Malignant melanoma
Pat Price, Karol Sikora in Treatment of Cancer, 2014
The mitogen activated protein kinase (MAPK) signalling pathway is a key intracellular signalling pathway involved in cell growth, differentiation and survival. Genetic mutations affecting key components of this pathway have been implicated in many different tumours including melanoma. Activation of the pathway occurs upon ligand-cell surface receptor tyrosine kinase binding. This causes downstream activation of Ras, a G protein with multiple isoforms, the most important in melanoma being NRAS. Phosphorylation and activation of the RAF proteins then occurs as a consequence of RAS activation. The RAF proteins, BRAF and CRAF, dimerise to activate extracellular signal-regulated kinase (ERK) which in turn activates downstream pathways to promote cell growth, differentiation and survival.
Effects of solar radiation, air pollution, and artificial blue light on the skin
Roger L. McMullen in Antioxidants and the Skin, 2018
While UV-induced cellular signaling pathways may lead to a variety of outcomes, some of the best understood pathways are those ultimately leading to skin photoaging.34–36 Other studies, strictly concerned with molecular signaling induced as a result of UV exposure, elucidate similar or related mechanisms that may be involved in photoaging or even interconnected with photoimmunosuppression or photocarcinogenesis.37–40 As shown in Figure 4.13, UV exposure results in the activation of cell surface receptors located at the plasma membrane: transforming growth factor-beta (TGF-beta), growth factor receptors, and cytokine receptors. As already noted, evidence indicates that the receptors are activated by UV-induced ROS.34 In turn, the receptors trigger signal transduction pathways in the cytoplasm. The mitogen-activated protein kinases (MAPKs) regulate cell proliferation, differentiation, apoptosis, and mitosis. They consist of extracellular signal related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK. In relation to photoaging, the MAPKs activate (in the nucleus) the transcription factor activator protein-1 (AP-1). Upon activation, AP-1 upregulates the expression of MMPs that are able to degrade the ECM and downregulates the synthesis of type I procollagen, which is the precursor for collagen I.
Herbs with Antidepressant Effects
Scott Mendelson in Herbal Treatment of Major Depression, 2019
Cimicifuga racemosa has also been found to exert potent anti-inflammatory effects in animals. This is consistent with its historic use to relieve the discomfort of rheumatic conditions. A single oral dose of methanolic extract of Cimicifuga racemosa attenuated inflammation in the carrageenan-induced paw edema model in rats. In fact, its anti-inflammatory effect was stronger than that of the standard anti-inflammatory medication indomethacin.6 Cimiracemate A, a specific constituent of the extracts of the Cimicifuga racemose rhizome, can suppress the production of TNF-α from lipopolysaccharide stimulated macrophages by nearly half. This anti-inflammatory effect appears to be due to blocking the effects of both nuclear factor-kappaB and mitogen activated protein kinase.7
Skin hyperpigmentation treatment using herbs: A review of clinical evidences
Published in Journal of Cosmetic and Laser Therapy, 2018
Mayuree Kanlayavattanakul, Nattaya Lourith
Mitogen-activated protein kinases (MAPKs) are composed of three subtypes: stress-activated protein kinases (SAPKs)/c-Jun NH2-terminal kinases (JNK), p38, and extracellular signal-regulated kinases (ERKs). JNK and p38 kinases are stimulated by pro-inflammatory cytokines and environmentally induced stresses such as exposure to UV irradiation, heat, and hydrogen peroxide, resulting in DNA damage. Melanogenesis is controlled by MAPKs, with MITF being activated by p38 phosphorylation. In contrast, ERK activation inhibits melanin synthesis by downregulating MITF expression. Thus, suppression of the ERK signaling pathway induces cell differentiation and upregulation of tyrosinase activity, stimulating melanogenesis. In addition, the MAPK signaling pathway modulates nuclear factor E2-related factor 2 (Nrf2), which is an important transcription factor controlling the antioxidant response to protect skin cells against oxidative stress, such as that occurring on the exposure of melanocytes to UV radiation (2). A summary of melanogenesis pathways is depicted in Figure 1.
S-Propargyl-cysteine prevents concanavalin A-induced immunological liver injury in mice
Published in Pharmaceutical Biology, 2022
Beilei Ma, Yicheng Mao, Lingling Chang, Tao Dai, Xiaoming Xin, Fenfen Ma, Zhijun Wang, Zhuqing Shen, Qibing Mei, Yizhun Zhu
Previous studies have established that the release of inflammatory cytokines leads to liver injury after the Con A injection. The mitogen-activated protein kinase (MAPK) signalling pathway has previously been described to regulate the production of inflammatory cytokines. In this pathway, activation of c-Jun N-terminal kinase (JNK) and protein kinase B (Akt) has been reported to play an important role in hepatitis and determine the fate of the hepatocytes (death or survival). In this study, western blot analysis of phosphorylated JNK (p-JNK) and phosphorylated Akt (p-Akt) revealed increased expressions of these proteins in the livers of mice intoxicated with Con A after 12 h. On the contrary, SPRC (10 mg/kg) administration reduced the expressions of p-JNK (p < 0.01 vs. Con A) and p-Akt (p < 0.05 vs. Con A). This result indicated that SPRC pre-treatment suppressed the activation of the MAPK pathway (Figure 4). However, this suppression was reversed by the CSE inhibitor PAG.
The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma
Published in Expert Opinion on Drug Safety, 2018
Sarah Knispel, Lisa Zimmer, Theodora Kanaki, Selma Ugurel, Dirk Schadendorf, Elisabeth Livingstone
Despite concerted efforts of skin cancer prevention, melanoma incidence is still on the rise, especially in fair-skinned individuals [1]. Less than a decade ago, survival rates for patients with distant metastatic melanoma were dismal with a median survival of only 9 months. Since 2010, several drugs have demonstrated their efficacy and have thus been approved for advanced stage melanoma changing the treatment landscape of melanoma patients to the better. The mainstay of melanoma therapy currently consists of immunotherapy and targeted therapy. The anti-CTLA-4 antibody ipilimumab was the first drug to show significant survival benefit in melanoma patients [2] and it is known that CTLA-4 and PD-1 immune-checkpoint inhibitors can lead to long-term survival in a subset of patients [3,4]. The success of the kinase inhibitors began with the discovery of activating somatic BRAF V600 mutations in melanoma cells [5]. Thereafter, small molecules targeting kinases in the mitogen-activated protein kinase (MAPK) signaling pathways were developed and soon investigated within clinical trials. Response rates were unprecedented and with longer follow-up time, 3-year survival rates for dual MAPK inhibition have reached 44% [6].
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