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1.
Methods Mol Biol ; 2576: 145-153, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36152183

RESUMO

Peroxisome proliferator-activated receptors (PPARs) have been exploited as drug targets for combating multiple diseases. Several activators with different selectivity for the PPAR α, γ, and δ subtypes have been introduced into the market or have reached advanced clinical trials. Binding assays are of utmost importance for the discovery and profiling of such PPAR ligands. Binding assays are often based on radioligands, in particular, tritiated molecules are applied. We developed synthetic procedures for tritiating various PPAR agonists and applied these radioligands for setting up a scintillation proximity assay (SPA) for PPAR α, γ, and δ. These SPAs allow to assess the binding affinities of PPAR α, γ, and δ ligands, along with their respective subtype selectivity profiles. Therefore, SPA is an important tool for hit discovery and lead optimization campaigns aimed at identifying next-generation PPAR ligands.


Assuntos
PPAR alfa , PPAR delta , Hipoglicemiantes , Ligantes , PPAR alfa/agonistas , PPAR alfa/metabolismo , PPAR delta/agonistas , PPAR delta/metabolismo , PPAR gama/metabolismo , Receptores Ativados por Proliferador de Peroxissomo
2.
Methods Mol Biol ; 2576: 155-169, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36152184

RESUMO

Peroxisome proliferator-activated receptors are a family of nuclear hormone receptors that control the expression of genes involved in a variety of physiologic processes, through heterodimerization with retinoid X receptor and complex formation with various cofactors. The specific cofactors recruited to PPAR-RXR complexes in response to different ligands lead to major differences in the transactivation of target genes. We developed a cofactor recruitment assay that is based on an europium-labeled anti-GST antibody and streptavidin-APC leading to a fluorescence resonance energy transfer signal. This assay allows for the determination of unique agonistic profiles in terms of potency and co-activator motif. Hence, it is a valuable drug discovery tool to support hit finding and lead optimization campaigns, enabling the characterization of next generation PPAR agonists.


Assuntos
PPAR alfa , PPAR gama , Európio , Transferência Ressonante de Energia de Fluorescência , PPAR alfa/agonistas , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR gama/metabolismo , Receptores X de Retinoides , Estreptavidina
3.
Platelets ; 34(1): 2135694, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36281771

RESUMO

Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease. Loss of immune tolerance plays a crucial role in the pathogenesis of ITP. Monocytes and macrophages play an indispensable role in the pathophysiology of hematopoietic malignancies and have been implicated as key players in platelet destruction. Approximately 80% of adult patients with ITP exhibit corticosteroid treatment failure or become dependent, requiring novel therapy. Thrombopoietin (TPO) receptor agonists (TPO-RAs) have been used clinically to manage ITP effectively, however, little is known about the effect of TPO-RAs on monocyte and macrophage modulation in adult ITP. In this study, we investigated the phenotypic evolution and potential immunomodulatory roles of monocytes/macrophages in ITP patients receiving eltrombopag therapy. Results showed that the peripheral monocyte count positively correlated with IFN-γ/IL-4 ratio in ITP patients. Moreover, numerous phenotype-associated genes in ITP macrophages exhibited diverse responses, and ITP macrophages exhibited more M1-related characteristics. After eltrombopag therapy, the peripheral monocyte count and IFN-γ/IL-4 ratio significantly decreased in ITP patients. M1-related characteristics of ITP macrophages were partially reversed by eltrombopag. Therefore, this study revealed eltrombopag restored the monocyte dynamics and the associated Th1/Th2 imbalance, and partially reversed the M1-related characteristics of the ITP macrophages, which suggest the potential vital roles of TPO-RAs in regulating the monocyte/macrophage plasticity in ITP.


What is the context? Primary immune thrombocytopenia (ITP) is an acquired autoimmune hemorrhagic disease. Loss of immune tolerance plays a crucial role in the pathogenesis of ITP.Monocytes and macrophages play an indispensable role in the pathophysiology of hematopoietic malignancies and have been implicated as key players in platelet destruction.Approximately 80% of adult patients with ITP exhibit corticosteroid treatment failure or become dependent, requiring novel therapy. Thrombopoietin (TPO) receptor agonists (TPO-RAs) have been used clinically to manage ITP effectively, however, little is known about the effect of TPO-RAs on monocyte and macrophage modulation in ITP.What is new?In this study, we investigated the phenotypic evolution and potential immunomodula-tory roles of monocytes/macrophages in ITP patients receiving eltrombopag therapy.The expansion of peripheral monocytes positively correlated with IFN-γ/IL-4 ratio in ITP patients.ITP macrophages exhibited more M1-related characteristics.After eltrombopag therapy, the peripheral monocyte count and IFN-γ/IL-4 ratio significantly decreased in ITP patients.M1-related characteristics of ITP macrophages were partially reversed by eltrombopag.What is the impact?This study provides evidence that the potential vital roles of TPO-RAs in regulating the monocyte/macrophage plasticity in ITP.


Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Monócitos , Receptores de Trombopoetina/agonistas , Interleucina-4 , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Trombopoetina , Trombocitopenia/induzido quimicamente , Fenótipo , Macrófagos , Proteínas Recombinantes de Fusão
4.
Med Clin North Am ; 107(1): 101-117, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36402493

RESUMO

The BALB/c mouse displays hypersensitivity to behavioral effects of MK-801 (dizocilpine), a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor "open-channel" blocker, and shows both no preference for an enclosed stimulus mouse over an inanimate object and reduced social interaction with a freely behaving stimulus mouse. NMDA receptor agonist interventions improved measures of social preference and social interaction of the BALB/c mouse model of autism spectrum disorder (ASD). A "proof of principle/proof of concept" translational 10-week clinical trial with 8-week of active medication administration was conducted comparing 20 DSM-IV-TR-diagnosed older adolescent/young adult patients with ASD randomized to once-weekly pulsed administration (50 mg/d) versus daily administration of d-cycloserine (50 mg/d). The results showed that d-cycloserine, a partial glycine agonist, was well tolerated, the 2 dosing strategies did not differ, and improvement was noted on the "lethargy/social withdrawal" and "stereotypic behavior" subscales of the Aberrant Behavior Checklist. NMDA receptor activation contributes to the regulation of mTOR signaling, a pathologic point of convergence in several monogenic syndromic forms of ASD. Furthermore, both NMDA receptor hypofunction and imbalance between NMDA receptor activation mediated by GluN2B and GluN2A-containing NMDA receptors occur as "downstream" consequences of several genetically unrelated abnormalities associated with ASD. NMDA receptor-subtype selective "positive allosteric modulators (PAMs)" are particularly appealing medication candidates for future translational trials.


Assuntos
Transtorno do Espectro Autista , Ciclosserina , Animais , Camundongos , Humanos , Ciclosserina/farmacologia , Ciclosserina/uso terapêutico , Receptores de N-Metil-D-Aspartato/agonistas , Transtorno do Espectro Autista/tratamento farmacológico , N-Metilaspartato , Comportamento Social , Camundongos Endogâmicos BALB C , Maleato de Dizocilpina/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Circulation ; 146(21): 1627-1635, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36409780

RESUMO

During the past few years, several innovative treatments for noncommunicable chronic disease have become available, including SGLT2i (sodium-glucose cotransporter-2 inhibitors), GLP-1a (glucagon-like-peptide 1 agonists), ARNI (angiotensin receptor-neprilysin inhibitors), and finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist. Each of these medications improves clinically relevant outcomes when added to existing therapies, and the indications for their use are rapidly expanding. Because existing drug regimens are already complex and costly, ensuring that society derives the maximal benefit from these new agents represents a major challenge. This Primer discusses how society can meet this challenge, which we address in terms of 5 principles: maximizing benefit, minimizing harm, optimizing uptake, increasing value for money, and ensuring equitable access. The Primer is most relevant for stakeholders in high-income countries, but the principles are broadly applicable to stakeholders in other settings, including low- and middle-income countries. We have focused the discussion on SGLT-2i, but the 5 principles herein could be used with reference to ARNI, finerenone, or any other health product.


Assuntos
Fármacos Cardiovasculares , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Fármacos Cardiovasculares/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia
6.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 47(10): 1324-1331, 2022 Oct 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-36411683

RESUMO

OBJECTIVES: The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily, and LXR-ß is an important receptor for cholesterol content in brain cells. LXR-ß/retinoic X receptor (RXR-α)/ATP binding cassette transporter A1 (ABCA1) cholesterol transmembrane transport system is closely related to the occurrence and development of Alzheimer's disease (AD). LXR agonist TO901317 can affect the accumulation of ß- amyloid protein in the brain tissue of APP/PS1 double transgenic AD mice. However, the molecular mechanism is not clarified in detail. This study aims to evaluate the effects of LXR agonist TO901317 on the cognitive function of AD mice fed with high cholesterol diet, and to explore its possible mechanism from the perspective of cholesterol metabolism. METHODS: Twenty four male 6-month-old APP/PS1 double transgenic AD mice were randomly divided into 4 groups, 6 mice in each group: a control group (fed with normal diet), a cholesterol rich diet (CRD) group, a TO901317 group (fed with CRD combined with TO901317), and a GSK2033 group (fed with CRD combined with TO901317 and LXR antagonist GSK2033). The mice were fed with pellet feed made of high cholesterol feed, mixed with lard, egg yolk powder, and cod liver oil twice a day. TO901317 and GSK2033 were dissolved and diluted to a final concentration at 0.03%. The drugs were given to the mice daily through gastric tube according to their body weight. Meanwhile, the mice in the drug group were fed with high cholesterol diet . After feeding for 3 months, Morris water maze was used to observe the changes of spatial exploration and memory ability of AD mice in each group. The contents of TC, LDL, and HDL in serum of mice in each group were detected by cholesterol enzyme colorimetry, and the differences among the groups were compared. The expression of Aß42 in the brain of AD mice was detected by ELISA. Western blotting was used to detect the protein levels of LXR-ß, RXR-α, ABCA1, and Caveolin-1 in the brain of each group. RESULTS: Morris water maze results showed that the times, distance and the duration of mice crossing the platform in the CRD group were significantly decreased compared with the control group (all P<0.05), while these three figures in TO901317 group were significantly increased compared with the CRD group (all P<0.05). Compared with the TO901317 group, there was a decrease of these figures in the GSK2033 group (all P<0.05). The serum TC and LDL levels in the CRD group were significantly higher than those in the control group, while HDL levels were significantly lower (all P<0.001). The figures of the TC and LDL contents level in the TO901317 group were lower than those in the CRD group, while HDL levels were higher (all P<0.001). Compared with TO901317 group, the contents of the TC and LDL in GSK2033 group were significantly increased, while HDL content was significantly decreased (all P<0.001). ELISA results showed that the production of Aß42 peptides in the brain of CRD group was the highest while the content in the TO901317 group was significantly decreased (P<0.001), which was the lowest among the groups. The figure in the control group was close to the GSK2033 group. Western blotting results showed that the protein levels of LXR-ß, RXR-α, and ABCA1 in the CRD group were significantly decreased compared with the control group, but the protein level of Caveolin-1 was increased (all P<0.01). After TO901317 treatment, the protein levels of LXR-ß, RXR-α and ABCA1 were significantly increased, while the protein level of Caveolin-1 was decreased partially (all P<0.001). In the GSK2033 group, the effect of TO901317 on AD mice was partially reversed by GSK2033. Compared to TO901317 group, the protein levels of LXR-ß, RXR-α, and ABCA1 showed a decrease trend, while the protein level of Caveolin-1 showed an increase state (all P<0.05). CONCLUSIONS: High cholesterol diet leads to severer spatial exploration, learning and memory impairment in transgenic AD mice, while the LXR agonist TO901317 attenuates this effect. The mechanism may be that TO901317 promotes cholesterol efflux by activating LXR-ß/RXR-α/ABCA1 transmembrane transport system, reduces the expression of Caveolin-1, improves the composition of lipid raft, and ultimately reduces the production of Aß42 in the brain.


Assuntos
Doença de Alzheimer , Masculino , Animais , Camundongos , Receptores X do Fígado/genética , Receptores X do Fígado/agonistas , Receptores X do Fígado/metabolismo , Camundongos Transgênicos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Caveolina 1/metabolismo , Hidrocarbonetos Fluorados/farmacologia , Cognição , Peptídeos beta-Amiloides/metabolismo , Colesterol
7.
Biomolecules ; 12(11)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36359001

RESUMO

A focused in-house library of about 1000 compounds comprising various heterocyclic motifs in combination with structural fragments similar to ß-phenethylamine (PEA) or tyramine was screened for the agonistic activity towards trace amine-associated receptor 1 (TAAR1). The screening yielded two closely related hits displaying EC50 values in the upper submicromolar range. Extensive analog synthesis and testing for TAAR1 agonism in a BRET-based cellular assay identified compound 62 (LK00764) with EC50 = 4.0 nM. The compound demonstrated notable efficacy in such schizophrenia-related in vivo tests as MK-801-induced hyperactivity and spontaneous activity in rats, locomotor hyperactivity of dopamine transporter knockout (DAT-KO) rats, and stress-induced hyperthermia (i.p. administration). Further preclinical studies are necessary to evaluate efficacy, safety and tolerability of this potent TAAR1 agonist for the potential development of this compound as a new pharmacotherapy option for schizophrenia and other psychiatric disorders.


Assuntos
Transtornos Psicóticos , Receptores Acoplados a Proteínas G , Animais , Ratos , Receptores Acoplados a Proteínas G/agonistas , Compostos de Bifenilo
8.
J Med Chem ; 65(22): 15085-15101, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36335509

RESUMO

The success of vaccination with subunit vaccines often relies on the careful choice of adjuvants. There is great interest in developing new adjuvants that can elicit a cellular immune response. Here, we address this challenge by taking advantage of the synergistic cross-talk between two pattern recognition receptors: nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) and Toll-like receptor 7 (TLR7). We designed two conjugated NOD2/TLR7 agonists, which showed potent immunostimulatory activities in human primary peripheral blood mononuclear cells and murine bone-marrow-derived dendritic cells. One of these, 4, also generated a strong antigen-specific immune response in vivo, with a Th1-polarized profile. Importantly, our study shows that novel NOD2/TLR7 agonists elicit sophisticated and fine-tuned immune responses that are inaccessible to individual NOD2 and TLR7 agonists.


Assuntos
Leucócitos Mononucleares , Receptor 7 Toll-Like , Humanos , Camundongos , Animais , Receptor 7 Toll-Like/agonistas , Adjuvantes Imunológicos/farmacologia , Imunidade Celular , Imunização , Proteína Adaptadora de Sinalização NOD2
9.
Front Public Health ; 10: 1031306, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36408008

RESUMO

Background: The use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with type 2 diabetes mellitus (T2DM) remains limited, especially in those with other compelling indications. Thus, this study aimed to describe the prescribing patterns of GLP-1-RA and SGLT2i in patients with T2DM and to determine the factors that affect the prescribing of these medications. Methods: This multicenter retrospective cross-sectional study reviewed the electronic health records of adult patients diagnosed with T2DM who received care between January and December 2020. The patients were classified according to their compelling indications into "patients who are more likely" to benefit from SGLT2i or GLP-1 RA and "patients who are less likely" to benefit from them. They were then further categorized depending on whether these medications were prescribed. Results: A total of 1,220 patients were included; most were female (56.9%). SGLT2i or GLP-1 RA were preferably prescribed in only 19% of the patients for reasons including BMI ≥ 27 kg/m2 (85.6%), uncontrolled T2DM (68.5%), high risk for ASCVD (23.9%), or established ASCVD (14%). The remaining 81.0% were underprescribed these agents. Patients at an older age or with a history of stroke or transient ischemic attack had higher odds of being underprescribed (OR 1.02; 95% CI: 1.01-1.03 and OR 2.86; 95% CI: 1.33-6.15), respectively. Conclusion: The results concur with those of previous studies highlighting the underutilization of GLP-1 RA and SGLT2i in patients with T2DM but also with compelling indications. To optimize the use of GLP-1 RA and SGLT2i for their additional benefits, prescribers need to assess the benefits of using these agents in patients who would likely benefit from them, regardless of DM control.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Feminino , Masculino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Estudos Transversais , Estudos Retrospectivos , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Glucose/uso terapêutico , Sódio/uso terapêutico
10.
Arq Neuropsiquiatr ; 80(9): 900-907, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36351417

RESUMO

BACKGROUND: Pain is an uncomfortable sensation in the body. Kaempferol is a flavonoid with antinociceptive effects. Transient receptor potential (TRP) channels have been characterized in the sensory system. OBJECTIVE: This study evaluated the central antinociceptive effect of Kaempferol and possible mechanisms of action of transient receptor potential cation channel subfamily V member 1 (TRPV1). METHODS: Capsaicin as a TRPV agonist (5 µg/µL, intracerebroventricular [ICV]) and capsazepine as its antagonist (10 µg/µL, icv) were used to test the analgesic effect of kaempferol (1.5 mg, ICV). Morphine (10 µg, ICV) was used as a positive control. The other groups were treated with a combination of kaempferol and capsaicin, kaempferol and capsazepine, and capsaicin and capsazepine. The cannula was implanted in the cerebroventricular area. The tail-flick, acetic acid, and formalin tests were used to assess analgesic activity. For evaluation of antiinflammatory effect, the formalin-induced rat paw edema was used. RESULTS: Kaempferol significantly decreased pain in the acute pain models, including the tail-flick and the first phase of the formalin test. In the late phase of the formalin test, as a valid model of nociception, capsazepine inhibited the antinociceptive effect of kaempferol. CONCLUSIONS: Kaempferol has an analgesic effect in the acute pain model and can affect inflammatory pain. Also, the TRPV1 channel plays a role in the antinociceptive activity of kaempferol.


ANTECEDENTES: A dor é uma sensação desconfortável no corpo. Kaempferol é um flavonoide com efeitos antinociceptivos. Canais receptores de potencial transitório têm sido caracterizados no sistema sensorial. OBJETIVO: Este estudo avaliou o efeito antinociceptivo central do kaempferol e os possíveis mecanismos de ação do TRPV1. MéTODOS: Capsaicina como agonista de TRPV (5 µg/µL, intracerebroventricular [ICV]) e capsazepina como seu antagonista (10 µg/µL, icv) foram usados para testar o efeito analgésico do kaempferol (1,5 mg, ICV). A morfina (10 µg, ICV) foi usada como controle positivo. Os outros grupos foram tratados com uma combinação de kaempferol e capsaicina, kaempferol e capsazepina e capsaicina e capsazepina. A cânula foi implantada na área cerebroventricular. Os testes de movimento de cauda, ácido acético e formalina foram usados para avaliar a atividade analgésica. Para avaliação do efeito anti-inflamatório, foi utilizado o edema de pata de rato induzido por formalina. RESULTADOS: Kaempferol diminuiu significativamente a dor nos modelos de dor aguda, incluindo o movimento da cauda e a primeira fase do teste de formalina. Na fase tardia do teste da formalina, como modelo válido de nocicepção, a capsazepina inibiu o efeito antinociceptivo do kaempferol. CONCLUSõES: Kaempferol tem efeito analgésico no modelo de dor aguda e pode afetar a dor inflamatória. Além disso, o canal TRPV1 desempenha um papel na atividade antinociceptiva do kaempferol.


Assuntos
Dor Aguda , Canais de Potencial de Receptor Transitório , Ratos , Animais , Capsaicina/farmacologia , Quempferóis/farmacologia , Flavonoides , Canais de Cátion TRPV/agonistas , Analgésicos/farmacologia , Anti-Inflamatórios
11.
ACS Appl Mater Interfaces ; 14(45): 50592-50600, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36334044

RESUMO

CpG, an agonist of toll-like receptor 9 (TLR9), has become a novel adjuvant that substantially potentiates cellular immunity. However, this agonist may increase systemic toxicity by diffusing into blood after administration and is difficult to be internalized by immune cells to reach TLR9 located in endosomes as a result of the characteristics of negative charge of CpG. Here, we applied a scalable and controllable flash nanocomplexation technology to prepare nanoparticulate CpG adjuvant (npCpG), CpG encapsulated in a physical cross-linking network of protamine and TPP. The nanoadjuvant could redirect CpG into draining lymph nodes to reduce systemic diffusion to improve safety. Further, a combination of npCpG and influenza H1N1 hemagglutinin antigen showed excellent humoral and cellular immunity, evoking high levels of antibodies and cytokines and inducing a great expansion of splenocytes in immunized mice. Also, the nanoadjuvant combined with ovalbumin antigen led to a potent cytotoxic T-cell response, substantially inhibited tumor growth, and improved the survival rate of mice in a melanoma model. This study showed the universal performances of npCpG in infectious disease prevention and tumor immunotherapy to demonstrate the translational potential.


Assuntos
Adjuvantes Imunológicos , Glicoproteínas de Hemaglutininação de Vírus da Influenza , Vírus da Influenza A Subtipo H1N1 , Neoplasias Experimentais , Animais , Camundongos , Adjuvantes Imunológicos/farmacologia , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos , Receptor Toll-Like 9/agonistas , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Ilhas de CpG , Nanopartículas , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia
12.
J Diabetes Res ; 2022: 1861940, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36387940

RESUMO

Background: GLP-1 receptor agonists (GLP-1RA) are common clinical agents that are clinically protective against diabetic complications, such as diabetic retinopathy (DR). Previous studies have shown that the RhoA/ROCK pathway plays an important role in the development of DR. However, the specific mechanism of action between GLP-1RA and DR remains unclear. The aim of this study was thus to investigate the main mechanism involved in the protective effect of GLP-1RA on DR. Methods: Type 2 diabetic mice were fed a high-sugar, high-fat diet. Changes in the retinal structure were observed via HE staining and transmission electron microscopy. The expression of retinal GLP-1R, blood-retinal barrier- (BRB-) related proteins, inflammatory factors, and related pathway proteins were studied via Western blot or immunohistochemistry/immunofluorescence analysis. Results: GLP-1RA treatment reduced the blood glucose and lipid levels as well as the body weight of the diabetic mice while also improving retinal thickness, morphology, and vascular ultrastructure. Moreover, restored GLP-1R expression, increased Occludin and ZO-1 levels, and decreased albumin expression led to reduced retinal leakage and improved the BRB by inhibiting the RhoA/ROCK pathway. Conclusions: We found that the protective effect of GLP-1RA on the retina may be realized through the GLP-1R-ROCK-p-MLC signaling pathway.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Camundongos , Animais , Barreira Hematorretiniana/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/prevenção & controle , Retinopatia Diabética/etiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Transdução de Sinais , Fatores de Transcrição
13.
Obesity (Silver Spring) ; 30(11): 2111-2121, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36321278

RESUMO

OBJECTIVE: Glucagon-like peptide-1 (GLP-1) receptor agonists recently demonstrated 15% to 20% weight loss in adults with obesity, a range which has previously been achieved only with bariatric surgery. This systematic review and meta-analysis compares weight loss between GLP-1 receptor agonists and bariatric surgery. METHODS: The databases MEDLINE, MEDLINE In-Process, MEDLINE Epubs Ahead of Print, Embase Classic + Embase (OvidSP), and Cochrane (Wiley) were searched from inception to April 21, 2021, for randomized controlled trials and observational studies. Two independent reviewers extracted data, reported risk of bias, and graded certainty of evidence. Random-effects models were used to pool change in weight, BMI, and glycated hemoglobin. RESULTS: Six studies, encompassing 332 patients, were included. Among randomized controlled trials, mean difference in weight between all bariatric surgery types and GLP-1 receptor agonists was -22.68 kg (95% CI: -31.41 to -13.96), mean difference in BMI was -8.18 kg/m2 (95% CI: -11.59 to -4.77), and mean difference in glycated hemoglobin was -1.28% (95% CI: -1.94% to -0.61%). Among observational studies, mean difference in weight was -25.11 kg (95% CI: -40.61 to -9.60), and mean difference in BMI was -10.60 kg/m2 (95% CI: -17.22 to -3.98). Only one observational study reported glycemic outcomes. CONCLUSION: In adults with obesity, bariatric surgery still confers the highest reductions in weight and BMI but confers similar effects in glycemic control when compared with GLP-1 receptor agonists.


Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Adulto , Humanos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hemoglobina A Glicada , Redução de Peso , Obesidade/cirurgia , Hipoglicemiantes , Estudos Observacionais como Assunto
14.
Clin Sci (Lond) ; 136(21): 1513-1533, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36326719

RESUMO

For years, the AT2R-selective ligand CGP42112 has been erroneously characterized as a partial agonist, partly due to its ability to also interact with the AT1R at high concentrations. As late as 2009, it was still being characterized as an antagonist as well. In this perspective/opinion piece, we try to resolve the ambiguity that surrounds the efficacy of this compound by extensively reviewing the literature, tracing its beginnings to 1989, showing that CGP42112 has never been convincingly shown to be a partial agonist or an antagonist at the AT2R. While CGP42112 is now routinely characterized as an AT2R agonist, regrettably, there is a paucity of studies that can validate its efficacy as a full agonist at the AT2R, leaving the door open for continuing speculation regarding the extent of its efficacy. Hopefully, the information presented in this perspective/opinion piece will firmly establish CGP42112 as a full agonist at the AT2R such that it can once again be used as a tool to study the AT2R.


Assuntos
Receptor Tipo 2 de Angiotensina , Sistema Renina-Angiotensina , Receptor Tipo 2 de Angiotensina/agonistas , Oligopeptídeos , Ligantes
15.
Cardiovasc Diabetol ; 21(1): 242, 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36380358

RESUMO

Several randomized controlled trials have demonstrated the benefits of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic stroke in patients with diabetes. In this review, we summarize and discuss the potential mechanisms of stroke protection by GLP-1RAs. GLP-1RAs exert multiple anti-atherosclerotic effects contributing to stroke prevention such as enhanced plaque stability, reduced vascular smooth muscle proliferation, increased nitric oxide, and improved endothelial function. GLP-1RAs also lower the risk of stroke by reducing traditional stroke risk factors including hyperglycemia, hypertension, and dyslipidemia. Independently of these peripheral actions, GLP-1RAs show direct cerebral effects in animal stroke models, such as reduction of infarct volume, apoptosis, oxidative stress, neuroinflammation, excitotoxicity, blood-brain barrier permeability, and increased neurogenesis, neuroplasticity, angiogenesis, and brain perfusion. Despite these encouraging findings, further research is still needed to understand more thoroughly the mechanisms by which GLP-1RAs may mediate stroke protection specifically in the human diabetic brain.


Assuntos
Diabetes Mellitus Tipo 2 , Hiperglicemia , Acidente Vascular Cerebral , Animais , Humanos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/efeitos adversos , Diabetes Mellitus Tipo 2/induzido quimicamente , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/induzido quimicamente , Hiperglicemia/induzido quimicamente
16.
Clin Sci (Lond) ; 136(22): 1631-1651, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36383188

RESUMO

Sodium-glucose transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide 1 (GLP-1) receptor agonists are newer antidiabetic drug classes, which were recently shown to decrease cardiovascular (CV) morbidity and mortality in diabetic patients. CV benefits of these drugs could not be directly attributed to their blood glucose lowering capacity possibly implicating a pleotropic effect as a mediator of their impact on cardiovascular disease (CVD). Particularly, preclinical and clinical studies indicate that SGLT-2i(s) and GLP-1 receptor agonists are capable of differentially modulating distinct adipose pools reducing the accumulation of fat in some depots, promoting the healthy expansion of others, and/or enhancing their browning, leading to the suppression of the metabolically induced inflammatory processes. These changes are accompanied with improvements in markers of cardiac structure and injury, coronary and vascular endothelial healing and function, vascular remodeling, as well as reduction of atherogenesis. Here, through a summary of the available evidence, we bring forth our view that the observed CV benefit in response to SGLT-2i or GLP-1 agonists therapy might be driven by their ameliorative impact on adipose tissue inflammation.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Doenças Metabólicas , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/efeitos adversos , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/complicações , Doenças Metabólicas/tratamento farmacológico , Tecido Adiposo/metabolismo , Peptídeo 1 Semelhante ao Glucagon
17.
N Engl J Med ; 387(21): 1923-1934, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36342113

RESUMO

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertrigliceridemia , Hipolipemiantes , PPAR alfa , Humanos , Apolipoproteína C-III/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Colesterol/sangue , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/complicações , Método Duplo-Cego , Fatores de Risco de Doenças Cardíacas , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Hipertrigliceridemia/tratamento farmacológico , Fatores de Risco , Triglicerídeos/sangue , Hipolipemiantes/uso terapêutico , PPAR alfa/agonistas , HDL-Colesterol/sangue
18.
Chin J Nat Med ; 20(11): 863-872, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36427920

RESUMO

Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O-GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O-GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O-GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Camundongos , Animais , Peptídeo 1 Semelhante ao Glucagon/agonistas , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptores de Glucagon/agonistas , Receptores de Glucagon/uso terapêutico , Xenopus laevis/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicopeptídeos/uso terapêutico , Obesidade/tratamento farmacológico , Hipoglicemiantes/farmacologia , Peptídeos/farmacologia
19.
Medicine (Baltimore) ; 101(43): e31334, 2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36316938

RESUMO

Asprosin is a newly identified adipokine with glucose-raising and appetite-enhancing effects which acts differently from the known hepatic glucose utilization pathway. This study investigated changes in serum asprosin levels in normal weight or overweight/obese liraglutide-treated patients with type 2 diabetes (T2DM). This study is a non-randomized, prospective observational study. The metabolic parameters and asprosin levels were compared between 90 people with T2DM and 66 people who had normal glucose tolerance (NGT). During the treatment phase, only T2DM patients were given liraglutide at doses of 0.6 mg/d for the first 2 weeks, 1.2 mg/d for the subsequent 4 weeks, and 1.8 mg/d for the following 16 weeks. T2DM patients were separated into a normal weight group and an overweight/obesity group to compare changes in asprosin and parameters pre- and post-treatment. The T2DM group had significantly higher fasting asprosin and 2h-postprandial asprosin levels than the NGT group (all P < .001). Fasting asprosin and postprandial asprosin positively correlated with BMI, 2hPG, HbA1c, TG, and HOMA-IR, and negatively correlated with HDL-C in both the T2DM and NGT groups. Asprosin levels decreased after liraglutide treatment in both normal and overweight/obesity T2DM groups (all P < .001), with significantly reduced body weight and BMI in overweight/obese T2DM patients (all P < .001). Fasting and postprandial serum asprosin concentrations are higher in T2DM patients compared to normal glucose controls. Fasting and postprandial asprosin positively correlated with BMI, 2hPG, HbA1c, TG, and HOMA-IR and negatively correlated with HDL-C in all participants. Liraglutide lowers asprosin levels in T2DM patients and can reduce weight and BMI in overweight or obese type 2 diabetics.


Assuntos
Diabetes Mellitus Tipo 2 , Fibrilina-1 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Resistência à Insulina , Humanos , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucose , Hemoglobina A Glicada/análise , Liraglutida/uso terapêutico , Obesidade/complicações , Sobrepeso/complicações , Fibrilina-1/sangue
20.
Cardiovasc Diabetol ; 21(1): 232, 2022 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-36335326

RESUMO

OBJECTIVE: To evaluate the cardiovascular and renal benefits of finerenone, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagonlike peptide-1 receptor agonists (GLP-1 RA) in patients with Type 2 Diabetes Mellitus (T2DM) and chronic kidney disease (CKD) with network meta-analysis. METHODS: Systematic literature searches were conducted of PubMed, Cochrane Library, Web of Science, Medline and Embase covering January 1, 2000 to December 30, 2021. Randomized control trials (RCTs) comparing finerenone, SGLT-2i and GLP-1 RA in diabetics with CKD were selected. We performed a network meta-analysis to compare the two drugs and finerenone indirectly. Results were reported as risk ratio (RR) with corresponding 95% confidence interval (CI). RESULTS: 18 RCTs involving 51,496 patients were included. Finerenone reduced the risk of major adverse cardiovascular events (MACE), renal outcome and hospitalization for heart failure (HHF) (RR [95% CI]; 0.88 [0.80-0.97], 0.86 [0.79-0.93], 0.79 [0.67,0.92], respectively). SGLT-2i were associated with reduced risks of MACE (RR [95% CI]; 0.84 [0.78-0.90]), renal outcome (RR [95% CI]; 0.67 [0.60-0.74], HHF (RR [95% CI]; 0.60 [0.53-0.68]), all-cause death (ACD) (RR [95% CI]; 0.89 [0.81-0.91]) and cardiovascular death (CVD) (RR [95% CI]; 0.86 [0.77-0.96]) compared to placebo. GLP-1 RA were associated with a lower risk of MACE (RR [95% CI]; 0.86 [0.78-0.94]). SGLT2i had significant effect in comparison to finerenone (finerenone vs SGLT2i: RR [95% CI]; 1.29 [1.13-1.47], 1.31 [1.07-1.61], respectively) and GLP-1 RA (GLP-1 RA vs SGLT2i: RR [95% CI]; 1.36 [1.16-1.59], 1.49 [1.18-1.89], respectively) in renal outcome and HHF. CONCLUSIONS: In patients with T2DM and CKD, SGLT2i, GLP-1 RA and finerenone were comparable in MACE, ACD and CVD. SGLT2i significantly decreased the risk of renal events and HHF compared with finerenone and GLP-1 RA. Among GLP-1 RA, GLP-1 analogues showed significant effect in reducing cardiovascular events compared with exendin-4 analogues.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Metanálise em Rede , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Hipoglicemiantes/efeitos adversos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico
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