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1.
Lancet Gastroenterol Hepatol ; 8(2): 179-191, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36620987

RESUMO

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that stimulate insulin secretion from pancreatic ß cells in response to food ingestion. Modified GLP-1 and GIP peptides are potent agonists for their incretin receptors, and some evidence shows that the dual GLP-1 and GIP receptor agonist tirzepatide is effective in promoting marked weight loss. GLP-1 receptor agonists signal in the CNS to suppress appetite, increase satiety, and thereby decrease calorie intake, but many other effects of incretin signalling have been recognised that are relevant to the treatment of non-alcoholic fatty liver disease (NAFLD). This Review provides an overview of the literature supporting the notion that endogenous incretins and incretin-receptor agonist treatments are important not only for decreasing risk of developing NAFLD, but also for treating NAFLD and NAFLD-related complications. We discuss incretin signalling and related incretin-receptor agonist treatments, mechanisms in key relevant tissues affecting liver disease, and clinical data from randomised controlled trials. Finally, we present future perspectives in this rapidly developing field of research and clinical medicine.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Incretinas/uso terapêutico , Incretinas/farmacologia , Incretinas/fisiologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/complicações , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon
2.
J Chin Med Assoc ; 86(1): 39-46, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36599141

RESUMO

BACKGROUND: Hyperglycemia-induced advanced glycation end products (AGEs) and receptor for AGEs (RAGEs) play major roles in diabetic nephropathy progression. In previous study, both glucagon-like peptide-1 (GLP-1) and peroxisome proliferator-activated receptors delta (PPARδ) agonists were shown to have anti-inflammatory effect on AGE-treated rat mesangial cells (RMCs). The interaction among PPARδ agonists, GLP-1, and AGE-RAGE axis is, however, still unclear. METHODS: In this study, the individual and synergic effect of PPARδ agonist (L-165 041) and siRNA of GLP-1 receptor (GLP-1R) on the expression of GLP-1, GLP-1R, RAGE, and cell viability in AGE-treated RMCs were investigated. RESULTS: L-165 041 enhanced GLP-1R mRNA and protein expression only in the presence of AGE. The expression of RAGE mRNA and protein was enhanced by AGE, attenuated by L-165 041, and siRNA of GLP-1R reversed L-165 041-induced inhibition. Cell viability was also inhibited by AGE. L-165 041 attenuated AGE-induced inhibition and siRNA GLP-1R diminished L-165 041 effect. CONCLUSION: PPARδ agonists increase GLP-1R expression on RMC in the presence of AGE. PPARδ agonists also attenuate AGE-induced upregulated RAGE expression and downregulated cell viability. The effect of PPARδ agonists needs the cooperation of GLP-1R activation.


Assuntos
Células Mesangiais , PPAR delta , Ratos , Animais , Células Mesangiais/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Produtos Finais de Glicação Avançada/farmacologia , Produtos Finais de Glicação Avançada/metabolismo , PPAR delta/agonistas , PPAR delta/metabolismo , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/farmacologia , RNA Mensageiro
3.
Nat Commun ; 14(1): 376, 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36690613

RESUMO

The M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled receptor (GPCR) that serves as a model system for understanding GPCR regulation by both orthosteric and allosteric ligands. Here, we investigate the mechanisms governing M2R signaling versatility using cryo-electron microscopy (cryo-EM) and NMR spectroscopy, focusing on the physiological agonist acetylcholine and a supra-physiological agonist iperoxo, as well as a positive allosteric modulator LY2119620. These studies reveal that acetylcholine stabilizes a more heterogeneous M2R-G-protein complex than iperoxo, where two conformers with distinctive G-protein orientations were determined. We find that LY2119620 increases the affinity for both agonists, but differentially modulates agonists efficacy in G-protein and ß-arrestin pathways. Structural and spectroscopic analysis suggest that LY211620 stabilizes distinct intracellular conformational ensembles from agonist-bound M2R, which may enhance ß-arrestin recruitment while impairing G-protein activation. These results highlight the role of conformational dynamics in the complex signaling behavior of GPCRs, and could facilitate design of better drugs.


Assuntos
Acetilcolina , Receptores Muscarínicos , Microscopia Crioeletrônica , Regulação Alostérica/fisiologia , Receptores Muscarínicos/metabolismo , Receptor Muscarínico M2/agonistas , Receptor Muscarínico M2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Ligantes , beta-Arrestinas/metabolismo
4.
Molecules ; 28(1)2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36615540

RESUMO

The κ-opioid receptor (KOR) has recently emerged as an alternative therapeutic target for the development of pain medications, without deleterious side effects associated with the µ-opioid receptor (MOR). However, modulation of KOR is currently under investigation for the treatment of depression, mood disorders, psychiatric comorbidity, and specific drug addictions. However, KOR agonists also trigger adverse effects including sedation, dysphoria, and hallucinations. In this respect, there is currently much debate on alternative paradigms. Recent effort has been devoted in search of biased ligands capable of selectively activating favorable signaling over signaling associated with unwanted side effects. On the other hand, the use of partial agonists is expected to allow the analgesia to be produced at dosages lower than those required to produce the adverse effects. More empirically, the unwanted central effects can be also avoided by using peripherally restricted agonists. In this review, we discuss the more recent trends in the design of KOR-selective, biased or partial, and finally, peripherally acting agonists. Special emphasis is given on the discussion of the most recent approaches for controlling functional selectivity of KOR-specific ligands.


Assuntos
Analgesia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Ligantes , Dor/tratamento farmacológico , Receptores Opioides kappa/agonistas , Transdução de Sinais , Analgésicos Opioides/efeitos adversos
5.
Molecules ; 28(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36615612

RESUMO

Pain is a common clinical symptom among patients. Although various opioid analgesics have been developed, their side effects hinder their application. This study aimed to develop a novel opioid analgesic, HAGD (H-Tyr-D-AIa-GIy-Phe-NH2), with limited side effects. In vivo studies on mouse models as well as in vitro studies on Chinese hamster ovary (CHO) cells expressing human mu, delta, or kappa opioid receptors (CHOhMOP, CHOhDOP, and CHOhKOP, respectively) and human sperm were conducted. Compared with subcutaneous morphine (10 mg/kg), subcutaneous HAGD (10 mg/kg) produced equipotent or even greater antinociception with a prolonged duration by activating mu/delta opioid receptors in preclinical mouse pain models. The analgesic tolerance, rewarding effects (i.e., conditioned place preference and acute hyperlocomotion), and gastrointestinal transit inhibition of HAGD were significantly reduced compared with those of morphine. Both HAGD and morphine exhibited a withdrawal response and had no impacts on motor coordination. In CHOhMOP and CHOhDOP, HAGD showed specific and efficient intracellular Ca2+ stimulation. HAGD had minimal impact on human sperm motility in vitro, whereas 1 × 10-7 and 1 × 10-8 mol/L of morphine significantly declined sperm motility at 3.5 h. Overall, HAGD may serve as a promising antinociceptive compound.


Assuntos
Analgésicos Opioides , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Cricetinae , Humanos , Masculino , Camundongos , Animais , Analgésicos Opioides/efeitos adversos , Receptores Opioides delta , Células CHO , Motilidade Espermática , Cricetulus , Sêmen , Morfina/efeitos adversos , Dor/induzido quimicamente , Dor/tratamento farmacológico , Receptores Opioides mu/agonistas
6.
Rev Med Liege ; 78(1): 40-45, 2023 Jan.
Artigo em Francês | MEDLINE | ID: mdl-36634066

RESUMO

Glucagon-like peptide-1 (GLP-1) receptor agonists have a privileged place in the management of type 2 diabetes (T2D). They not only improve glucose control without inducing hypoglycaemia and trigger weight loss, but also protect against atherosclerotic cardiovascular disease. Increasing the dose of three of them (liraglutide, semaglutide, dulaglutide) allows better glycaemic results and of potential interest a greater weight reduction. Liraglutide at a daily dose of 3.0 mg and semaglutide at a weekly dose of 2.4 mg received the indication for the therapy of obesity. A recent innovation consists in the development of dual unimolecular agonists that target GLP-1 and GIP («glucose-dependent insulinotropic polypeptide¼) receptors (tirzepatide) or GLP-1 and glucagon receptors (cotadutide). Tirzepatide, in the SURPASS programme, showed impressive reductions in glycated haemoglobin level and body weight, greater than those observed with dulaglutide or semaglutide. Tirzepatide received the indication of the treatment of T2D and is currently tested in obesity (SURMOUNT programme). Interestingly, triagonists GIP/GLP-1/glucagon are currently developed for the management of T2D and obesity, with also perspectives for treating metabolic-associated fatty liver disease.


Les agonistes du glucagon-like peptide-1 (GLP-1) ont une place de choix dans la prise en charge des patients avec un diabète de type 2 (DT2). Non seulement ils améliorent le contrôle glycémique sans provoquer des hypoglycémies et font perdre du poids, mais ils protègent également contre les maladies cardiovasculaires athéromateuses. Une augmentation de la posologie de trois d'entre eux (liraglutide, sémaglutide, dulaglutide) a permis de meilleurs résultats glycémiques et surtout une plus grande perte pondérale. Le liraglutide, à la dose de 3,0 mg/jour, et le sémaglutide, à la dose de 2,4 mg/semaine, ont d'ailleurs reçu l'indication pour le traitement de l'obésité. Une innovation récente consiste dans le développement d'agonistes unimoléculaires doubles ciblant les récepteurs du GLP-1 et du GIP («glucose-dependent insulinotropic polypeptide¼) (tirzépatide) ou les récepteurs du GLP-1 et du glucagon (cotadutide). Le tirzépatide, dans le programme SURPASS, a montré des réductions importantes du taux d'hémoglobine glyquée et du poids corporel, supérieures à celles observées avec le dulaglutide ou le sémaglutide. Il a reçu l'indication du traitement du DT2 et est actuellement testé dans l'obésité (programme SURMOUNT). Des triagonistes GIP/GLP-1/glucagon sont également développés pour le traitement du DT2 et de l'obésité, avec des perspectives également dans la stéatopathie hépatique.


Assuntos
Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Redução de Peso , Obesidade/tratamento farmacológico
7.
Platelets ; 34(1): 2159019, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36636835

RESUMO

Increased platelet destruction is central in the pathogenesis of immune thrombocytopenia. However, impaired platelet production is also relevant and its significance underlies the rationale for treatment with thrombopoietin receptor agonists (TPO-RAs). Previous studies have associated enhanced complement activation with increased disease severity. Additionally, treatment refractoriness has been demonstrated to resolve by the administration of complement-targeted therapeutics in a subset of patients. The association between complement activation and the platelet response to TPO-RA therapy has previously not been investigated. In this study, blood samples from patients with immune thrombocytopenia (n = 15) were prospectively collected before and two, six and 12 weeks after the initiation of TPO-RA therapy. Plasma levels of complement degradation product C4d and soluble terminal complement complexes were assessed. Patients with significantly elevated baseline levels of terminal complement complexes exhibited more often an inadequate platelet response (p = .04), were exclusively subjected to rescue therapy with intravenous immunoglobulin (p = .02), and did not respond with a significant platelet count increase during the study period. C4d showed a significant (p = .01) ability to distinguish samples with significant terminal complement activation, implying engagement of the classical complement pathway. In conclusion, elevated levels of complement biomarkers were associated with a worse TPO-RA treatment response. Larger studies are needed to confirm these results. Biomarkers of complement activation may prove valuable as a prognostic tool to predict which patients that potentially could benefit from complement-inhibiting therapy in the future.


What is the context?Primary immune thrombocytopenia (ITP) is a potentially serious illness associated with an increased risk of bleeds. Manifestations range from confined skin bruising to life-threatening intracranial hemorrhages.It is an acquired immune disorder characterized by increased destruction and impaired production of platelets.Treatments aim at suppressing the destruction and supporting the production of platelets.Thrombopoietin receptor agonists (TPO-RA) are medically approved platelet growth factors that contribute to the generation of new platelets.The complement system is an evolutionary preserved part of innate immunity.Previous studies have indicated that complement activation may be an important contributor to disease and that the administration of complement-inhibiting therapy improves the platelet count in a subset of patients with primary ITP.What is new? The potential association between complement activation and a poor platelet response to TPO-RA therapy in primary ITP has not been previously studied.In fifteen patients with primary ITP starting TPO-RA therapy, we prospectively followed the platelet response and levels of complement biomarkers for 12 weeks.We showed that patients with high levels of complement biomarkers exhibited a worse treatment response during the study period.What is the impact?Our results suggest that levels of complement biomarkers may be valuable to predict which patients with treatment-refractory ITP that potentially could benefit from complement-inhibiting therapy in the futureLarger studies are needed to confirm our results.


Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Receptores de Trombopoetina/agonistas , Estudos Prospectivos , Biomarcadores , Ativação do Complemento , Trombopoetina/farmacologia , Trombopoetina/uso terapêutico , Proteínas Recombinantes de Fusão
8.
Eur J Med Res ; 28(1): 28, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36642707

RESUMO

BACKGROUND: Progestins can suppress endogenous luteinising hormone (LH) secretion from the pituitary gland and have shown similar efficacy in terms of collecting competent oocytes and embryos; however, some inconsistencies have been proposed regarding the quality of embryos collected with the use of progestins. This study aimed to evaluate euploidy rates and pregnancy outcomes in preimplantation genetic testing for aneuploidy (PGT-A) cycles using the progestin-primed ovarian stimulation (PPOS) protocol versus the gonadotropin-releasing hormone (GnRH) agonist/antagonist protocol. METHODS: This retrospective cohort study included 608 PGT-A cycles: 146 women in the PPOS group, 160 women in the GnRH agonist group, and 302 women in the GnRH antagonist group. This study was performed at the in vitro fertilisation (IVF) centre of Shanghai First Maternity and Infant Hospital between January 2019 and December 2021. Additionally, 267 corresponding first frozen embryo transfer (FET) cycles were analysed to assess pregnancy outcomes. RESULTS: The euploid blastocyst rate per injected metaphase II(MII) oocytes (14.60% vs. 14.09% vs. 13.94%) was comparable among the three groups (p > 0.05). No significant differences were observed among the three groups regarding pregnancy outcomes, including biochemical pregnancy, clinical pregnancy, ongoing pregnancy, implantation, miscarriage, ectopic pregnancy, and live birth rates per transfer in the first FET cycles (p > 0.05). CONCLUSIONS: The PPOS protocol had no negative effect on euploid blastocyst formation, and the pregnancy outcomes in FET cycles using the PPOS protocol were similar to those of the GnRH agonist and antagonist protocols. Trial registration This trial was retrospectively registered.


Assuntos
Aneuploidia , Testes Genéticos , Progestinas , Feminino , Humanos , Gravidez , China , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Estudos Retrospectivos , Esteroides , Resultado da Gravidez , Técnicas de Reprodução Assistida
9.
J Mol Model ; 29(2): 35, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36626012

RESUMO

OBJECTIVE: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in both men and women. Toll-like receptor 5 (TLR5), an autoimmune signaling receptor that plays a role in cancer, can be exploited for the suppression of human colon cancer. Salmonella flagellin protein, a novel agonist of TLR5 activating downstream signaling, could be a basis for designing anticancer peptides. METHODS: The three-dimensional crystal structure of TLR5 (PDB ID: 3J0A, Resolution = 26.0 Å) was optimized using the AMBER force field in the YASARA suit. In silico enzymatic digestion tool, PeptideCutter, was used to identify peptides from Salmonella flagellin, an agonist against human TLR5. The 3D structure of the peptides was generated using PEP-FOLD3. These peptides were screened against human TLR5 using shape complementarity principles based on the binding affinity and interactions with the active residue of TLR5 monomer, and the selected peptides were further validated by molecular dynamic (MD) simulation. RESULTS: In this study, we generated 42 peptides from Salmonella flagellin protein by in silico protein digestion. Then, based on a new hidden Markov model sub-optimal conformation sampling approach as well as the size of the fragments, we select 38 effective peptides from these 42 cleavages. These peptides were screened against the monomeric Xray structure of human TLR5 using shape complementarity principles. Based on the binding affinity and interactions with the active residue of TLR5 monomer (residues 294 and 366 of TLR5), nine top-scored peptides were selected for the initial molecular dynamic (MD) simulation. Among these peptides, Clv10, Clv17, and Clv28 showed high stability and less flexibility during MD simulation. A 1 µs MD simulation was performed on TLR5-Clv10, TLR-Clv17, and TLR5-Clv28 complexes to further analyze the stability, conformational changes, and binding mode (Clv10, Clv17, and Clv28). During this MD study, the peptides showed high salt bridges and ionic interactions with residue ASP294 and residue ASP366 throughout the simulation and remained in the concave of the human TLR5 monomer. The RMSD and Rg values showed that the peptide-protein complexes become stable after 200 ns of contraction and extraction. CONCLUSION: These findings can facilitate the rational design of selected peptides as an agonist of TLR5, which have antitumor activity, suppress colorectal cancer tumors, and can be used as promising candidates and novel agonists of TLR5.


Assuntos
Neoplasias Colorretais , Receptor 5 Toll-Like , Masculino , Humanos , Feminino , Receptor 5 Toll-Like/agonistas , Receptor 5 Toll-Like/metabolismo , Flagelina/farmacologia , Flagelina/química , Flagelina/metabolismo , Ligação Proteica , Transdução de Sinais , Peptídeos/farmacologia , Peptídeos/metabolismo , Neoplasias Colorretais/tratamento farmacológico
10.
Commun Biol ; 6(1): 31, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36635337

RESUMO

Primary and adaptive resistance to immune checkpoint therapies (ICT) represent a considerable obstacle to achieving enhanced overall survival. Innate immune activators have been actively pursued for their antitumor potential. Herein we report that a syngeneic 4T1 mammary carcinoma murine model for established highly-refractory triple negative breast cancer showed enhanced survival when treated intra-tumorally with either the TLR5 agonist flagellin or CBLB502, a flagellin derivative, in combination with antibodies targeting CTLA-4 and PD-1. Long-term survivor mice showed immunologic memory upon tumor re-challenge and a distinctive immune activating cytokine profile that engaged both innate and adaptive immunity. Low serum levels of G-CSF and CXCL5 (as well as high IL-15) were candidate predictive biomarkers correlating with enhanced survival. CBLB502-induced enhancement of ICT was also observed in poorly immunogenic B16-F10 melanoma tumors. Combination immune checkpoint therapy plus TLR5 agonists may offer a new therapeutic strategy to treat ICT-refractory solid tumors.


Assuntos
Melanoma Experimental , Receptor 5 Toll-Like , Animais , Camundongos , Imunidade Adaptativa , Citocinas , Flagelina/farmacologia , Melanoma Experimental/tratamento farmacológico , Receptor 5 Toll-Like/agonistas
11.
Anesth Analg ; 136(2): 373-386, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36638515

RESUMO

BACKGROUND: Increasing attention has been attracted to the development of bifunctional compounds to minimize the side effects of opioid analgesics. Pharmacological studies have verified the functional interaction between opioid and cannabinoid systems in pain management, suggesting that coactivation of the opioid and cannabinoid receptors may provide synergistic analgesia with fewer adverse reactions. Herein, we developed and characterized a novel bifunctional compound containing the pharmacophores of the mu-opioid receptor agonist DALDA and the cannabinoid peptide VD-Hpα-NH2, named OCP002. METHODS: The opioid and cannabinoid agonistic activities of OCP002 were investigated in calcium mobilization and western blotting assays, respectively. Moreover, the central and peripheral antinociceptive effects of OCP002 were evaluated in mouse preclinical models of tail-flick test, carrageenan-induced inflammatory pain, and acetic acid-induced visceral pain, respectively. Furthermore, the potential opioid and cannabinoid side effects of OCP002 were systematically investigated in mice after intracerebroventricular (ICV) and subcutaneous (SC) administrations. RESULTS: OCP002 functioned as a mixed agonist toward mu-opioid, kappa-opioid, and cannabinoid CB1 receptors in vitro. ICV and SC injections of OCP002 produced dose-dependent antinociception in mouse models of nociceptive (the median effective dose [ED50] values with 95% confidence interval [CI] are 0.14 [0.12-0.15] nmol and 0.32 [0.29-0.35] µmol/kg for ICV and SC injections, respectively), inflammatory (mechanical stimulation: ED50 values [95% CI] are 0.76 [0.64-0.90] nmol and 1.23 [1.10-1.38] µmol/kg for ICV and SC injections, respectively; thermal stimulation: ED50 values [95% CI] are 0.13 [0.10-0.17] nmol and 0.23 [0.08-0.40] µmol/kg for ICV and SC injections, respectively), and visceral pain (ED50 values [95% CI] are 0.0069 [0.0050-0.0092] nmol and 1.47 [1.13-1.86] µmol/kg for ICV and SC injections, respectively) via opioid and cannabinoid receptors. Encouragingly, OCP002 cannot cross the blood-brain barrier and exerted nontolerance-forming analgesia over 6-day treatment at both supraspinal and peripheral levels. Consistent with these behavioral results, repeated OCP002 administration did not elicit microglial hypertrophy and proliferation, the typical features of opioid-induced tolerance, in the spinal cord. Furthermore, at the effective analgesic doses, SC OCP002 exhibited minimized opioid and cannabinoid side effects on motor performance, body temperature, gastric motility, physical and psychological dependence, as well as sedation in mice. CONCLUSIONS: This study demonstrates that OCP002 produces potent and nontolerance-forming antinociception in mice with reduced opioid- and cannabinoid-related side effects, which strengthen the candidacy of bifunctional drugs targeting opioid/cannabinoid receptors for translational-medical development to replace or assist the traditional opioid analgesics.


Assuntos
Analgésicos , Agonistas de Receptores de Canabinoides , Canabinoides , Receptores Opioides , Dor Visceral , Animais , Camundongos , Analgésicos/farmacologia , Analgésicos Opioides , Relação Dose-Resposta a Droga , Receptores de Canabinoides , Receptores Opioides/agonistas , Dor Visceral/induzido quimicamente , Dor Visceral/tratamento farmacológico , Agonistas de Receptores de Canabinoides/farmacologia
12.
Proc Natl Acad Sci U S A ; 120(2): e2216814120, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36603028

RESUMO

Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron 1 gene (SMN1). SMA is characterized by the degeneration of spinal alpha motor neurons (αMNs), associated with muscle paralysis and atrophy, as well as other peripheral alterations. Both growth hormone-releasing hormone (GHRH) and its potent agonistic analog, MR-409, exert protective effects on muscle atrophy, cardiomyopathies, ischemic stroke, and inflammation. In this study, we aimed to assess the protective role of MR-409 in SMNΔ7 mice, a widely used model of SMA. Daily subcutaneous treatment with MR-409 (1 or 2 mg/kg), from postnatal day 2 (P2) to euthanization (P12), increased body weight and improved motor behavior in SMA mice, particularly at the highest dose tested. In addition, MR-409 reduced atrophy and ameliorated trophism in quadriceps and gastrocnemius muscles, as determined by an increase in fiber size, as well as upregulation of myogenic genes and inhibition of proteolytic pathways. MR-409 also promoted the maturation of neuromuscular junctions, by reducing multi-innervated endplates and increasing those mono-innervated. Finally, treatment with MR-409 delayed αMN death and blunted neuroinflammation in the spinal cord of SMA mice. In conclusion, the present study demonstrates that MR-409 has protective effects in SMNΔ7 mice, suggesting that GHRH agonists are promising agents for the treatment of SMA, possibly in combination with SMN-dependent strategies.


Assuntos
Hormônio Liberador de Hormônio do Crescimento , Atrofia Muscular Espinal , Animais , Camundongos , Atrofia/metabolismo , Modelos Animais de Doenças , Hormônio Liberador de Hormônio do Crescimento/agonistas , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/tratamento farmacológico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Medula Espinal/metabolismo , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo
13.
Comput Biol Med ; 153: 106515, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36610217

RESUMO

Transgelin-2 (TG2) is a novel promising therapeutic target for the treatment of asthma as it plays an important role in relaxing airway smooth muscles and reducing pulmonary resistance in asthma. The compound TSG12 is the only reported TG2 agonist with in vivo anti-asthma activity. However, the dynamic behavior and ligand binding sites of TG2 and its binding mechanism with TSG12 remain unclear. In this study, we performed 12.6 µs molecular dynamics (MD) simulations for apo-TG2 and TG2-TSG12 complex, respectively. The results suggested that the apo-TG2 has 4 most populated conformations, and that its binding of the agonist could expand the conformation distribution space of the protein. The simulations revealed 3 potential binding sites in 3 most populated conformations, one of which is induced by the agonist binding. Free energy decomposition uncovered 8 important residues with contributions stronger than -1 kcal/mol. Computational alanine scanning for the important residues by 100 ns conventional MD simulation for each mutated TG2-TSG12 complexes demonstrated that E27, R49 and F52 are essential residues for the agonist binding. These results should be helpful to understand the dynamic behavior of TG2 and its binding mechanism with the agonist TSG12, which could provide some structural insights into the novel mechanism for anti-asthma drug development.


Assuntos
Antiasmáticos , Simulação de Dinâmica Molecular , Antiasmáticos/farmacologia , Proteínas Musculares/agonistas , Proteínas Musculares/metabolismo , Sítios de Ligação , Descoberta de Drogas , Ligação Proteica , Simulação de Acoplamento Molecular
14.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675147

RESUMO

Endometriosis (EM), defined as the presence of endometrial-like tissue with surrounding smooth muscle cells outside the uterus, is a disregarded gynecological disease reported to affect 6-10% of women of reproductive age, with 30-50% of them suffering from chronic pelvic pain and infertility. Since the exact pathogenic mechanisms of EM are still unclear, no curative therapy is available. As pain is an important factor in EM, optimal analgesia should be sought, which to date has been treated primarily with non-steroidal anti-inflammatory drugs (NSAIDs), metamizole or, in extreme cases, opioids. Here, we review the pain therapy options, the mechanisms of pain development in EM, the endogenous opioid system and pain, as well as the opioid receptors and EM-associated pain. We also explore the drug abuse and addiction to opioids and the possible use of NOP receptors in terms of analgesia and improved tolerability as a target for EM-associated pain treatment. Emerging evidence has shown a promising functional profile of bifunctional NOP/MOP partial agonists as safe and nonaddictive analgesics. However, until now, the role of NOP receptors in EM has not been investigated. This review offers a thought which still needs further investigation but may provide potential options for relieving EM-associated pain.


Assuntos
Endometriose , Receptores Opioides , Feminino , Humanos , Receptores Opioides/agonistas , Analgésicos Opioides/efeitos adversos , Endometriose/tratamento farmacológico , Dor/tratamento farmacológico , Analgésicos/uso terapêutico , Receptores Opioides mu/agonistas
15.
Int J Mol Sci ; 24(2)2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36675217

RESUMO

To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Diabetes Mellitus Tipo 2/patologia , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Fígado/patologia
16.
Cells ; 12(2)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36672199

RESUMO

The G-protein coupled receptor 39 (GPR39) is gaining increasing attention as a target for future drugs, yet there are gaps in the understanding of its pharmacology. Zinc is an endogenous agonist or an allosteric modulator, while TC-G 1008 is a synthetic, small molecule agonist. Zinc is also a positive allosteric modulator for the activity of TC-G 1008 at GPR39. Activation of GPR39 by TC-G 1008 facilitated the development of epileptogenesis in the pentylenetetrazole (PTZ)-induced kindling model of epilepsy. Congruently, TC-G 1008 decreased the seizure threshold in the maximal electroshock seizure threshold (MEST) test. Here, we investigated the effects of TC-G 1008 under the condition of zinc deficiency. Mice were fed a zinc-adequate diet (ZnA, 50 mg Zn/kg) or a zinc-deficient diet (ZnD, 3 mg Zn/kg) for 4 weeks. Following 4 weeks of dietary zinc restriction, TC-G 1008 was administered as a single dose and the MEST test was performed. Additional groups of mice began the PTZ-kindling model during which TC-G 1008 was administered repeatedly and the diet was continued. TC-G 1008 administered acutely decreased the seizure threshold in the MEST test in mice fed the ZnD diet but not in mice fed the ZnA diet. TC-G 1008 administered chronically increased the maximal seizure severity and the percentage of fully kindled mice in those fed the ZnA diet, but not in mice fed the ZnD diet. Our data showed that the amount of zinc in a diet is a factor contributing to the effects of TC-G 1008 in vivo.


Assuntos
Epilepsia , Pentilenotetrazol , Camundongos , Animais , Eletrochoque/efeitos adversos , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Receptores Acoplados a Proteínas G/agonistas , Zinco
17.
Cochrane Database Syst Rev ; 1: CD010693, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36625492

RESUMO

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists are insulin-sensitising drugs used for the treatment of insulin resistance. In addition to lowering glucose in diabetes, these drugs may also protect against hyperlipidaemia and arteriosclerosis, which are risk factors for stroke. This is an update of a review first published in January 2014 and subsequently updated in December 2017 and October 2019. OBJECTIVES: To assess the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events for people with stroke or transient ischaemic attack (TIA). SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (1 January 2022), the Cochrane Central Register of Controlled Trials (CENTRAL; 2021, Issue 12), MEDLINE (1949 to 1 January 2022), Embase (1980 to 1 January 2022), CINAHL (1982 to 1 January 2022), AMED (1985 to 1 January 2022), and 11 Chinese databases (1 January 2022). In an effort to identify further published, unpublished, and ongoing trials, we searched ongoing trials registers, reference lists, and relevant conference proceedings, and contacted authors and pharmaceutical companies. We did not impose any language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating PPAR-γ agonists versus placebo for the secondary prevention of stroke and related vascular events in people with stroke or TIA, with the outcomes of recurrent stroke, vascular events, and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed methodological quality and risk of bias. We evaluated the certainty of evidence for each outcome using the GRADE approach. MAIN RESULTS: We identified five RCTs with 5039 participants; two studies had a low risk of bias for all domains. Four studies evaluated the drug pioglitazone, and one study evaluated rosiglitazone. The participants in different studies were heterogeneous. Recurrent stroke Three studies evaluated the number of participants with recurrent stroke (4979 participants, a single study contributing 3876 of these). Peroxisome proliferator-activated receptor gamma agonists probably reduce the recurrence of stroke compared with placebo (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.44 to 0.99; moderate-certainty evidence). Adverse events Evidence that adverse events occurred more frequently in participants treated with PPAR-γ agonists when compared with placebo was uncertain due to wide confidence intervals and high levels of statistical heterogeneity: risk difference 10%, 95% CI -8% to 28%; low-certainty evidence). Data were available on additional composite outcomes reflecting serious vascular events (all-cause death and other major vascular events; all-cause mortality, non-fatal myocardial infarction or non-fatal stroke) from one study in 984 people. This study provided low-certainty evidence that PPAR-γ agonists led to fewer events (data not meta-analysed). Vascular events Peroxisome proliferator-activated receptor gamma agonists given over a mean duration of 34.5 months in a single trial of 984 participants may reduce serious vascular events expressed as a composite outcome of total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke (RR 0.73, 95% CI 0.54 to 0.99; low-certainty evidence). Other outcomes One study in 20 people measured insulin sensitivity, and one study in 40 people measured the ubiquitin-proteasome activity in carotid plaques. Our confidence in the improvements observed with PPAR-γ agonists were limited by small sample sizes and risk of bias. None of the studies reported the number of participants with disability due to vascular events or improvement in quality of life. AUTHORS' CONCLUSIONS: Peroxisome proliferator-activated receptor gamma agonists probably reduce recurrent stroke and total events of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, and may improve insulin sensitivity and the stabilisation of carotid plaques. Their effects on adverse events are uncertain. Our conclusions should be interpreted with caution considering the small number and the quality of the included studies. Further well-designed, double-blind RCTs with large samples are required to assess the efficacy and safety of PPAR-γ agonists in the secondary prevention of stroke and related vascular events in people with stroke or TIA.


Assuntos
Resistência à Insulina , Ataque Isquêmico Transitório , Infarto do Miocárdio , Acidente Vascular Cerebral , Humanos , Ataque Isquêmico Transitório/prevenção & controle , PPAR gama/agonistas , PPAR gama/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
18.
Bioorg Med Chem Lett ; 80: 129120, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36587872

RESUMO

GPR88 is an orphan G protein-coupled receptor which has been implicated in a number of striatal-associated disorders. Herein we describe the synthesis and pharmacological characterization of the first GPR88 radioligand, [3H]RTI-33, derived from a synthetic agonist RTI-13951-33. [3H]RTI-33 has a specific activity of 83.4 Ci/mmol and showed one-site, saturable binding (KD of 85 nM) in membranes prepared from stable PPLS-HA-hGPR88-CHO cells. A competition binding assay was developed to determine binding affinities of several known GPR88 agonists. This radioligand represents a powerful tool for future mechanistic and cell-based ligand-receptor interaction studies of GPR88.


Assuntos
Proteínas de Transporte , Receptores Acoplados a Proteínas G , Cricetinae , Animais , Cricetulus , Receptores Acoplados a Proteínas G/agonistas , Ensaio Radioligante
19.
Obesity (Silver Spring) ; 31(1): 96-110, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36478180

RESUMO

OBJECTIVE: Obesity is a growing global concern compounded by limited availability of effective treatment options. The SURMOUNT development program aims to evaluate the efficacy and safety of tirzepatide as an adjunct to lifestyle intervention compared with placebo on chronic weight management in adults with BMI ≥ 27 kg/m2 with or without type 2 diabetes. METHODS: The SURMOUNT program includes four global phase 3 trials NCT04184622 (SURMOUNT-1), NCT04657003 (SURMOUNT-2), NCT04657016 (SURMOUNT-3), and NCT04660643 (SURMOUNT-4). Participants are randomized to once-weekly subcutaneous tirzepatide versus placebo in a double-blind manner. The primary end point in all trials is the percentage change in body weight from randomization to end of treatment. Results for the primary end point for SURMOUNT-1 were published recently and results for the other trials are expected in 2023. RESULTS: Across trials, participants have a mean age of 44.9 to 54.2 years, are mostly female (50.7% to 69.7%), and have a mean BMI of 36.1 to 38.9. CONCLUSIONS: The extensive assessment of once-weekly tirzepatide in the global SURMOUNT program will detail the clinical effects of this first-in-class glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist in chronic weight management.


Assuntos
Polipeptídeo Inibidor Gástrico , Obesidade , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glicemia , Diabetes Mellitus Tipo 2/complicações , Polipeptídeo Inibidor Gástrico/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico
20.
Obesity (Silver Spring) ; 31(1): 20-30, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36502288

RESUMO

OBJECTIVE: Postprandial hyperinsulinemic hypoglycemia with neuroglycopenia is an increasingly recognized complication of Roux-en-Y gastric bypass and gastric sleeve surgery that may detrimentally affect patient quality of life. One likely causal factor is glucagon-like peptide-1 (GLP-1), which has an exaggerated rise following ingestion of carbohydrates after bariatric surgery. This paper sought to assess the role of GLP-1 receptor agonists (GLP-1RAs) in managing postprandial hypoglycemia following bariatric surgery. METHODS: MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Scopus were systematically and critically appraised for all peer-reviewed publications that suitably fulfilled the inclusion criteria established a priori. This systematic review was developed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols (PRISMA-P). It followed methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions and is registered with PROSPERO (International Prospective Register of Systematic Reviews; identifier CRD420212716429). RESULTS AND CONCLUSIONS: Postprandial hyperinsulinemic hypoglycemia remains a notoriously difficult to manage metabolic complication of bariatric surgery. This first, to the authors' knowledge, systematic review presents evidence suggesting that use of GLP-1RAs does not lead to an increase of hypoglycemic episodes, and, although this approach may appear counterintuitive, the findings suggest that GLP-1RAs could reduce the number of postprandial hypoglycemic episodes and improve glycemic variability.


Assuntos
Cirurgia Bariátrica , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemia , Humanos , Cirurgia Bariátrica/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Hipoglicemia/etiologia , Hipoglicemia/prevenção & controle , Qualidade de Vida
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