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Neuropeptide Regulation of Ion Channels and Food Intake
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Dysfunctional melanocortin signaling caused by MC4R mutation is linked to obesity. Setmelanotide is an MC4R agonist that has been tested clinically for decreasing food intake and body weight control. In patients with leptin receptor deficiency, setmelanotide treatment significantly reduced food intake and body weight (Kuhnen et al. 2016). Unlike other MC4R agonists, no increase in blood pressure or severe adverse effect related to setmelanotide was observed in the study. However, in obese MC4R mutation carriers, setmelanotide treatment produces no significant difference in body weight change compared to control (Collet et al. 2017). These findings suggest that MC4R is required for setmelanotide to produce an inhibitory effect on food intake and body weight. In POMC-deficient patients, treatment with setmelanotide restores the MC4R signaling pathway, which leads to severe weight loss (Kuhnen et al. 2016; Clement et al. 2018). According to the mechanism for the MC4R-activated signaling in controlling neuronal activity, both Kir7.1 and KATP channels may contribute to the decrease in food intake by setmelanotide.
Disorders of pigmentation
Published in Rashmi Sarkar, Anupam Das, Sumit Sethi, Concise Dermatology, 2021
It has to be determined whether the pigmentation is due to melanin or some other pigment (Table 19.2). Generalized melanin hyperpigmentation is seen in Addison’s disease due to destruction of the adrenal cortex from tuberculosis, autoimmune influences, metastases, or amyloidosis. Pigmentation is marked in the flexures, sites of trauma, scars, and sun-exposed areas, but the mucosae and nails are also hyperpigmented. The pigmentation is mediated via activation of the melanocortin-1 receptor. The diagnosis is supported by hypotension, hyponatraemia, and extreme weakness. The hyperpigmentation is due to an excess of pituitary peptides resulting from the lack of adrenal steroids. After bilateral adrenalectomy, pigmentation may be extreme (Nelson’s syndrome). This is associated with an enlarged pituitary gland, elevated fasting plasma ACTH level, and neurologic symptoms. Pheochromocytoma is characterized by Addisonian pigmentation due to ectopic ACTH and MSH production. Carcinoid syndrome manifests with diffuse hyperpigmentation due to an MSH-secreting tumor; along with pellagroid dermatitis.
Newer Agents in Systemic Treatment
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Rachita Dhurat, Shilpi Agarwal
The cutaneous melanocortin system comprises the following bioactive peptides: α-MSH, β-endorphin, corticotropin, and various other peptides that are obtained from the precursor proopiomelanocortin [16–22]. The peptide α-MSH has a pivotal role in melanogenesis and stimulating melanocyte proliferation [16–22]. It acts via melanocortin-1 receptor present on the melanoblasts and increases melanin synthesis via production of eumelanin [16–22]. When combined with NB-UVB phototherapy, it increases differentiation of melanoblasts and upregulates melanocortin-1 receptor [22].
Effects of Subcutaneous Repository Corticotropin Gel Injection on Regulatory T Cell Population in Noninfectious Retinal Vasculitis
Published in Ocular Immunology and Inflammation, 2023
Stephen D. Anesi, Peter Y. Chang, Arash Maleki, Ambika Manhapra, Sydney Look-Why, Soheila Asgari, Marisa Walsh, Kayla Drenen, C. Stephen Foster
The melanocortin pathway is thought to suppress inflammation by inhibiting both the innate and adaptive immune systems.13 Through negative control, the pathway blocks the proinflammatory interleukin-1 (IL-1) and tumor necrosis factor (TNF-) -α receptors in effector cells.14 These changes suppress the production of interferon (IFN-) -γ by effector T cells, while increasing the levels of transforming growth factor (TGF-) -β, and subsequently, increasing the regulatory functions of T-cells. These induced T cells are CD4 +T cells that express CD25 as well at the same level of CD4 on their surface in contrary to effector T cells.15,16 These induced T cells are referred to as T regulatory cells or Tregs. It has been shown that Treg cells are CD25+ CD4 + T cells that share similar surface markers as effector T cells, except that they also express the surface latency-associated peptide (LAP).13 Additionally, melanocortins promote FoxP3 messaging in effector T cells and subsequently increase the regulatory activities of the CD25 + T-cell population.13
Dihydrofolate reductase inhibitors: patent landscape and phases of clinical development (2001–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Kavita Bhagat, Nitish Kumar, Harmandeep Kaur Gulati, Aanchal Sharma, Amandeep Kaur, Jatinder Vir Singh, Harbinder Singh, Preet Mohinder Singh Bedi
In 2006, Hallberg et. al. claimed 2,4-diaminoquinzoline and Pyridopyrimidine ester derivatives endowed with excellent selectivity toward cellular reductase and improved pharmacokinetic profile and further could be utilized further as immuno-modulators cytostatic compounds. Synthesized compounds were evaluated against cellular and pathogen DHFR. In addition to this, binding assay was also carried to determine the affinity of synthesized derivatives against melanocortin (MC) MC-1, MC-3, MC-4, and MC-5 receptors using B16 mouse melanoma cells, taking NDP-MSH as a standard. Also DHFR assay was carried out of these synthesized compounds using a spectrophotometric assay. Addition to in-vitro studies, in-vivo studies were also carried out using Dextran Sodium Sulfate model to evaluate the mechanisms involved in IBD in humans. However, results of both the studies demonstrated that compound 4 (Table 2) exposed higher in vitro inhibitory activity as well in vivo activity against P. carinii and rat lungs (RL) with IC50 values 0.0035 and 0.33 nM respectively [62].
Outcomes of Repository Corticotropin Gel for Ocular Sarcoidosis
Published in Ocular Immunology and Inflammation, 2022
Daniel J. Oh, Arjun Singh, Levi N. Kanu, Ann-Marie Lobo-Chan, Peter W MacIntosh, Pooja Bhat
It has been proposed that RCI, a peptide form of ACTH, suppresses ocular inflammation via its direct effect on cortisol production as well as indirectly via α-MSH (melanocyte stimulating hormone).9 ACTH induces steroidogenesis via binding to melanocortin 2 receptor (MC2R) which is abundantly expressed on the adrenal cortex.1 The melanocortin system encompasses multiple peptides including α-, β-, γ- MSH, ACTH, and five melanocortin receptors (MC1-5R) that are expressed in a multitude of cells and tissues including the eye.10,11 The melanocortin pathway has been implicated in maintaining ocular immune privilege and α-MSH, which suppresses pro-inflammatory signals in innate immune cells, has been found in the aqueous humor.9,12 Few studies in the literature evaluating the effect of ACTH in multiple sclerosis have shown that ACTH functions via binding to other MC receptors besides MC2R, stimulating production of α-MSH with resultant anti-inflammatory effects rather than induction of steroidogenesis alone.13