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2.
Lancet Diabetes Endocrinol ; 12(6): 380-389, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38697184

RESUMO

BACKGROUND: Hypothalamic obesity resulting from hypothalamic damage might affect melanocortin signalling. We investigated the melanocortin-4 receptor agonist setmelanotide for treatment of hypothalamic obesity. METHODS: This phase 2, open-label, multicentre trial was done in five centres in the USA. Eligible patients were aged between 6 and 40 years with obesity and history of hypothalamic injury or diagnosis of a non-malignant tumour affecting the hypothalamus that was treated with surgery, chemotherapy, or radiation. Setmelanotide was titrated up to a dose of 3·0 mg and administered subcutaneously once a day for a total duration of 16 weeks. The primary endpoint was the proportion of patients with a reduction in BMI of at least 5% from baseline after 16 weeks, compared with a historic control rate of less than 5% in this population. The primary endpoint was analysed using the full analysis set, which includes all patients with baseline data who received at least one dose of setmelanotide. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04725240) and is complete. FINDINGS: Between June 6, 2021, and Jan 13, 2022, 19 patients were screened for inclusion. One patient was excluded, and 18 were enrolled and received at least one dose of setmelanotide. Patients were primarily White (n=14 [78%]) and male (n=11 [61%]). Enrolled patients had a mean age of 15·0 years (SD 5·3) and a mean BMI of 38·0 kg/m2 (SD 6·5). Of 18 patients enrolled, 16 (89%) of 18 patients completed the study and met the primary endpoint of reduction in BMI of at least 5% from baseline after 16 weeks (p<0·0001). The mean reduction in BMI across all patients was 15% (SD 10). A composite proportion of patients had a clinically meaningful change (89%, 90% CI 69-98%; p<0·0001), comprising a reduction in BMI Z score of at least 0·2 points for patients younger than 18 years (92%, 68-100%; p<0·0001) and reduction in bodyweight of at least 5% for patients aged 18 years or older (80%, 34-99%; p<0·0001). Patients aged 12 years or older had a mean reduction in hunger score of 45%. Frequent adverse events included nausea (61%), vomiting (33%), skin hyperpigmentation (33%), and diarrhoea (22%). Of 14 patients who continued treatment in a long-term extension study (NCT03651765), 12 completed at least 12 months of treatment at the time of publication and had a mean change in BMI of -26% (SD 12) from index trial baseline. INTERPRETATION: These findings support setmelanotide as a novel effective treatment of hypothalamic obesity. FUNDING: Rhythm Pharmaceuticals.


Assuntos
Doenças Hipotalâmicas , Obesidade , alfa-MSH , Humanos , Masculino , Feminino , Adulto , Adolescente , Obesidade/tratamento farmacológico , Adulto Jovem , Doenças Hipotalâmicas/tratamento farmacológico , Criança , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêutico , alfa-MSH/administração & dosagem , Receptor Tipo 4 de Melanocortina/agonistas , Resultado do Tratamento , Índice de Massa Corporal
3.
Am J Pathol ; 194(1): 150-164, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37827217

RESUMO

Corneal endothelial cells (CEnCs) regulate corneal hydration and maintain tissue transparency through their barrier and pump function. However, these cells exhibit limited regenerative capacity following injury. Currently, corneal transplantation is the only established therapy for restoring endothelial function, and there are no pharmacologic interventions available for restoring endothelial function. This study investigated the efficacy of the neuropeptide α-melanocyte-stimulating hormone (α-MSH) in promoting endothelial regeneration during the critical window between ocular injury and the onset of endothelial decompensation using an established murine model of injury using transcorneal freezing. Local administration of α-MSH following injury prevented corneal edema and opacity, reduced leukocyte infiltration, and limited CEnC apoptosis while promoting their proliferation. These results suggest that α-MSH has a proregenerative and cytoprotective function on CEnCs and shows promise as a therapy for the prevention and management of corneal endothelial dysfunction.


Assuntos
Córnea , Edema da Córnea , alfa-MSH , Feminino , Gravidez , Animais , Camundongos , Camundongos Endogâmicos BALB C , Humanos , Linhagem Celular , Córnea/citologia , Células Endoteliais , Edema da Córnea/tratamento farmacológico , Edema da Córnea/patologia , Preservação de Tecido , alfa-MSH/uso terapêutico , Citoproteção , Infiltração de Neutrófilos , Monócitos/metabolismo , Macrófagos/metabolismo , Cicatrização/efeitos dos fármacos
4.
Lasers Surg Med ; 55(5): 490-502, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37051852

RESUMO

OBJECTIVES: One symptom of hypertrophic scar (HTS) that can develop after burn injury is dyschromia with hyper- and hypopigmentation. There are limited treatments for these conditions. Previously, we showed there is no expression of alpha melanocyte stimulating hormone (α-MSH) in hypopigmented scars, and if these melanocytes are treated with synthetic α-MSH in vitro, they respond by repigmenting. The current study tested the same hypothesis in the in vivo environment using laser-assisted drug delivery (LADD). METHODS: HTSs were created in red Duroc pigs. At Day 77 (pre), they were treated with CO2 fractional ablative laser (FLSR). Synthetic α-MSH was delivered as a topical solution dissolved in  l-tyrosine (n = 6, treated). Control scars received LADD of  l-tyrosine only (n = 2, control). Scars were treated and examined weekly through Week 4. Digital images and punch biopsies of hyper, hypo-, and normally pigmented scar and skin were collected. Digital pictures were analyzed with ImageJ by tracing the area of hyperpigmentation. Epidermal sheets were obtained from punch biopsies through dispase separation and RNA was isolated. qRT-PCR was run for melanogenesis-related genes: tyrosinase (TYR), tyrosinase-related protein-1 (TYRP1), and dopachrome tautomerase (DCT). Two-way ANOVA with multiple comparisons and Dunnett's correction compared the groups. RESULTS: The areas of hyperpigmentation were variable before treatment. Therefore, data is represented as fold-change where each scar was normalized to its own pre value. Within the LADD of NDP α-MSH + l-tyrosine group, hyperpigmented areas gradually increased each week, reaching 1.3-fold over pre by Week 4. At each timepoint, area of hyperpigmentation was greater in the treated versus the control (1.04 ± 0.05 vs. 0.89 ± 0.08, 1.21 ± 0.07 vs. 0.98 ± 0.24, 1.21 ± 0.08 vs. 1.04 ± 0.11, 1.28 ± 0.11 vs. 0.94 ± 0.25; fold-change from pre-). Within the treatment group, pretreatment, levels of TYR were decreased -17.76 ± 4.52 below the level of normal skin in hypopigmented scars. After 1 treatment, potentially due to laser fractionation, the levels decreased to -43.49 ± 5.52. After 2, 3, and 4 treatments, there was ever increasing levels of TYR to almost the level of normally pigmented skin (-35.74 ± 15.72, -23.25 ± 6.80, -5.52 ± 2.22 [p < 0.01, Week 4]). This pattern was also observed for TYRP1 (pre = -12.94 ± 1.82, Week 1 = -48.85 ± 13.25 [p < 0.01], Weeks 2, 3, and 4 = -34.45 ± 14.64, -28.19 ± 4.98, -6.93 ± 3.05 [p < 0.01, Week 4]) and DCT (pre = -214.95 ± 89.42, Week 1 = -487.93 ± 126.32 [p < 0.05], Weeks 2, 3, and 4 = -219.06 ± 79.33, -72.91 ± 20.45 [p < 0.001], -76.00 ± 24.26 [p < 0.001]). Similar patterns were observed for scars treated with LADD of  l-tyrosine alone without NDP α-MSH. For each gene, in hyperpigmented scar, levels increased at Week 4 of treatment compared to Week 1 (p < 0.01). CONCLUSIONS: A clinically-relevant FLSR treatment method can be combined with topical delivery of synthetic α-MSH and l-tyrosine to increase the area of pigmentation and expression of melanogenesis genes in hypopigmented HTS. LADD of  l-tyrosine alone leads to increased expression of melanogenesis genes. Future studies will aim to optimize drug delivery, timing, and dosing.


Assuntos
Cicatriz Hipertrófica , Hiperpigmentação , Hipopigmentação , Lasers de Gás , Animais , Suínos , Cicatriz Hipertrófica/tratamento farmacológico , Cicatriz Hipertrófica/genética , Cicatriz Hipertrófica/patologia , Tirosina , alfa-MSH/uso terapêutico , alfa-MSH/metabolismo , Preparações Farmacêuticas , Pigmentação , Hipopigmentação/tratamento farmacológico , Hipopigmentação/genética , Hiperpigmentação/tratamento farmacológico , Hiperpigmentação/genética , Lasers de Gás/uso terapêutico , Melaninas/metabolismo
5.
Front Endocrinol (Lausanne) ; 14: 1307889, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38239988

RESUMO

Children with acquired hypothalamic obesity, e.g. following treatment for pediatric craniopharyngioma are at great risk for metabolic syndrome, cardiovascular health problems and premature mortality. Treatment for acquired hypothalamic obesity has thus far been disappointing. Several interventions were reported to be partially successful, including dextro-amphetamine and GLP-1R agonists, although results in acquired hypothalamic obesity are conflicting. Disruption of signaling through the melanocortin-4 receptor (MC4R) pathway results in hyperphagia and severe early-onset hypothalamic obesity. Recently, the MC4R agonist setmelanotide has shown promising results in children with genetic forms of hypothalamic obesity; POMC, PCSK1 and LEPR. Patient quotes such as "we have our family life back" illustrate the magnitude of the effect. Targeted hormone replacement therapy with a MC4R agonist for acquired hypothalamic obesity could be a game-changer. Preliminary results of setmelanotide treatment in 14, mostly pediatric, patients with acquired hypothalamic obesity are promising. The FDA has recommended that a prospective, randomized, blinded trial be conducted over a 12 months treatment period, comparable to pivotal trials for other obesity drugs. It may be discussed whether setmelanotide should be regarded as an obesity drug or whether it may be envisioned as an agent for hypothalamic substitution therapy. In this commentary we discuss the trial that is currently recruiting patients with acquired hypothalamic obesity.


Assuntos
Doenças Hipotalâmicas , Obesidade Mórbida , Humanos , Criança , Estudos Prospectivos , Obesidade/metabolismo , alfa-MSH/uso terapêutico , Obesidade Mórbida/tratamento farmacológico , Doenças Hipotalâmicas/complicações , Doenças Hipotalâmicas/tratamento farmacológico
6.
Lung ; 200(4): 463-472, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35717488

RESUMO

PURPOSE: Alpha-melanocyte stimulating hormone (α-MSH) is known to have anti-inflammatory effects. However, the anti-inflammatory properties of α-MSH on normal bronchial epithelial cells are largely unknown, especially in the context of in vitro sarcoidosis models. METHODS: We evaluated the anti-inflammatory effects of α-MSH on two different in vitro sarcoidosis models (lung-on-membrane model; LOMM and three-dimensional biochip pulmonary sarcoidosis model; 3D-BSGM) generated from NBECs and an in vivo sarcoidosis mouse model. RESULTS: Treatment with α-MSH decreased inflammatory cytokine levels and downregulated type I interferon pathway genes and related proteins in LOMM and 3D-BSGM models. Treatment with α-MSH also significantly decreased macrophages and cytotoxic T-cells counts in a sarcoidosis mice model. CONCLUSION: Our results confirm the direct role of type I IFNs in the pathogenesis of sarcoid lung granulomas and highlight α-MSH as a potential novel therapeutic agent for treating pulmonary sarcoidosis.


Assuntos
Sarcoidose Pulmonar , Sarcoidose , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Granuloma/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Sarcoidose/tratamento farmacológico , Sarcoidose Pulmonar/tratamento farmacológico , alfa-MSH/metabolismo , alfa-MSH/farmacologia , alfa-MSH/uso terapêutico
7.
CNS Spectr ; 27(3): 281-289, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-33455598

RESUMO

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD.


Assuntos
Serotonina , Disfunções Sexuais Psicogênicas , Animais , Dopamina/metabolismo , Feminino , Humanos , Neurotransmissores/uso terapêutico , Peptídeos Cíclicos , Serotonina/metabolismo , Disfunções Sexuais Psicogênicas/tratamento farmacológico , alfa-MSH/uso terapêutico
8.
Neurochem Res ; 47(2): 394-408, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34586586

RESUMO

Persons with type 1 diabetes have an increased risk of stroke compared with the general population. α-Melanocyte-stimulating hormone (α-MSH) is a neuropeptide that has protective effects against ischemia/reperfusion (I/R) induced organ damages. In this study, we aimed to investigate the neuroprotective role of this peptide on I/R induced brain damage after experimental stroke associated with hyperglycemia using C57BL/6J Ins2Akita/+ mice. Experimental stroke was induced by blocking the right middle cerebral artery for 2 h with reperfusion for 2 and 22 h, respectively using the intraluminal method. Animals were treated intraperitoneally with or without α-MSH at 1 h after ischemia and 1 h after reperfusion. Significantly higher survival rate and lower neurological scores were recorded in animals injected with α-MSH. Similarly, neuron death, glial cells activation as well as oxidative and nitrosative stress were significantly decreased in α-MSH treated group. Relative intensities of matrix metallopeptidases 9, cyclooxygenase 2 and nuclear factor-κB were significantly decreased while intensities of Akt, heme oxygenase (HO) 1, HO-2 and B-cell lymphoma 2 were significantly increased after α-MSH treatment. In addition, gene expressions of monocarboxylate transporter (MCT) 1, MCT-2 and activity-regulated cytoskeleton-associated protein were significantly higher in brain samples treated with α-MSH, suggesting this peptide may have role in neuron survival by an involvement of lactate metabolism. In conclusion, α-MSH is neuroprotective under hyperglycemic condition against I/R induced brain damage by its anti-inflammatory, anti-oxidative and anti-apoptotic properties. The use of α-MSH analogues may be potential therapeutic agents for diabetic stroke.


Assuntos
Isquemia Encefálica , Diabetes Mellitus Tipo 1 , Traumatismo por Reperfusão , Animais , Isquemia Encefálica/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão/metabolismo , alfa-MSH/farmacologia , alfa-MSH/uso terapêutico
9.
Curr Eye Res ; 47(3): 343-351, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34766863

RESUMO

PURPOSE: To investigate the anti-inflammatory and antifungal role of α-melanocyte stimulating hormone (α-MSH) in Aspergillus Fumigatus (A. fumigatus) keratitis. METHOD: Corneas of C57BL/6 mice were infected with A. Fumigatus. α-MSH (5 ul, 1×10-4 mmol/ml) was given by subconjunctival injection from day 1 to day 3 post infection (p.i.). After 3 days p.i., clinical score was recorded and HE staining was tested. Fungal load in mice corneas was observed by plate counting. Proinflammatory mediators and pattern recognition receptors (PRRs) were detected. The number of neutrophils and macrophages was tested by immunofluorescence staining. The role of α-MSH in RAW264.7 cells after A. fumigatus stimulation were evaluated by PCR and Western blot, and MPKA protein levels including total-JNK (T-JNK), phosphorylated-JNK (P-JNK), total-ERK (T-ERK), and phosphorylated-ERK (P-ERK) were tested via Western blot with or without α-MSH treatment. RESULTS: Compared with PBS control group, α-MSH treatment alleviated disease response and decreased clinical score at 3 days p.i. HE staining showed less infiltration in corneal tissue after α-MSH treatment. Plate counting experiment showed that number of viable fungus in corneas of α-MSH treated group was less than control group. mRNA levels of IL-1ß, TNF-α, IL-6, MIP-2, LOX-1, Dectin-1, and iNOS were decreased. Protein levels of IL-1ß, TNF-α, IL-6, and Dectin-1 were decreased. α-MSH treatment also decreased the infiltrating neutrophils and macrophages. The levels of proinflammatory cytokines, Dectin-1 and LOX-1 stimulated by A. fumigatus, were also suppressed by pretreatment of α-MSH in RAW264.7 cells. The ratio of P-JNK/T-JNK and P-ERK/T-ERK was downregulated in α-MSH group compared with PBS control group. CONCLUSION: α-MSH alleviates the severity and decreases fungal load of A. fumigatus keratitis in mice. Migration of neutrophils and macrophages are restrained. α-MSH downregulates the expression of dectin-1 and the ratio of P-JNK/T-JNK and P-ERK/T-ERK in A. fumigatus infection.


Assuntos
Infecções Oculares Fúngicas , Ceratite , Animais , Anti-Inflamatórios/farmacologia , Aspergillus fumigatus/fisiologia , Modelos Animais de Doenças , Infecções Oculares Fúngicas/microbiologia , Interleucina-6 , Ceratite/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores Depuradores Classe E/uso terapêutico , Fator de Necrose Tumoral alfa , alfa-MSH/uso terapêutico
10.
Dermatology ; 237(6): 995-999, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34464955

RESUMO

BACKGROUND: Melanotan II (MT II) is a synthetic analogue of α-melanocyte-stimulating hormone that, via interaction with the melanocortin 1 receptor, induces skin hyperpigmentation. The unregulated acquisition of MT II injections via the internet and other outlets has become popular over the last decades in order to exploit its properties for use as a tanning agent. Due to the covert nature of MT II use, it is difficult to assess the extent of its use among the general population and to characterise any associated side effects. OBJECTIVES: The aim of this study was to qualitatively examine MT II use, as portrayed on online forums, and to explore the motivations for its use and side effect profile. METHODS: Data were extracted retrospectively from UK and Ireland online chatrooms and forums from January 2016 to October 2017. Inclusion criteria were active MT II chatrooms and forums considered to be within the public domain. An inductive thematic analysis identified themes within discussion threads. RESULTS: A total of 623 discussion entries were extracted; 205 participants contributed to these entries. Emergent themes included motivation for MT II use, misinformation in the context of using an unregulated product, product preparation and administration, dosing regimens, sunbed use, side effects and concerning practices associated with MT II use. CONCLUSION: Motivations for MT II use included the pursuit of a tanned appearance, often in anticipation of sun holidays and fitness/body building competitions. Clinicians should be aware not only of the potential risks in relation to pigmented skin lesions, but also remain cognisant of the other medical hazards associated with the use of this substance, namely transmission of infectious diseases, use of potentially contaminated products, polypharmacy, and sunbed exposure.


Assuntos
Internet , Motivação , Peptídeos Cíclicos/uso terapêutico , Pigmentação da Pele/efeitos dos fármacos , alfa-MSH/análogos & derivados , Humanos , Satisfação do Paciente , Pesquisa Qualitativa , Estudos Retrospectivos , Banho de Sol , Reino Unido , alfa-MSH/uso terapêutico
11.
Exp Eye Res ; 210: 108685, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34252414

RESUMO

Dry eye (DE) is a chronic, multifactorial ocular surface disease associated with visual disturbance, tear film instability, hyperosmolarity, ocular surface inflammation and damage. Effective intervention is necessary to control this disease. In this study we topically applied α-melanocyte stimulating hormone (α-MSH) on the ocular surface of scopolamine-induced DE rats and found that it promoted tear secretion, reduced tear breakup time and fluorescein sodium staining and increased the number of conjunctival goblet cells. To investigate the mechanism, protein array was conducted, which showed that α-MSH exerted its effects via epithelial growth factor receptor (EGFR) in the JAK-STAT signaling pathway. Furthermore, in vitro experiments showed that α-MSH protected human corneal epithelial cells (hCECs) by maintaining their migration ability and viability and decreasing apoptosis. However, blockade of EGFR abolished these protective effects. Moreover, α-MSH decreased the level of autophagy in benzalkonium chloride (BAC)-stressed hCECs via EGFR. These results demonstrated that α-MSH ameliorated lesions and restored ocular surface functions by upregulating EGFR expression.


Assuntos
Síndromes do Olho Seco/tratamento farmacológico , Receptores ErbB/genética , Regulação da Expressão Gênica/fisiologia , Hormônios/uso terapêutico , alfa-MSH/uso terapêutico , Administração Oftálmica , Animais , Apoptose , Autofagia , Linhagem Celular , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Modelos Animais de Doenças , Síndromes do Olho Seco/induzido quimicamente , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/patologia , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/metabolismo , Epitélio Corneano/patologia , Feminino , Citometria de Fluxo , Células Caliciformes/efeitos dos fármacos , Hormônios/administração & dosagem , Humanos , Soluções Oftálmicas , Interferência de RNA , Ratos , Ratos Wistar , Escopolamina/toxicidade , Lágrimas/fisiologia , alfa-MSH/administração & dosagem
12.
Clin Exp Dermatol ; 46(7): 1189-1204, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33872410

RESUMO

Systemic photoprotection aims to negate the negative effects of ultraviolet radiation-induced DNA damage. Systemic supplements may be used as a monotherapy or in combination with topical sunscreens. Using the keywords 'carotenoids', 'flavonoids', 'systemic photoprotection', 'polyphenols' and 'polypodium leucotomos extract', we searched the databases MEDLINE and EMBASE to find relevant English-language articles. Few trials have supported the use of any of these supplements as monotherapy, impeding the recommendation of these systemic supplements as an alternative to sunscreen for photoprotection. Nicotinamide has exhibited clinically relevant benefits in reducing nonmelanoma skin cancers in trials and could be recommended as an adjunctive therapy for the most vulnerable indviduals. Further research is required, which needs to be of higher statistical power, using more clinically meaningful outcome measures with comparison to the current gold standard of care (topical photoprotection) to support the use of alternative therapies in clinical practice.


Assuntos
Suplementos Nutricionais , Extratos Vegetais/uso terapêutico , Neoplasias Cutâneas/prevenção & controle , Protetores Solares , Antioxidantes/uso terapêutico , Carotenoides/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Flavonoides/uso terapêutico , Humanos , Raios Ultravioleta , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêutico
13.
Int J Mol Sci ; 22(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33922961

RESUMO

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones. Recently, we discovered a spontaneous compound heterozygous mutation within the leptin receptor, resulting in a considerably more obese phenotype than described for the homozygous leptin receptor deficient mice. Accordingly, we focus on compound heterozygous mutations of the leptin receptor and their effects on health, as well as possible therapy options in human and animal models in this review.


Assuntos
Obesidade/terapia , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Animais , Fármacos Antiobesidade/uso terapêutico , Cirurgia Bariátrica , Modelos Animais de Doenças , Heterozigoto , Humanos , Hiperfagia/genética , Camundongos , Mutação , Obesidade/genética , Receptores para Leptina/química , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêutico
14.
Photochem Photobiol Sci ; 20(2): 315-320, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33721252

RESUMO

BACKGROUND: Afamelanotide (AFA) is a synthetic analogue of α-melanocyte-stimulating hormone that is approved for the treatment of patients affected by erythropoietic protoporphyria (EPP). AFA induces a "sun free" tanning and changes of acquired melanocytic nevi (AMN) that are generically described as "darkening". OBJECTIVES: To assess clinical and dermoscopic AMN changes during AFA treatment. METHODS: Adult EPP patients treated with two AFA implants 50 days apart were enrolled. They underwent a clinical and dermoscopic examination of all AMN at baseline (T0), and after 5 (T1) and 12 (T2) months from the first AFA implant. The general pattern, symmetry, number, and size of pigmented globules, morphology of the pigment network, and dermoscopic melanoma features were assessed. RESULTS: Fifteen patients were enrolled with 103 AMN. At T1 all reticular and 2-component AMN showed a focal network thickening that returned to baseline by T2. The increase of globules' number was observed at T1 but not at T2. The difference in number was not influenced by patients' age or phototype. Dermoscopic changes suggestive of malignancy were never seen. The development of new AMN was never registered. CONCLUSIONS: AFA treatment induces reversible changes of AMN dermoscopic morphology without findings suggestive of malignant transformation and it does not stimulate the development of new AMN.


Assuntos
Fármacos Dermatológicos/efeitos adversos , Nevo Pigmentado/diagnóstico , Protoporfiria Eritropoética/patologia , alfa-MSH/análogos & derivados , Adulto , Fármacos Dermatológicos/uso terapêutico , Dermoscopia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nevo Pigmentado/etiologia , Protoporfiria Eritropoética/tratamento farmacológico , Receptor Tipo 1 de Melanocortina/metabolismo , Luz Solar , Fatores de Tempo , alfa-MSH/efeitos adversos , alfa-MSH/uso terapêutico
15.
Clin Exp Dermatol ; 46(2): 248-258, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33350506

RESUMO

Vitiligo is an autoimmune skin condition characterized by depigmented macules and patches, and has a huge psychosocial impact on patients. Treatment of vitiligo aims to prevent the spread of disease and facilitate repigmentation of affected lesions. The mainstay of treatment for unstable vitiligo has been topical agents (corticosteroids, calcineurin inhibitors) and phototherapy. However, systemic treatments are increasingly being shown to have a significant impact on the course of the disease as monotherapy or adjunctive therapy. Of note, oral mini-pulsed corticosteroid therapy, methotrexate, minocycline, ciclosporin, Janus kinase inhibitors and certain supplements have been used in the systemic treatment of vitiligo. We review the underlying evidence supporting the use of each of these systemic treatments.


Assuntos
Corticosteroides/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Terapia Neoadjuvante/métodos , Fototerapia/métodos , Vitiligo/patologia , Vitiligo/terapia , Administração Oral , Administração Tópica , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Inibidores de Calcineurina/administração & dosagem , Inibidores de Calcineurina/efeitos adversos , Terapia Combinada , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Ciclosporina/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/uso terapêutico , Humanos , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Inibidores de Janus Quinases/uso terapêutico , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Minociclina/administração & dosagem , Minociclina/efeitos adversos , Minociclina/uso terapêutico , Avaliação de Resultados em Cuidados de Saúde , Fototerapia/efeitos adversos , Psicologia , Vitiligo/psicologia , alfa-MSH/administração & dosagem , alfa-MSH/efeitos adversos , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêutico
16.
Eur J Endocrinol ; 183(5): R149-R166, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33107433

RESUMO

Obesity, defined by an excess of body fat impacting on health, is a complex disease resulting from the interaction between many genetic/epigenetic factors and environmental triggers. For some clinical situations with severe obesity, it has been possible to classify these obesity forms according to the molecular alterations. These include: (i) syndromic obesity, which associates severe early-onset obesity with neurodevelopmental disorders and/or polymalformative syndrome and (ii) non-syndromic monogenic obesity, due to gene variants most often located in the leptin-melanocortin pathway. In addition to severe obesity, patients affected by these diseases display complex somatic conditions, eventually including obesity comorbidities, neuropsychological and psychiatric disorders. These conditions render the clinical management of these patients particularly challenging. Patients' early diagnosis is critical to allow specialized and multidisciplinary care, with a necessary interaction between the health and social sectors. Up to now, the management of genetic obesity was only based, above all, on controlling the patient's environment, which involves limiting access to food, ensuring a reassuring daily eating environment that limits impulsiveness, and the practice of adapted, supported, and supervised physical activity. Bariatric surgery has also been undertaken in genetic obesity cases with uncertain outcomes. The context is rapidly changing, as new innovative therapies are currently being tested both for syndromic and monogenic forms of obesity. This review focuses on care management and new therapeutic opportunities in genetic obesity, including the use of the melanocortin 4 agonist, setmelanotide. The results from ongoing trials will hopefully pave the way to a future precision medicine approach for genetic obesity.


Assuntos
Cirurgia Bariátrica/tendências , Endocrinologia/tendências , Obesidade Mórbida/terapia , Obesidade/terapia , Adulto , Fármacos Antiobesidade/uso terapêutico , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Obesidade/genética , Obesidade Mórbida/genética , Síndrome , alfa-MSH/análogos & derivados , alfa-MSH/uso terapêutico
17.
J Hepatol ; 71(2): 422-433, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31102718

RESUMO

Porphyrias are rare inherited disorders caused by specific enzyme dysfunctions in the haem synthesis pathway, which result in abnormal accumulation of specific pathway intermediates. The symptoms depend upon the chemical characteristics of these substances. Porphyrins are photoreactive and cause photocutaneous lesions on sunlight-exposed areas, whereas accumulation of porphyrin precursors is related to acute neurovisceral attacks. Current therapies are suboptimal and mostly address symptoms rather than underlying disease mechanisms. Advances in the understanding of the molecular bases and pathogenesis of porphyrias have paved the way for the development of new therapeutic strategies. In this Clinical Trial Watch we summarise the basic principles of these emerging approaches and what is currently known about their application to porphyrias of hepatic origin or with hepatic involvement.


Assuntos
Acetilgalactosamina/análogos & derivados , Transplante de Medula Óssea/métodos , Resina de Colestiramina/uso terapêutico , Terapia Genética/métodos , Transplante de Fígado/métodos , Porfirias Hepáticas/tratamento farmacológico , Porfirias Hepáticas/cirurgia , Pirrolidinas/uso terapêutico , Receptor Tipo 1 de Melanocortina/agonistas , alfa-MSH/análogos & derivados , 5-Aminolevulinato Sintetase/antagonistas & inibidores , Acetilgalactosamina/farmacologia , Acetilgalactosamina/uso terapêutico , Heme/biossíntese , Humanos , Fígado/metabolismo , Porfirias Hepáticas/classificação , Porfirias Hepáticas/patologia , Porfirinas/metabolismo , Pirrolidinas/farmacologia , alfa-MSH/uso terapêutico
18.
ACS Chem Neurosci ; 10(3): 1055-1065, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30048591

RESUMO

Human melanocortin-4 receptor (hMC4R) mutations have been implicated as the cause for about 6-8% of all severe obesity cases. Drug-like molecules that are able to rescue the functional activity of mutated receptors are highly desirable to combat genetic obesity among this population of patients. One such molecule is the selective MC4R agonist RM-493 (setmelanotide). While this molecule has been shown to activate mutated receptors with 20-fold higher potency over the endogenous agonist, little is known about its binding mode and how it effectively interacts with hMC4R despite the presence of mutations. In this study, a MC4R homology model was constructed based on the X-ray crystal structure of the adenosine A2A receptor in the active state. Four MC4R mutations commonly found in genetically obese patients and known to effect ligand binding in vitro were introduced into the constructed model. RM-493 was then docked into the wild-type and mutated models in order to better elucidate the possible binding modes for this promising drug candidate and assess how it may be interacting with MC4R to effectively activate receptor polymorphisms. The results reflected the orthosteric interactions of both the endogenous and synthetic ligands with the MC4R, which is supported by the site-directed mutagenesis studies. Meanwhile it helped explain the decremental affinity and potency of these ligands with the receptor polymorphisms. More significantly, our findings indicated that the structural characteristics of RM-493 may allow for enhanced receptor-ligand interactions, particularly through those with the putative allosteric binding sites, which facilitated the ligand to stabilize the active state of native and mutant MC4Rs to maintain reasonably high affinity and potency.


Assuntos
Fármacos Antiobesidade/química , Simulação por Computador , Obesidade/genética , Receptor Tipo 4 de Melanocortina/química , Receptor Tipo 4 de Melanocortina/genética , alfa-MSH/análogos & derivados , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Sequência de Aminoácidos , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Humanos , Simulação de Acoplamento Molecular/métodos , Obesidade/tratamento farmacológico , Mutação Puntual/genética , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptor Tipo 4 de Melanocortina/agonistas , alfa-MSH/química , alfa-MSH/farmacologia , alfa-MSH/uso terapêutico
19.
Int J Mol Sci ; 19(12)2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30513637

RESUMO

α-melanocyte-stimulating hormone (α-MSH) has been characterized as a novel angiogenesis inhibitor. The homeostasis of nitric oxide (NO) plays an important role in neovascularization. However, it remains unclear whether α-MSH mitigates angiogenesis through modulation of NO and its signaling pathway. The present study elucidated the function and mechanism of NO signaling in α-MSH-induced angiogenesis inhibition using cultured human umbilical vein endothelial cells (HUVECs), rat aorta rings, and transgenic zebrafish. By Griess reagent assay, it was found α-MSH dose-dependently reduced the NO release in HUVECs. Immunoblotting and immunofluorescence analysis revealed α-MSH potently suppressed endothelial and inducible nitric oxide synthase (eNOS/iNOS) expression, which was accompanied with inhibition of nuclear factor kappa B (NF-κB) activities. Excessive supply of NO donor l-arginine reversed the α-MSH-induced angiogenesis inhibition in vitro and in vivo. By using antibody neutralization and RNA interference, it was delineated that melanocortin-1 receptor (MC1-R) and melanocortin-2 receptor (MC2-R) participated in α-MSH-induced inhibition of NO production and NF-κB/eNOS/iNOS signaling. This was supported by pharmaceutical inhibition of protein kinase A (PKA), the downstream effector of MC-Rs signaling, using H89 abolished the α-MSH-mediated suppression of NO release and eNOS/iNOS protein level. Therefore, α-MSH exerts anti-angiogenic function by perturbing NO bioavailability and eNOS/iNOS expression in endothelial cells.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , NF-kappa B/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Receptores de Melanocortina/metabolismo , alfa-MSH/uso terapêutico , Células Endoteliais da Veia Umbilical Humana , Humanos , Óxido Nítrico , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos
20.
Cell Physiol Biochem ; 45(2): 505-522, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29402864

RESUMO

BACKGROUND/AIMS: Blood-retinal barrier (BRB) breakdown and vascular leakage is the leading cause of blindness of diabetic retinopathy (DR). Hyperglycemia-induced oxidative stress and inflammation are primary pathogenic factors of this severe DR complication. An effective interventional modality against the pathogenic factors during early DR is needed to curb BRB breakdown and vascular leakage. This study sought to examine the protective effects of α-Melanocyte-stimulating hormone (α-MSH) on early diabetic retina against vascular hyperpermeability, electrophysiological dysfunction, and morphological deterioration in a rat model of diabetes and probe the mechanisms underlying the α-MSH's anti-hyperpermeability in both rodent retinas and simian retinal vascular endothelial cells (RF6A). METHODS: Sprague Dawley rats were injected through tail vein with streptozotocin to induce diabetes. The rats were intravitreally injected with α-MSH or saline at Week 1 and 3 after hyperglycemia. In another 2 weeks, Evans blue assay, transmission electron microscopy, electroretinogram (ERG), and hematoxylin and eosin (H&E) staining were performed to examine the protective effects of α-MSH in diabetic retinas. The expression of pro-inflammatory factors and tight junction at mRNA and protein levels in retinas was analyzed. Finally, the α-MSH's anti-hyperpermeability was confirmed in a high glucose (HG)-treated RF6A cell monolayer transwell culture by transendothelial electrical resistance (TEER) measurement and a fluorescein isothiocyanate-Dextran assay. Universal or specific melanocortin receptor (MCR) blockers were also employed to elucidate the MCR subtype mediating α-MSH's protection. RESULTS: Evans blue assay showed that BRB breakdown and vascular leakage was detected, and rescued by α-MSH both qualitatively and quantitatively in early diabetic retinas; electron microscopy revealed substantially improved retinal and choroidal vessel ultrastructures in α-MSH-treated diabetic retinas; scotopic ERG suggested partial rescue of functional defects by α-MSH in diabetic retinas; and H&E staining revealed significantly increased thickness of all layers in α-MSH-treated diabetic retinas. Mechanistically, α-MSH corrected aberrant transcript and protein expression of pro-inflammatory factor and tight junction genes in the diseased retinas; moreover, it prevented abnormal changes in TEER and permeability in HG-stimulated RF6A cells, and this anti-hyperpermeability was abolished by a universal MCR blocker or an antagonist specific to MC4R. CONCLUSIONS: This study showed previously undescribed protective effects of α-MSH on inhibiting BRB breakdown and vascular leakage, improving electrophysiological functions and morphology in early diabetic retinas, which may be due to its down-regulating pro-inflammatory factors and augmenting tight junctions. α-MSH acts predominantly on MC4R to antagonize hyperpermeability in retinal microvessel endothelial cells.


Assuntos
Barreira Hematorretiniana/metabolismo , Retinopatia Diabética/patologia , alfa-MSH/farmacologia , Animais , Barreira Hematorretiniana/efeitos dos fármacos , Linhagem Celular , Citratos/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/etiologia , Retinopatia Diabética/prevenção & controle , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Potenciais Evocados/efeitos dos fármacos , Glucose/farmacologia , Masculino , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Melanocortina/antagonistas & inibidores , Receptores de Melanocortina/metabolismo , Retina/efeitos dos fármacos , Retina/metabolismo , Retina/patologia , Vasos Retinianos/citologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Citrato de Sódio , Estreptozocina/toxicidade , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , alfa-MSH/uso terapêutico
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