TTT group. These changes were in parallel with the expression of TGF-β1, PDGF-BB, and VEGF in the foot wounds and the frequency of EPCs in both bone marrow and peripheral circulation, which implied that the secreted TGF-β1, PDGF-BB, and VEGF promote proliferation and migration of EPCs to the foot wounds. The expression of CD31 cells, SMA-α cells, and the Ras/Raf/MEK/ERK pathway was higher in the TTT group than in the control and sham groups. The findings showed that TTT enhanced the production of growth factors that in turn activated EPC proliferation and migration through the Ras/Raf/MEK/ERK pathway, ultimately contributing to angiogenesis and DFU healing. Based on these findings, we proposed a theory that remote continuous microinjuries can trigger the repair of target tissues (ie, microinjury-induced remote repair, MIRR). Future studies are needed to validate this theory.

Atherosclerosis is a chronic vascular disease characterized by the accumulation of cholesterol‐rich lipids within the intima of large and medium‐sized arteries. It is a leading cause of morbidity and mortality worldwide, contributing to the majority of myocardial infarctions and strokes. Ellagic acid (EA), a naturally occurring polyphenolic compound found in various plant species, exhibits promising potential in enhancing cholesterol metabolism and reducing the risk of atherosclerosis. However, the precise mechanisms and molecular targets underlying EA's cholesterol‐regulating effects remain poorly understood. In this study, we demonstrate that EA effectively binds to the epidermal growth factor receptor (EGFR), exhibiting a dissociation constant (Kd) of 4.33 × 10 −7  M and a binding energy of −7.1 kcal/mol. This binding activates EGFR and specifically engages the mitogen‐activated protein kinase (MAPK) pathway, leading to the upregulation of low‐density lipoprotein receptor (LDLR) expression in HepG2 cells. Furthermore, cetuximab, an EGFR‐blocking antibody, inhibits the LDLR upregulation induced by EA, confirming EGFR as a key target in the regulation of LDLR expression. To evaluate the in vivo effects of EA on atherosclerosis, we encapsulated EA within human serum albumin to form nanoparticles (EA‐NPs). This approach addresses poor water solubility and its tendency to convert into urolithin derivatives of EA following oral administration. In HepG2 cells, EA‐NPs significantly enhanced LDLR expression, accompanied by increased phosphorylation of EGFR and extracellular signal‐regulated kinase (ERK). In an ApoE − / − mouse model, EA‐NPs exhibited potent anti‐atherosclerotic effects mediated through the EGFR and MAPK pathways. Additionally, EA‐NPs reduced hepatic lipid accumulation and attenuated the formation of aortic plaques. In conclusion, EA and its nanoparticle formulation effectively impede the progression of atherosclerosis, underscoring their therapeutic potential. These findings provide a robust foundation for the development of EA‐based strategies as a viable daily therapeutic intervention for atherosclerosis management.

The mitogen activated protein kinase (MAPK)-extracellular regulated kinase 1/2 (ERK1/2) pathway is a central downstream signaling pathway that is activated in cardiac muscle cells during mechanical and agonist-mediated hypertrophy. Studies in genetic mouse models deficient in ERK-associated MAPK components pathway have further reinforced a direct role for this pathway in stress-induced cardiac hypertrophy and disease. However, more recent studies have highlighted that these signaling pathways may exert their regulatory functions in a more compartmentalized manner in cardiac muscle. Emerging data has uncovered specific MAPK scaffolding proteins that tether MAPK/ERK signaling specifically at the sarcomere and plasma membrane in cardiac muscle and show that deficiencies in these scaffolding proteins alter ERK activity and phosphorylation, which are then critical in altering the cardiac myocyte response to stress-induced hypertrophy and disease progression. In this review, we provide insights on ERK-associated scaffolding proteins regulating cardiac myofilament function and their impact on cardiac hypertrophy and disease.

Cancer is characterized as a complex disease caused by coordinated alterations of multiple signaling pathways. The Ras/RAF/MEK/ERK (MAPK) signaling is one of the best-defined pathways in cancer biology, and its hyperactivation is responsible for over 40% human cancer cases. To drive carcinogenesis, this signaling promotes cellular overgrowth by turning on proliferative genes, and simultaneously enables cells to overcome metabolic stress by inhibiting AMPK signaling, a key singular node of cellular metabolism. Recent studies have shown that AMPK signaling can also reversibly regulate hyperactive MAPK signaling in cancer cells by phosphorylating its key components, RAF/KSR family kinases, which affects not only carcinogenesis but also the outcomes of targeted cancer therapies against the MAPK signaling. In this review, we will summarize the current proceedings of how MAPK-AMPK signalings interplay with each other in cancer biology, as well as its implications in clinic cancer treatment with MAPK inhibition and AMPK modulators, and discuss the exploitation of combinatory therapies targeting both MAPK and AMPK as a novel therapeutic intervention.

Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC.

Renal cell carcinoma (RCC) is a common urological system malignancy lack of effective therapeutic options. Upregulation of the Bcl-2 proteins was correlated with poor prognosis of RCC, suggesting that BH-3 mimetics may be a promising treatment option. ABT-263 is a BH3 mimetic that possesses anti-tumor effects. TW-37 is another inhibitor of Bcl-2 family protein with potential anti-tumor activities. However, since their effect as single agent is limited, combination treatment represents a strategy to improve the efficiency. We studied the ABT-263 in combination with TW-37 and analyzed the molecular mechanisms of action in RCC cells. MTT and colony formation assays were used to measure the proliferation of RCC cells. Transwell assay was used to assay the migration and invasion of RCC cells. Cell cycle distribution and apoptosis were measured using the flow cytometry and apoptotic nucleosome assay, respectively. Western blotting was performed to measure the change of proteins. The anti-tumor effects of ABT-263, TW-37 and their combination were also evaluated . Cotreatment of TW-37 and ABT-263 synergistically repressed the proliferation of RCC cells. TW-37 and ABT-263 also synergistically inhibited the migration and invasion of RCC cells It was also showed that TW-37 and ABT-263 synergistically induced cell cycle arrest at the G2/M phase. Furthermore, increased apoptosis was observed after exposure to TW-37 and ABT-263. Mechanism investigation showed that TW-37 and ABT-263 synergistically induced apoptosis via the mitochondrial pathway and relied on the activation of Bax and caspases. Furthermore, ERK signaling pathway activation was detected after treated with TW-37 and ABT-263. Finally, TW-37 and ABT-263 also synergistically repressed the growth of RCC cells in xenograft mice. In summary, our data demonstrated that combined treatment with TW-37 and ABT-263 exhibited synergistic RCC cell death and this combination may be applied as an effective therapeutic strategy against RCC.

How complex interactions of genetic, environmental factors and aging jointly contribute to dopaminergic degeneration in Parkinson's disease (PD) is largely unclear. Here, we applied frequent gene co‐expression analysis on human patient substantia nigra‐specific microarray datasets to identify potential novel disease‐related genes. In vivo Drosophila studies validated two of 32 candidate genes, a chromatin‐remodeling factor SMARCA4 and a biliverdin reductase BLVRA. Inhibition of SMARCA4 was able to prevent aging‐dependent dopaminergic degeneration not only caused by overexpression of BLVRA but also in four most common Drosophila PD models. Furthermore, down‐regulation of SMARCA4 specifically in the dopaminergic neurons prevented shortening of life span caused by α‐synuclein and LRRK2. Mechanistically, aberrant SMARCA4 and BLVRA converged on elevated ERK‐ETS activity, attenuation of which by either genetic or pharmacological manipulation effectively suppressed dopaminergic degeneration in Drosophila in vivo. Down‐regulation of SMARCA4 or drug inhibition of MEK/ERK also mitigated mitochondrial defects in PINK1 (a PD‐associated gene)‐deficient human cells. Our findings underscore the important role of epigenetic regulators and implicate a common signaling axis for therapeutic intervention in normal aging and a broad range of age‐related disorders including PD. Using bioinformatics analysis of large‐scale human transcriptomic data and Drosophila disease models, Sun et al. identified novel Parkinson's disease (PD) genes and revealed a potential common pathogenic signaling pathway consisting of the chromatin‐remodeling factor SMARCA4 and the ERK‐ETS signaling axis in normal aging and age‐related disorders such as PD. The cancer drug Trametinib, previously shown to have lifespan extending capacity, was found to have therapeutic potency in multiple PD disease models.

The RAF/MEK/ERK signaling pathway regulates diverse cellular processes as exemplified by cell proliferation, differentiation, motility, and survival. Activation of ERK1/2 generally promotes cell proliferation, and its deregulated activity is a hallmark of many cancers. Therefore, components and regulators of the ERK pathway are considered potential therapeutic targets for cancer, and inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic. Notably, ERK1/2 kinases also have pro-apoptotic functions under certain conditions and enhanced ERK1/2 signaling can cause tumor cell death. Although the repertoire of the compounds which mediate ERK activation and apoptosis is expanding, and various anti-cancer compounds induce ERK activation while exerting their anti-proliferative effects, the mechanisms underlying ERK1/2-mediated cell death are still vague. Recent studies highlight the importance of dual-specificity phosphatases (DUSPs) in determining the pro- versus anti-apoptotic function of ERK in cancer. In this review, we will summarize the recent major findings in understanding the role of ERK in apoptosis, focusing on the major compounds mediating ERK-dependent apoptosis. Studies that further define the molecular targets of these compounds relevant to cell death will be essential to harnessing these compounds for developing effective cancer treatments.

Apoptotic liver cancer cells have important roles in liver tumorigenesis and liver cancer progression. Recent studies have shown that δ-opioid receptors are highly expressed in human liver and liver cancer cells. The present study aimed to investigate the role of activated δ-opioid receptors on human liver cancer cell apoptosis and its interrelation with the mitochondria and the protein kinase C/extracellular-signal-regulated kinase (PKC/ERK) signaling pathway. H2O2 was used to induce apoptosis in human liver cancer cells. During apoptosis, mitochondrial transmembrane potentials were observed to decrease, cytochrome c expression was found to increase and B cell lymphoma 2 (Bcl-2) expression decreased. These findings suggested that H2O2-induced apoptosis was mediated through the mitochondrial pathway. Of note, activated δ-opioid receptors were observed to inhibit H2O2-induced apoptosis in human liver cancer cells. Following δ-opioid receptor activation, the number of apoptotic liver cancer cells decreased, mitochondrial transmembrane potentials were restored, cytoplasmic cytochrome c and Bcl-2-associated X protein expression decreased and Bcl-2 expression increased. These data suggested that δ-opioid receptor activation inhibited mitochondria-mediated apoptosis. In addition, activation of δ-opioid receptors was observed to increase the expression of PKC and ERK in human liver cancer cells. Furthermore, upon inhibition of the PKC/ERK signaling pathway, the protective effect associated with the δ-opioid receptor on liver cancer cell apoptosis was inhibited, which was not associated with the status of δ-opioid receptor activation. These findings suggested that the PKC/ERK signaling pathway has an important role in δ-opioid receptor-mediated inhibition of apoptosis in human liver cancer cells.