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1.
Expert Opin Drug Metab Toxicol ; 15(10): 787-802, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31512529

RESUMO

Introduction: Drug-drug interactions (DDI) between antiretroviral drugs and drugs for the treatment of metabolic disturbances in people living with human immunodeficiency virus (HIV) (PLWH) have represented a problem of paramount importance in the recent times. The problem has been mainly driven by sharing common metabolizing pathways. This problem has classically been worsened by the frequent use of pharmacokinetic boosters to enhance protease inhibitors and some integrase inhibitors plasma levels. Areas covered: This article focuses on the interactions between antiretroviral drugs and those drugs used to treat metabolic disturbances which frequently appear in PLWH. These include dyslipidemia, diabetes mellitus, hyperuricemia, and finally, drugs for the treatment of overweight and clinical obesity. References from PubMed, Embase, or Web of Science, among others, were reviewed. Expert opinion: The advent of safer drugs, in terms of DDI, in the antiretroviral and the metabolic field,such as non-boosted antiretrovirals and drugs with divergent metabolizing paths. Besides, learning by the caregivers on how to decrease and manage DDI, together with the extensive use of online updated DDI databases, has undoubtedly minimized the problem. The foreseeable increase in the burden of HIV-associated comorbidities and their associated treatments anticipates further complexities in the management of DDI in PLWH.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Interações de Medicamentos , Infecções por HIV/complicações , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Humanos , Doenças Metabólicas/etiologia , Doenças Metabólicas/fisiopatologia
2.
Expert Opin Investig Drugs ; 28(10): 917-930, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31430206

RESUMO

Introduction: Acetyl-CoA Carboxylase (ACC) is an essential rate-limiting enzyme in fatty acid metabolism. For many years, ACC inhibitors have gained great attention for developing therapeutics for various human diseases including microbial infections, metabolic syndrome, obesity, diabetes, and cancer. Areas covered: We present a comprehensive review and update of ACC inhibitors. We look at the current advance of ACC inhibitors in clinical studies and the implications in drug discovery. We searched ScienceDirect ( https://www.sciencedirect.com/ ), ACS ( https://pubs.acs.org/ ), Wiley ( https://onlinelibrary.wiley.com/ ), NCBI ( https://www.ncbi.nlm.nih.gov/ ) and World Health Organization ( https://www.who.int/ ). The keywords used were Acetyl-CoA Carboxylase, lipid, inhibitors and metabolic syndrome. All documents were published before June 2019. Expert opinion: The key regulatory role of ACC in fatty acid synthesis and oxidation pathways makes it an attractive target for various metabolic diseases. In particular, the combination of ACC inhibitors with other drugs is a new strategy for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Expanding the clinical indications for ACC inhibitors will be one of the hot directions in the future. It is also worth looking forward to exploring safe and efficient inhibitors that act on the BC domain of ACC.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Síndrome Metabólica/tratamento farmacológico , Acetil-CoA Carboxilase/metabolismo , Animais , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Inibidores Enzimáticos/efeitos adversos , Ácidos Graxos/metabolismo , Humanos , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/fisiopatologia , Síndrome Metabólica/fisiopatologia
3.
Curr Top Med Chem ; 19(16): 1399-1417, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31284862

RESUMO

The pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor (PAC1R, ADCYAP1R1) is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon family of G protein-coupled receptors (GPCRs). PAC1R has been shown to play crucial roles in the central and peripheral nervous systems. The activation of PAC1R initiates diverse downstream signal transduction pathways, including adenylyl cyclase, phospholipase C, MEK/ERK, and Akt pathways that regulate a number of physiological systems to maintain functional homeostasis. Accordingly, at times of tissue injury or insult, PACAP/PAC1R activation of these pathways can be trophic to blunt or delay apoptotic events and enhance cell survival. Enhancing PAC1R signaling under these conditions has the potential to mitigate cellular damages associated with cerebrovascular trauma (including stroke), neurodegeneration (such as Parkinson's and Alzheimer's disease), or peripheral organ insults. Conversely, maladaptive PACAP/PAC1R signaling has been implicated in a number of disorders, including stressrelated psychopathologies (i.e., depression, posttraumatic stress disorder, and related abnormalities), chronic pain and migraine, and metabolic diseases; abrogating PAC1R signaling under these pathological conditions represent opportunities for therapeutic intervention. Given the diverse PAC1R-mediated biological activities, the receptor has emerged as a relevant pharmaceutical target. In this review, we first describe the current knowledge regarding the molecular structure, dynamics, and function of PAC1R. Then, we discuss the roles of PACAP and PAC1R in the activation of a variety of signaling cascades related to the physiology and diseases of the nervous system. Lastly, we examine current drug design and development of peptides and small molecules targeting PAC1R based on a number of structure- activity relationship studies and key pharmacophore elements. At present, the rational design of PAC1R-selective peptide or small-molecule therapeutics is largely hindered by the lack of structural information regarding PAC1R activation mechanisms, the PACAP-PAC1R interface, and the core segments involved in receptor activation. Understanding the molecular basis governing the PACAP interactions with its different cognate receptors will undoubtedly provide a basis for the development and/or refinement of receptor-selective therapeutics.


Assuntos
Doenças Metabólicas/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Peptídeos/farmacologia , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Humanos , Doenças Metabólicas/metabolismo , Modelos Moleculares , Estrutura Molecular , Doenças do Sistema Nervoso/metabolismo , Peptídeos/síntese química , Peptídeos/química , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/química , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
4.
Handb Exp Pharmacol ; 256: 207-234, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31236687

RESUMO

Farnesoid X receptor controls bile acid metabolism, both in the liver and intestine. This potent nuclear receptor not only maintains homeostasis of its own ligands, i.e., bile acids, but also regulates glucose and lipid metabolism as well as the immune system. These findings have led to substantial interest for FXR as a therapeutic target and to the recent approval of an FXR agonist for treating primary biliary cholangitis as well as ongoing clinical trials for other liver diseases. Given that FXR biology is complex, including moderate expression in tissues outside of the enterohepatic circulation, temporal expression of isoforms, posttranscriptional modifications, and the existence of several other bile acid-responsive receptors such as TGR5, clinical application of FXR modulators warrants thorough understanding of its actions. Recent findings have demonstrated remarkable physiological effects of targeting FXR specifically in the intestine (iFXR), thereby avoiding systemic release of modulators. These include local effects such as improvement of intestinal barrier function and intestinal cholesterol turnover, as well as systemic effects such as improvements in glucose homeostasis, insulin sensitivity, and nonalcoholic fatty liver disease (NAFLD). Intriguingly, metabolic improvements have been observed with both an iFXR agonist that leads to production of enteric Fgf15 and increased energy expenditure in adipose tissues and antagonists by reducing systemic ceramide levels and hepatic glucose production. Here we review the recent findings on the role of intestinal FXR and its targeting in metabolic disease.


Assuntos
Intestinos , Doenças Metabólicas/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Ácidos e Sais Biliares , Humanos , Metabolismo dos Lipídeos
5.
Drugs ; 79(11): 1187-1197, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31243696

RESUMO

Obesity, type 2 diabetes, and the numerous associated metabolic co-morbidities are growing global threats to public health. Despite recent progress in pharmacotherapies for metabolic diseases, the current treatment options have limited efficacy and provide mostly symptomatic relief with little or no impact on disease reversal. Thus, improved therapies are urgently needed. As a result, the scientific community has increasingly invested in leveraging new pathophysiological insights into more efficacious pharmacotherapies for metabolic complications. A heightened understanding of the large, interindividual variation in responsiveness to certain metabolic medicines combined with advances in engineering multi-agonist candidates are important steps towards this goal. Additionally, the emerging pharmacological concept of peptide-mediated targeting of small molecules for tissue-specific delivery holds promise for more powerful treatment solutions in the future. In this review, we summarize recent advances in medicinal chemistry and molecular pharmacology that have enabled the engineering of several, novel, poly-agonist drug candidates for treatment of metabolic diseases, and we discuss the recent results from clinical trials assessing the efficacy and safety of glucagon-like peptide (GLP)-1/glucagon and GLP-1/GIP co-agonists.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/metabolismo , Doenças Metabólicas/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Glucagon/agonistas , Animais , Ensaios Clínicos como Assunto , Quimioterapia Combinada , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Terapia de Alvo Molecular , Medicina de Precisão , Receptores de Glucagon/metabolismo
6.
Inorg Chem ; 58(20): 13528-13545, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31247859

RESUMO

The indispensable requirement for metals in life processes has led to the evolution of sophisticated mechanisms that allow organisms to maintain dynamic equilibria of these ions. This dynamic control of the level, speciation, and availability of a variety of metal ions allows organisms to sustain biological processes while avoiding toxicity. When functioning properly, these mechanisms allow cells to return to their metal homeostatic set points following shifts in the metal availability or other stressors. These periods of transition, when cells are in a state of flux in which they work to regain homeostasis, present windows of opportunity to pharmacologically manipulate targets associated with metal-trafficking pathways in ways that could either facilitate a return to homeostasis and the recovery of cellular function or further push cells outside of homeostasis and into cellular distress. The purpose of this Viewpoint is to highlight emerging opportunities for chemists and chemical biologists to develop compounds to manipulate metal-trafficking processes for therapeutic benefit.


Assuntos
Doenças Metabólicas/tratamento farmacológico , Metais/metabolismo , Neoplasias/tratamento farmacológico , Compostos Orgânicos/farmacologia , Homeostase/efeitos dos fármacos , Humanos , Doenças Metabólicas/metabolismo , Neoplasias/metabolismo
7.
Int J Mol Sci ; 20(12)2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31200447

RESUMO

Several lines of evidence point out the relevance of nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome as a pivotal player in the pathophysiology of several neurological and psychiatric diseases (i.e., Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis, and major depressive disorder), metabolic disorders (i.e., obesity and type 2 diabetes) and chronic inflammatory diseases (i.e., intestinal inflammation, arthritis, and gout). Intensive research efforts are being made to achieve an integrated view about the pathophysiological role of NLRP3 inflammasome pathways in such disorders. Evidence is also emerging that the pharmacological modulation of NLRP3 inflammasome by phytochemicals could represent a promising molecular target for the therapeutic management of neurological, psychiatric, metabolic, and inflammatory diseases. The present review article has been intended to provide an integrated and critical overview of the available clinical and experimental evidence about the role of NLRP3 inflammasome in the pathophysiology of neurological, psychiatric, metabolic, and inflammatory diseases, including PD, AD, MS, depression, obesity, type 2 diabetes, arthritis, and intestinal inflammation. Special attention has been paid to highlight and critically discuss current scientific evidence on the effects of phytochemicals on NLRP3 inflammasome pathways and their potential in counteracting central neuroinflammation, metabolic alterations, and immune/inflammatory responses in such diseases.


Assuntos
Anti-Inflamatórios/farmacologia , Doenças do Sistema Nervoso Central/tratamento farmacológico , Inflamassomos/metabolismo , Doenças Metabólicas/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Compostos Fitoquímicos/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Humanos , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Compostos Fitoquímicos/uso terapêutico
8.
Nat Commun ; 10(1): 1981, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31040273

RESUMO

Cardiovascular and metabolic disease (CMD) remains a main cause of premature death worldwide. Berberine (BBR), a lipid-lowering botanic compound with diversified potency against metabolic disorders, is a promising candidate for ameliorating CMD. The liver is the target of BBR so that liver-site accumulation could be important for fulfilling its therapeutic effect. In this study a rational designed micelle (CTA-Mic) consisting of α-tocopheryl hydrophobic core and on-site detachable polyethylene glycol-thiol shell is developed for effective liver deposition of BBR. The bio-distribution analysis proves that the accumulation of BBR in liver is increased by 248.8% assisted by micelles. Up-regulation of a range of energy-related genes is detectable in the HepG2 cells and in vivo. In the high fat diet-fed mice, BBR-CTA-Mic intervention remarkably improves metabolic profiles and reduces the formation of aortic arch plaque. Our results provide proof-of-concept for a liver-targeting strategy to ameliorate CMD using natural medicines facilitated by Nano-technology.


Assuntos
Berberina/farmacologia , Hipoglicemiantes/uso terapêutico , Nanotecnologia/métodos , Animais , Células CACO-2 , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/tratamento farmacológico , Células Hep G2 , Humanos , Hipoglicemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/tratamento farmacológico , Camundongos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
9.
Top Antivir Med ; 27(1): 34-40, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31137001

RESUMO

The 2019 Conference on Retroviruses and Opportunistic Infections provided a considerable amount of new information on the progress in implementation of strategies to reduce morbidity and mortality from complications and coinfections that occur in people with HIV infection, and on the clinical management of these important problems. This review will address new insights into the prevention and treatment of tuberculosis, fungal infections, sexually transmitted infections, malignancies, and a range of metabolic complications and noncommunicable diseases.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Coinfecção/epidemiologia , Infecções por HIV/complicações , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Coinfecção/diagnóstico , Coinfecção/tratamento farmacológico , Coinfecção/prevenção & controle , Humanos , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/prevenção & controle , Micoses/diagnóstico , Micoses/tratamento farmacológico , Micoses/prevenção & controle , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/prevenção & controle
10.
J Med Food ; 22(5): 469-478, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31084539

RESUMO

Aging and lifestyle factors, including high-sugar and high-fat diets, promote a systemic metabolic imbalance that promotes neurodegeneration. Hericium erinaceus has long been used in traditional Chinese medicine. Recently, its functional activities, such as antimetabolic dysfunction, antineuroinflammatory activities, and stimulation of nerve growth factor (NGF) synthesis, have been revealed. This study demonstrated that Hericium erinaceus mycelium (HEM) and an isolated diterpenoid derivative, erinacine A (EA), may reverse spatial learning disabilities in aging mice (15 months old) fed with a high-fat and high-sucrose diet (HFSD). Aging mice were randomly assigned to one of four treatment groups: (1) a chow diet (control), (2) an HFSD, and an HFSD supplemented with either (3) HEM or (4) EA for 18 weeks. The Morris water maze (MWM) and Y-maze were used for behavioral assessments. Both HEM- and EA-treated mice had shorter mean daily escape latencies than HFSD-treated mice in the MWM. In addition, HEM-treated mice had a slightly increased exploratory time and frequency in the novel arm in the Y-maze. Quantitative PCR revealed that both HEM- and EA-treated mice exhibited reduced messenger RNA (mRNA) expression of tumor necrosis factor-α, interleukin-1ß, and HEM-treated mice exhibited increased mRNA expression of NGF and NeuN in the hippocampus. Moreover, HEM and EA also decreased body weight, abdominal fat, plasma glucose, serum and liver total cholesterol, and liver triacylglycerol. Thus, HEM may be a potential health-promoting supplement for minimizing the progression of aging and obesity-induced neurodegeneration by reducing metabolic abnormalities and neuroinflammatory cytokines and increasing neurogenesis factors.


Assuntos
Envelhecimento/efeitos dos fármacos , Basidiomycota/química , Dieta Hiperlipídica/efeitos adversos , Diterpenos/administração & dosagem , Doenças Metabólicas/tratamento farmacológico , Sacarose/efeitos adversos , Envelhecimento/metabolismo , Envelhecimento/psicologia , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Masculino , Aprendizagem em Labirinto , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/psicologia , Camundongos , Camundongos Endogâmicos C57BL , Micélio/química , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Aprendizagem Espacial/efeitos dos fármacos
11.
Int J Mol Sci ; 20(9)2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31052427

RESUMO

Biological membranes are key elements for the maintenance of cell architecture and physiology. Beyond a pure barrier separating the inner space of the cell from the outer, the plasma membrane is a scaffold and player in cell-to-cell communication and the initiation of intracellular signals among other functions. Critical to this function is the plasma membrane compartmentalization in lipid microdomains that control the localization and productive interactions of proteins involved in cell signal propagation. In addition, cells are divided into compartments limited by other membranes whose integrity and homeostasis are finely controlled, and which determine the identity and function of the different organelles. Here, we review current knowledge on membrane lipid composition in the plasma membrane and endomembrane compartments, emphasizing its role in sustaining organelle structure and function. The correct composition and structure of cell membranes define key pathophysiological aspects of cells. Therefore, we explore the therapeutic potential of manipulating membrane lipid composition with approaches like membrane lipid therapy, aiming to normalize cell functions through the modification of membrane lipid bilayers.


Assuntos
Membrana Celular/efeitos dos fármacos , Ácidos Graxos Insaturados/farmacologia , Lipídeos de Membrana/química , Doenças Metabólicas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Compartimento Celular , Membrana Celular/química , Membrana Celular/metabolismo , Ácidos Graxos Insaturados/uso terapêutico , Humanos , Lipídeos de Membrana/metabolismo
12.
Genomics Proteomics Bioinformatics ; 17(1): 64-75, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31026583

RESUMO

Inulin has been used as a prebiotic to alleviate glucose and lipid metabolism disorders in mice and humans by modulating the gut microbiota. However, the mechanism underlying the alleviation of metabolic disorders by inulin through interactions between the gut microbiota and host cells is unclear. We use ob/ob mice as a model to study the effect of inulin on the cecal microbiota by 16S rRNA gene amplicon sequencing and its interaction with host cells by transcriptomics. The inulin-supplemented diet improved glucose and lipid metabolism disorder parameters in ob/ob mice, alleviating fat accumulation and glucose intolerance. The α diversity of gut microbial community of ob/ob mice was reduced after inulin treatment, while the ß diversity tended to return to the level of wild type mice. Interestingly, Prevotellaceae UCG 001 (family Prevotellaceae) was obviously enriched after inulin treatment. A comparative analysis of the gene expression profile showed that the cecal transcriptome was changed in leptin gene deficiency mice, whereas the inulin-supplemented diet partially reversed the changes in leptin gene-related signaling pathways, especially AMPK signaling pathway, where the levels of gene expression became comparable to those in wild type mice. Further analysis indicated that Prevotellaceae UCG 001 was positively correlated with the AMPK signaling pathway, which was negatively correlated with markers of glycolipid metabolism disorders. Our results suggest that the inulin-supplemented diet alleviates glucose and lipid metabolism disorders by partially restoring leptin related pathways mediated by gut microbiota.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Inulina/uso terapêutico , Leptina/genética , Doenças Metabólicas/tratamento farmacológico , Prebióticos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ceco/enzimologia , Ceco/metabolismo , Ceco/microbiologia , Masculino , Doenças Metabólicas/enzimologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/microbiologia , Camundongos , Camundongos Obesos , Transdução de Sinais/efeitos dos fármacos , Transcriptoma
13.
Molecules ; 24(6)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884797

RESUMO

As a cellular bile acid sensor, farnesoid X receptor (FXR) and the membrane G-coupled receptor (GPBAR1) participate in maintaining bile acid, lipid, and glucose homeostasis. To date, several selective and dual agonists have been developed as promising pharmacological approach to metabolic disorders, with most of them possessing an acidic conjugable function that might compromise their pharmacokinetic distribution. Here, guided by docking calculations, nonacidic 6-ethyl cholane derivatives have been prepared. In vitro pharmacological characterization resulted in the identification of bile acid receptor modulators with improved pharmacokinetic properties.


Assuntos
Colanos/química , Doenças Metabólicas/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Acoplados a Proteínas-G/agonistas , Ácidos e Sais Biliares/metabolismo , Colanos/síntese química , Colanos/farmacocinética , Glucose/metabolismo , Células HEK293 , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação Proteica/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Relação Estrutura-Atividade
14.
Mar Drugs ; 17(3)2019 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-30857204

RESUMO

Phlorotannins are phloroglucinol-based phenolic compounds, occurring particularly in brown macroalgae, that have been recognized for their promising bioactive properties. In this study, the extraction of phlorotannins from Fucus vesiculosus was evaluated with particular emphasis on the influential parameters, including the solvent concentration, solvent-solid ratio, extraction temperature and extraction time, using a single-factor design followed by a Box-Behnken design. The maximum total phlorotannin content, determined using the 2,4-dimethoxybenzaldehyde (DMBA) method, corresponded to 2.92 ± 0.05 mg of phloroglucinol equivalents/g dry seaweed (mg PGE/g DS), and was achieved for extracts carried out with acetone 67% (v/v), a solvent-solid ratio of 70 mL/g and temperature at 25 °C. This crude extract, together with a semi-purified phlorotannin fraction, were further evaluated for their anti-enzymatic capacity against α-glucosidase, α-amylase and pancreatic lipase, both showing promising inhibitory effects, particularly against α-glucosidase for which a greater inhibitory effect was observed compared to the pharmaceutical drug acarbose (IC50 = 4.5 ± 0.8 and 0.82 ± 0.3 µg/mL, respectively, against 206.6 ± 25.1 µg/mL). Additionally, the ultra-high-pressure liquid chromatography coupled to mass spectrometry (UHPLC-MS) analysis carried out on the ethyl acetate fraction revealed the presence of fucols, fucophlorethols, fuhalols and several other phlorotannin derivatives. Moreover, possible new phlorotannin compounds, including fucofurodiphlorethol, fucofurotriphlorethol and fucofuropentaphlorethol, have been tentatively identified in this extract. Overall, this study provides evidence that F. vesiculosus phlorotannin-rich extracts hold potential for the management of the activity of α-glucosidase, α-amylase and pancreatic lipase, which are well known to be linked to metabolic disorders such as diabetes and obesity.


Assuntos
Inibidores Enzimáticos/farmacologia , Fucus/química , Extratos Vegetais/farmacologia , Alga Marinha/química , Taninos/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Ensaios Enzimáticos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/uso terapêutico , Lipase/antagonistas & inibidores , Lipase/metabolismo , Espectrometria de Massas , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Floroglucinol/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Taninos/química , Taninos/isolamento & purificação , Taninos/uso terapêutico , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Glucosidases/metabolismo
15.
Biomed Pharmacother ; 114: 108781, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30903919

RESUMO

AIMS: Activation of brown adipose tissue (BAT) thermogenesis could contribute to energy expenditure, which is critical for the treatment of obesity and type 2 diabetes mellitus (T2DM). In the present study, we aimed to systematically investigate whether traditional Chinese medication Jinlida (JLD) granules could improve metabolic disorders and activate BAT thermogenesis in C57BL/6 J mice fed with a high-fat diet (HFD). METHODS: In the present study, JLD (3.8 g/kg) in 0.5% of carboxymethyl cellulose (CMC) solution was administrated daily by oral gavage to HFD-induced mice for 15 weeks. The body weight, biochemical analysis, histology analysis, intraperitoneal glucose and insulin tolerance (OGTT and ITT) tests were measured to explore metabolic disorders. Cold tolerance test, real-time PCR (qRT-PCR), immunohistochemistry, and western blot were performed to evaluate BAT function. RESULTS: As results, JLD treatment significantly ameliorated HFD-induced obesity and fat mass gain, maintained glucose and lipid homeostasis, and improved hepatic steatosis and inflammation. More importantly, we observed that JLD markedly activated BAT thermogenesis in HFD-induced obese mice. Moreover, our data confirmed that JLD promoted mitochondrial biogenesis and fatty acid oxidation metabolism in BAT. CONCLUSIONS: These data suggested that JLD could improve metabolic disorders in associated with activation of BAT thermogenesis via enhancement of mitochondrial biogenesis and fatty acid oxidation metabolism, thus providing a new pharmacological evidence for the clinical usage of JLD in T2DM treatment.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Doenças Metabólicas/tratamento farmacológico , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Termogênese/efeitos dos fármacos
16.
BMJ Case Rep ; 12(3)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30904888

RESUMO

An 8-month-old boy presented to hospital with a fever, irritability and 'back arching'. On examination, he demonstrated profound opisthotonic posturing and had tonsillitis. He had a full septic screen and was treated with broad spectrum antibiotics. Blood tests showed a transaminitis, raised alpha fetoprotein and deranged clotting. The clotting abnormalities and raised alpha fetoprotein persisted post discharge and an abdominal ultrasound showed steatosis, splenomegaly and bilateral increased renal cortical reflectivity. A full metabolic screen revealed type 1 tyrosinaemia. The opisthotonic posturing, a major part of this child's presentation, has not been reported as a presenting feature of tyrosinaemia. It was part of a 'neurological crisis' caused by tyrosinaemia and exacerbated by the intercurrent infection. These are known to occur in tyrosinaemia but not commonly as the first presentation. This represents an unusual presentation of a metabolic condition which, without intervention, can lead to severe hepatic, renal and neurodevelopmental complications.


Assuntos
Doenças Metabólicas/diagnóstico , Esplenomegalia/diagnóstico , Tonsilite/diagnóstico , Cicloexanonas/administração & dosagem , Cicloexanonas/uso terapêutico , Dieta com Restrição de Proteínas , Gerenciamento Clínico , Febre/etiologia , Humanos , Lactente , Masculino , Doenças Metabólicas/complicações , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Nitrobenzoatos/administração & dosagem , Nitrobenzoatos/uso terapêutico , Esplenomegalia/etiologia , Tonsilite/etiologia
17.
J Enzyme Inhib Med Chem ; 34(1): 405-419, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30734596

RESUMO

The increase in non-communicable chronic diseases has aroused interest in the research of adjuvants to the classic forms of treatments. Obesity and metabolic syndrome are the main targets of confrontation because they relate directly to other chronic diseases. In this context, trypsin inhibitors, molecules with wide heterologous application, appear as possibilities in the treatment of overweight and obesity due to the action on satiety related mechanisms, mainly in the modulation of satiety hormones, such as cholecystokinin. In addition, trypsin inhibitors have the ability to also act on some biochemical parameters related to these diseases, thus, emerging as potential candidates and promising molecules in the treatment of the obesity and metabolic syndrome. Thus, the present article proposes to approach, through a systematic literature review, the advantages, disadvantages and viabilities for the use of trypsin inhibitors directed to the treatment of overweight and obesity.


Assuntos
Doenças Metabólicas/tratamento farmacológico , Obesidade/tratamento farmacológico , Inibidores da Tripsina/farmacologia , Tripsina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Inibidores da Tripsina/síntese química , Inibidores da Tripsina/química
18.
World J Gastroenterol ; 25(7): 859-869, 2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30809085

RESUMO

BACKGROUND: Disorders of primary bile acid synthesis may be life-threatening if undiagnosed, or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5ß-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid (CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic acid, which is currently unavailable in China. AIM: To evaluate the therapeutic responses of patients with AKR1D1 deficiency to oral bile acid therapy, specifically CDCA. METHODS: Twelve patients with AKR1D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in AKR1D1, were treated with differing doses of CDCA or ursodeoxycholic acid (UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters, notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry. RESULTS: Physical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA. CONCLUSION: The primary bile acid CDCA is effective in treating AKR1D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.


Assuntos
Ácido Quenodesoxicólico/administração & dosagem , Fármacos Gastrointestinais/administração & dosagem , Doenças Metabólicas/tratamento farmacológico , Oxirredutases/deficiência , Ácido Ursodesoxicólico/administração & dosagem , Administração Oral , Ácido Quenodesoxicólico/efeitos adversos , Análise Mutacional de DNA , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Fármacos Gastrointestinais/efeitos adversos , Humanos , Recém-Nascido , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/urina , Mutação , Oxirredutases/genética , Estudos Retrospectivos , Resultado do Tratamento , Ácido Ursodesoxicólico/efeitos adversos
20.
Trends Pharmacol Sci ; 40(2): 142-153, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30616873

RESUMO

Endocrine fibroblast growth factors (eFGFs) control pathways that are crucial for maintaining metabolic homeostasis of lipids, glucose, energy, bile acids, and minerals. Unlike the heparin-binding paracrine FGFs, eFGFs require a unique Klotho family protein to form a productive triad complex, but the structural and mechanistical details of this complex have remained obscure since the beginning of the eFGF field. However, recent breakthroughs in resolving the 3D structures of eFGF signaling complexes have now unveiled the atomic details of multivalent interactions among eFGF, FGFR, and Klotho. We provide here a timely review on the architecture and the structure-function relationships of these complexes, and highlight how the structural knowledge opens a new door to structure-based drug design against a repertoire of eFGF-associated metabolic diseases.


Assuntos
Fatores de Crescimento de Fibroblastos/química , Fatores de Crescimento de Fibroblastos/metabolismo , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Animais , Desenho de Drogas , Sistema Endócrino/metabolismo , Glucuronidase/química , Glucuronidase/metabolismo , Humanos , Receptores de Fatores de Crescimento de Fibroblastos/química , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Relação Estrutura-Atividade
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