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1.
FASEB J ; 38(7): e23595, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38572811

RESUMO

This study evaluates the sustained antidepressant-like effects and neurogenic potential of a 3-day intranasal co-administration regimen of galanin receptor 2 (GALR2) agonist M1145 and neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31, Pro34]NPY in the ventral hippocampus of adult rats, with outcomes analyzed 3 weeks post-treatment. Utilizing the forced swimming test (FST), we found that this co-administration significantly enhances antidepressant-like behaviors, an effect neutralized by the GALR2 antagonist M871, highlighting the synergistic potential of these neuropeptides in modulating mood-related behaviors. In situ proximity ligation assay (PLA) indicated a significant increase in GALR2/NPYY1R heteroreceptor complexes in the ventral hippocampal dentate gyrus, suggesting a molecular basis for the behavioral outcomes observed. Moreover, proliferating cell nuclear antigen (PCNA) immunolabeling revealed increased cell proliferation in the subgranular zone of the dentate gyrus, specifically in neuroblasts as evidenced by co-labeling with doublecortin (DCX), without affecting quiescent neural progenitors or astrocytes. The study also noted a significant uptick in the number of DCX-positive cells and alterations in dendritic morphology in the ventral hippocampus, indicative of enhanced neuronal differentiation and maturation. These morphological changes highlight the potential of these agonists to facilitate the functional integration of new neurons into existing neural circuits. By demonstrating the long-lasting effects of a brief, 3-day intranasal administration of GALR2 and NPY1R agonists, our findings contribute significantly to the understanding of neuropeptide-mediated neuroplasticity and herald novel therapeutic strategies for the treatment of depression and related mood disorders, emphasizing the therapeutic promise of targeting neurogenesis and neuronal maturation processes.


Assuntos
Neuropeptídeo Y , Neuropeptídeos , Ratos , Animais , Receptor Tipo 2 de Galanina/agonistas , Receptor Tipo 2 de Galanina/metabolismo , Administração Intranasal , Galanina/farmacologia , Galanina/metabolismo , Hipocampo/metabolismo , Receptores de Neuropeptídeo Y/metabolismo , Neuropeptídeos/farmacologia , Antidepressivos/farmacologia , Neurogênese
2.
Pharmacoepidemiol Drug Saf ; 33(4): e5790, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38575389

RESUMO

PURPOSE: The prevalent new user design extends the active comparator new user design to include patients switching to a treatment of interest from a comparator. We examined the impact of adding "switchers" to incident new users on the estimated hazard ratio (HR) of hospitalized heart failure. METHODS: Using MarketScan claims data (2000-2014), we estimated HRs of hospitalized heart failure between patients initiating GLP-1 receptor agonists (GLP-1 RA) and sulfonylureas (SU). We considered three estimands: (1) the effect of incident new use; (2) the effect of switching; and (3) the effect of incident new use or switching, combining the two population. We used time-conditional propensity scores (TCPS) and time-stratified standardized morbidity ratio (SMR) weighting to adjust for confounding. RESULTS: We identified 76 179 GLP-1 RA new users, of which 12% were direct switchers (within 30 days) from SU. Among incident new users, GLP-1 RA was protective against heart failure (adjHRSMR = 0.74 [0.69, 0.80]). Among switchers, GLP-1 RA was not protective (adjHRSMR = 0.99 [0.83, 1.18]). Results in the combined population were largely driven by the incident new users, with GLP-1 RA having a protective effect (adjHRSMR = 0.77 [0.72, 0.83]). Results using TCPS were consistent with those estimated using SMR weighting. CONCLUSIONS: When analyses were conducted only among incident new users, GLP-1 RA had a protective effect. However, among switchers from SU to GLP-1 RA, the effect estimates substantially shifted toward the null. Combining patients with varying treatment histories can result in poor confounding control and camouflage important heterogeneity.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Compostos de Sulfonilureia/uso terapêutico , Fatores de Risco , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/induzido quimicamente , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes/uso terapêutico
3.
Eur Rev Med Pharmacol Sci ; 28(6): 2272-2287, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38567590

RESUMO

OBJECTIVE: This study aimed to systematically evaluate the efficacy, safety and optimal dose of polyethylene glycol loxenatide (PEX168) for treating type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Clinical trials of PEX168 for T2DM were identified in 8 databases, with a build time limit of January 2023. Included studies were subjected to meta-analysis and trial sequential analysis (TSA). RESULTS: On the efficacy endpoint, the meta-analysis showed that PEX168 100 µg significantly reduced 0.86% glycated hemoglobin type A1c (HbA1c) (MD -0.86, 95% CI -1.02 - -0.70,  p<0.00001), 1.11 mmol/L fasting plasma glucose (FPG) (MD -1.11, 95% CI -1.49 - -0.74, p<0.00001) and 1.91 mmol/L 2h postprandial glucose (PPG) (MD -1.91, 95% CI -3.35 - -0.46, p=0.01) compared with placebo. The TSA showed that all these benefits were conclusive. On safety endpoints, total adverse events (AEs), gastrointestinal (GI) AEs, serious AEs, and hypoglycemia were comparable to placebo for PEX168 100 µg (p>0.05). In the dose comparison, the HbA1c, FPG, and 2h PPG of PEX168 200 µg were comparable to 100 µg (p>0.05), while GI AEs were significantly higher than 100 µg (RR=2.84, 95% CI 1.64-4.93,  p=0.0002). CONCLUSIONS: PEX168 100 µg can significantly lower blood glucose and does not increase the risk of total AEs, GI AEs, and hypoglycemia, which may be a preferred glucagon-like peptide-1 receptor agonist for type 2 diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Peptídeos , Polietilenoglicóis , Humanos , Hipoglicemiantes , Hemoglobinas Glicadas , Glicemia , Hipoglicemia/induzido quimicamente , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas
4.
PLoS One ; 19(4): e0301447, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38557762

RESUMO

Rexinoids are agonists of nuclear rexinoid X receptors (RXR) that heterodimerize with other nuclear receptors to regulate gene transcription. A number of selective RXR agonists have been developed for clinical use but their application has been hampered by the unwanted side effects associated with the use of rexinoids and a limited understanding of their mechanisms of action across different cell types. Our previous studies showed that treatment of organotypic human epidermis with the low toxicity UAB30 and UAB110 rexinoids resulted in increased steady-state levels of all-trans-retinoic acid (ATRA), the obligatory ligand of the RXR-RAR heterodimers. Here, we investigated the molecular mechanism underlying the increase in ATRA levels using a dominant negative RXRα that lacks the activation function 2 (AF-2) domain. The results demonstrated that overexpression of dnRXRα in human organotypic epidermis markedly reduced signaling by resident ATRA, suggesting the existence of endogenous RXR ligand, diminished the biological effects of UAB30 and UAB110 on epidermis morphology and gene expression, and nearly abolished the rexinoid-induced increase in ATRA levels. Global transcriptome analysis of dnRXRα-rafts in comparison to empty vector-transduced rafts showed that over 95% of the differentially expressed genes in rexinoid-treated rafts constitute direct or indirect ATRA-regulated genes. Thus, the biological effects of UAB30 and UAB110 are mediated through the AF-2 domain of RXRα with minimal side effects in human epidermis. As ATRA levels are known to be reduced in certain epithelial pathologies, treatment with UAB30 and UAB110 may represent a promising therapy for normalizing the endogenous ATRA concentration and signaling in epithelial tissues.


Assuntos
Furilfuramida , Tretinoína , Humanos , Receptores X de Retinoides/genética , Receptores X de Retinoides/agonistas , Receptores X de Retinoides/metabolismo , Ligantes , Tretinoína/farmacologia , Tretinoína/metabolismo , Epiderme/metabolismo , Receptores Citoplasmáticos e Nucleares
5.
J Diabetes Res ; 2024: 3212795, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38529046

RESUMO

Background: Beyond glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been proposed to reduce the risk of cardiovascular events. The aim of the present systematic review and meta-analysis is to demonstrate the effects of GLP-1 RA and SGLT2is on intima-media thickness (IMT). Methods: PubMed, EMBASE, Web of Science, SCOPUS, and Google Scholar databases were searched from inception to September 9, 2023. All interventional and observational studies that provided data on the effects of GLP-1 RAs or SGLT2is on IMT were included. Critical appraisal was performed using the Joanna Briggs Institute checklists. IMT changes (preintervention and postintervention) were pooled and meta-analyzed using a random-effects model. Subgroup analyses were based on type of medication (GLP-1 RA: liraglutide and exenatide; SGLT2i: empagliflozin, ipragliflozin, tofogliflozin, and dapagliflozin), randomized clinical trials (RCTs), and diabetic patients. Results: The literature search yielded 708 related articles after duplicates were removed. Eighteen studies examined the effects of GLP-1 RA, and eleven examined the effects of SGLT2i. GLP-1 RA and SGLT2i significantly decreased IMT (MD = -0.123, 95% CI (-0.170, -0.076), P < 0.0001, I2 = 98% and MD = -0.048, 95% CI (-0.092, -0.004), P = 0.031, I2 = 95%, respectively). Metaregression showed that IMT change correlated with baseline IMT, whereas it did not correlate with gender, duration of diabetes, and duration of treatment. Conclusions: Treatment with GLP-1 RA and SGLT2i can lower IMT in diabetic patients, and GLP-1 RA may be more effective than SGLT2i.


Assuntos
Espessura Intima-Media Carotídea , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle
6.
Diabetes Metab Res Rev ; 40(4): e3791, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38549238

RESUMO

AIMS: To evaluate the impact of adherence to glucagon like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose transporter two inhibitors (SGLT2-I) on clinical outcomes and costs in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: The 121,115 residents of the Lombardy Region (Italy) aged ≥40 years newly treated with metformin during 2007-2015 were followed to identify those who started therapy with GLP1-RA or SGLT2-I. Adherence to drug therapy over the first year was defined as the proportion of days covered >80%. Within each drug class, for each adherent patient, one non-adherent patient was matched for age, sex, duration, adherence to metformin treatment and propensity score. The primary clinical outcome was a composite of insulin initiation, hospitalisation for micro- and macrovascular complications and all-cause mortality after the first year of drug treatment. Costs were evaluated based on reimbursements from the national healthcare system. RESULTS: After matching, 1182 pairs of adherent and non-adherent GLP1-RA users and 1126 pairs of adherent and non-adherent SGLT2-I users were included. In both groups, adherent patients experienced a significantly lower incidence of the primary outcome (HR: 0.85, 95% CI 0.72-0.98 for GLP1-RA and HR: 0.69, 95% CI 0.55-0.87 for SGLT2-I). A significant reduction in hospitalizations was found for adherent patients in the GLP1-RA group but not for the SGLT2-I group. Results were consistent when analyses were stratified by age and sex. While higher drug-related costs in the adherent group were counterbalanced by decreased hospitalisation costs in SGLT2-I treated patients, this was not the case for GLP1-RA. CONCLUSIONS: Higher adherence to drug treatment with GLP1-RA and SGLT2-I during the first year of the drug intake is associated with a lower incidence of adverse clinical outcomes in a real-world setting.


Assuntos
Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Adesão à Medicação , Metformina , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/farmacologia , Metformina/uso terapêutico , Transportador 2 de Glucose-Sódio , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
7.
Eur J Med Chem ; 269: 116344, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38522113

RESUMO

Liver fibrosis is commonly occurred in chronic liver diseases, but there is no approved drug for clinical use. The nuclear receptor peroxisome proliferator-activated receptors (PPARs) could not only regulate metabolic homeostasis but also possess anti-inflammatory and antifibrotic effects, and pan-PPARs agonist was considered as a potential anti-liver fibrosis agent. In this study, a series of novel piperazine pan-PPARs agonists were developed, and the preferred compound 12 displayed potent and well-balanced pan-PPARs agonistic activity. Moreover, compound 12 could dose-dependently stimulate the PPARs target genes expression and showed high selectivity over other related nuclear receptors. Importantly, compound 12 exhibited excellent pharmacokinetic profiles and good anti-liver fibrosis effects in vivo. Collectively, compound 12 holds promise for developing an anti-liver fibrosis agent.


Assuntos
Compostos Heterocíclicos , Receptores Ativados por Proliferador de Peroxissomo , Humanos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Cirrose Hepática/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares , Hipoglicemiantes , Piperazinas
8.
Eur J Med Chem ; 269: 116342, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38531211

RESUMO

Glucagon-like peptide-1 (GLP-1), secreted by L cells in the small intestine, assumes a central role in managing type 2 diabetes mellitus (T2DM) and obesity. Its influence on insulin secretion and gastric emptying positions it as a therapeutic linchpin. However, the limited applicability of native GLP-1 stems from its short half-life, primarily due to glomerular filtration and the inactivating effect of dipeptidyl peptidase-IV (DPP-IV). To address this, various structural modification strategies have been developed to extend GLP-1's half-life. Despite the commendable efficacy displayed by current GLP-1 receptor agonists, inherent limitations persist. A paradigm shift emerges with the advent of unimolecular multi-agonists, such as the recently introduced tirzepatide, wherein GLP-1 is ingeniously combined with other gastrointestinal hormones. This novel approach has captured the spotlight within the diabetes and obesity research community. This review summarizes the physiological functions of GLP-1, systematically explores diverse structural modifications, delves into the realm of unimolecular multi-agonists, and provides a nuanced portrayal of the developmental prospects that lie ahead for GLP-1 analogs.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Humanos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Secreção de Insulina , Obesidade/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico
9.
Chemosphere ; 354: 141723, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38494006

RESUMO

Perfluorooctanoic acid (PFOA) is a widespread environmental pollutant of the perfluoroalkyl substance (PFAS) class that is extremely resistant to environmental and metabolic degradation, leading to bioaccumulation. PFOA exposure has been linked to many health effects including endocrine disruption and metabolic dysregulation, but our understanding of the molecular mechanisms resulting in these outcomes remains incomplete. One target affected by PFOA is the ligand regulated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) which plays a critical role in controlling metabolic homeostasis through regulating processes such as adipogenesis, glucose homeostasis, inflammation and osteogenesis. It has been previously established that PFOA activates PPARγ through binding to the PPARγ ligand binding domain (PPARγ LBD) leading to increased expression of PPARγ controlled target genes. However, the mechanism by which PFOA achieves this has remained elusive. Here, we employed a combination of X-ray crystallography and fluorescence polarization assays to provide a structural basis for PFOA mediated activation of PPARγ via binding to the PPARγ LBD. Using X-ray crystallography, the cocrystal structure of the PPARγ LBD:PFOA complex was solved. This revealed that PFOA occupies three distinct sites, two within the PPARγ LBD and one within the activation function 2 (AF2) on the protein surface. Structural comparison of PFOA binding with previously reported PPARγ:ligand complexes supports that PFOA activates PPARγ by a partial agonist mechanism at micromolar concentrations. Fluorescence polarization assays also revealed that PFOA binding to the AF2 is unlikely to occur in a cellular context and confirmed that PFOA behaves as a partial agonist in vitro, weakly recruiting a coactivator peptide to the AF2 of the PPARγ LBD. This discovery provides an advancement in understanding PFOA mediated regulation of PPARγ, giving new insight regarding regulation of PPARγ by PFAS and PFAS substitutes in general and can be applied to the design and assessment of safer PFAS.


Assuntos
Caprilatos , Fluorocarbonos , PPAR gama , PPAR gama/agonistas , Ligantes , Furilfuramida , Fluorocarbonos/toxicidade
10.
Clin Invest Med ; 47(1): 13-22, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38546381

RESUMO

INTRODUCTION: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. After corticosteroids with or without intravenous immune globulin (first-line treatment), second-line treatment options include rituximab, splenectomy, thrombopoietin receptor agonists (TPO-RAs), and fostamatinib. In Canada, the choice of second-line therapy is influenced by access to medications. The goals of this narrative review are to 1) summarize the evidence for the use of TPO-RAs and other second-line therapies in ITP and 2) highlight differences in public funding criteria for TPO-RAs across provinces and territories in Canada. METHODS: We conducted a literature review of second-line therapies for ITP. We solicited information on public funding programs for TPO-RAs in Canada from health care providers, pharmacists, and provincial ministries of health. RESULTS: Head-to-head trials involving TPO-RAs, rituximab, splenectomy, and fostamatinib are lacking. There is substantial evidence of effect for TPO-RAs in improving platelet count levels, health-related quality of life, bleeding, and fatigue from placebo-controlled trials and observational studies; however, access to TPO-RAs through provincial funding programs in Canada is variable. Splenectomy failure is a prerequisite for the funding of TPO-RAs in Ontario, Manitoba, and Saskatchewan, but not in Alberta or Quebec. Other provinces either do not have access to public funding or funding is provided on a case-by-case basis. DISCUSSION: TPO-RAs are effective second-line therapies for the treatment of ITP; however, access is variable across Canada, which results in health disparities and poor uptake of international treatment guidelines.


Assuntos
Aminopiridinas , Morfolinas , Púrpura Trombocitopênica Idiopática , Pirimidinas , Receptores de Trombopoetina , Humanos , Aminopiridinas/uso terapêutico , Morfolinas/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirimidinas/uso terapêutico , Qualidade de Vida , Receptores de Trombopoetina/agonistas , Rituximab/uso terapêutico
11.
Org Biomol Chem ; 22(14): 2764-2773, 2024 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-38497199

RESUMO

Pattern recognition receptors (PRRs) play a critical role in the innate immune response, and toll-like receptor 7 (TLR7) is an important member of PRRs. Although several TLR7 agonists are available, most of them are being tested clinically, with only one available on the market. Thus, it is imperative to develop new TLR7 agonists. In this study, we designed and synthesized three kinds of quinazoline derivatives and five kinds of pyrrolo[3,2-d]pyrimidine derivatives targeting TLR7. The antiviral efficacy of these compounds was evaluated in vitro and in vivo. Our findings indicated that four kinds of compounds showed exceptional antiviral activity. Furthermore, molecular docking studies confirmed that compound 11 successfully positioned itself in the pocket of the TLR7 guanosine loading site with a binding energy of -4.45 kcal mol-1. These results suggested that these compounds might be potential antiviral agents.


Assuntos
Quinazolinas , Receptor 7 Toll-Like , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/metabolismo , Quinazolinas/química , Simulação de Acoplamento Molecular , Adjuvantes Imunológicos , Antivirais/farmacologia , Pirimidinas/química
12.
Proc Natl Acad Sci U S A ; 121(13): e2306814121, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38513102

RESUMO

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody-drug conjugates, and immune-checkpoint inhibitors, have been developed for clinical use. Previous reports have demonstrated the essential role of estrogen receptor ß (ERß) in TNBC, but the detailed molecular mechanisms downstream ERß activation in TNBC are still far from elucidated. In this study, we demonstrated that a specific ERß agonist, LY500307, potently induces R-loop formation and DNA damage in TNBC cells. Subsequent interactome experiments indicated that the residues 151 to 165 of U2 small nuclear RNA auxiliary factor 1 (U2AF1) and the Trp439 and Lys443 of ERß were critical for the binding between U2AF1 and ERß. Combined RNA sequencing and ribosome sequencing analysis demonstrated that U2AF1-regulated downstream RNA splicing of 5-oxoprolinase (OPLAH) could affect its enzymatic activity and is essential for ERß-induced R-loop formation and DNA damage. In clinical samples including 115 patients from The Cancer Genome Atlas (TCGA) and 32 patients from an in-house cohort, we found a close correlation in the expression of ESR2 and U2AF1 in TNBC patients. Collectively, our study has unraveled the molecular mechanisms that explain the therapeutic effects of ERß activation in TNBC, which provides rationale for ERß activation-based single or combined therapy for patients with TNBC.


Assuntos
Processamento Alternativo , Benzopiranos , Receptor beta de Estrogênio , Estruturas R-Loop , Fator de Processamento U2AF , Neoplasias de Mama Triplo Negativas , Humanos , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Fator de Processamento U2AF/química , Fator de Processamento U2AF/genética , Fator de Processamento U2AF/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Terapia Combinada , Células MDA-MB-231 , Processamento Alternativo/efeitos dos fármacos , Benzopiranos/farmacologia , Benzopiranos/uso terapêutico , Ligação Proteica , Sítios de Ligação
13.
Med Clin North Am ; 108(3): 469-487, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38548458

RESUMO

Patients with type 2 diabetes and/or obesity and established cardiovascular disease are at increased risk for recurrent cardiovascular events. The indications of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors have been expanded in the last decade due to benefit in cardiovascular outcome trials and are now considered guideline-recommended therapy for patients with type 2 diabetes and cardiovascular disease. Emerging data have begun to suggest that GLP-1RAs can decrease major adverse cardiovascular events among patients with obesity without diabetes. Overall, prescription of these agents remains low, despite being key to improve disparities in recurrent cardiovascular events. In this review, we discuss optimal medical therapy for secondary prevention for stable ischemic heart disease.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Isquemia Miocárdica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Obesidade/complicações , Isquemia Miocárdica/complicações , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/prevenção & controle , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas
14.
Behav Brain Funct ; 20(1): 6, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38549164

RESUMO

BACKGROUND: Spatial memory deficits and reduced neuronal survival contribute to cognitive decline seen in the aging process. Current treatments are limited, emphasizing the need for innovative therapeutic strategies. This research explored the combined effects of intranasally co-administered galanin receptor 2 (GALR2) and neuropeptide Y1 receptor (NPY1R) agonists, recognized for their neural benefits, on spatial memory, neuronal survival, and differentiation in adult rats. After intranasal co-delivery of the GALR2 agonist M1145 and a NPY1R agonist to adult rats, spatial memory was tested with the object-in-place task 3 weeks later. We examined neuronal survival and differentiation by assessing BrdU-IR profiles and doublecortin (DCX) labeled cells, respectively. We also used the GALR2 antagonist M871 to confirm GALR2's crucial role in promoting cell growth. RESULTS: Co-administration improved spatial memory and increased the survival rate of mature neurons. The positive effect of GALR2 in cell proliferation was confirmed by the nullifying effects of its antagonist. The treatment boosted DCX-labeled newborn neurons and altered dendritic morphology, increasing cells with mature dendrites. CONCLUSIONS: Our results show that intranasal co-delivery of GALR2 and NPY1R agonists improves spatial memory, boosts neuronal survival, and influences neuronal differentiation in adult rats. The significant role of GALR2 is emphasized, suggesting new potential therapeutic strategies for cognitive decline.


Assuntos
Disfunção Cognitiva , Receptor Tipo 2 de Galanina , Ratos , Animais , Receptor Tipo 2 de Galanina/agonistas , Receptor Tipo 2 de Galanina/fisiologia , Receptores de Neuropeptídeo Y , Galanina/farmacologia , Neurogênese , Cognição , Disfunção Cognitiva/tratamento farmacológico
15.
Diabetes Res Clin Pract ; 209: 111604, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38447911

RESUMO

AIMS: Sodium glucose co-transporter 2 inhibitors (SGLT2is) and/or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) with proven cardio- and reno-protective benefits are recommended in people with type 2 diabetes (T2D) at high risk of cardiovascular disease, chronic kidney disease, and/or heart failure. This pooled analysis compared efficacy and safety outcomes of iGlarLixi with or without SGLT2is in people with T2D. METHODS: This post hoc analysis evaluated outcomes in participants who were receiving an SGLT2i when initiating iGlarLixi (SGLT2i users) and those who were not (SGLT2i non-users) in a pooled dataset from three trials: LixiLan-G (advancing from a GLP-1 RA), SoliMix and LixiLan ONE CAN (advancing from basal insulin). RESULTS: Baseline characteristics were generally similar between 219 users and 746 non-users. Least squares mean changes in HbA1c from baseline to Week 26 were similar for users (-1.2 % [95 % confidence intervals: -1.4 %, -1.1 %]) and non-users (-1.2 % [-1.2 %, -1.1 %]). Changes in body weight, fasting glucose and post-prandial glucose were similar between groups, as were hypoglycaemic events. CONCLUSIONS: Pooled results from three studies of adults with T2D demonstrated that iGlarLixi provided similar clinically meaningful improvements in glycaemic control without increased hypoglycaemia risk, regardless of concomitant use of SGLT2is.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Simportadores , Adulto , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Insulina Glargina/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Glicemia , Hemoglobinas Glicadas , Combinação de Medicamentos , Peptídeos/uso terapêutico , Hipoglicemiantes/efeitos adversos , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Glucose/uso terapêutico , Simportadores/uso terapêutico , Sódio/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas
16.
Environ Sci Technol ; 58(11): 4872-4883, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38440973

RESUMO

G protein-coupled receptors (GPCRs) are central mediators of cell signaling and physiological function. Despite their biological significance, GPCRs have not been widely studied in the field of toxicology. Herein, we investigated these receptors as novel targets of plastic chemicals using a high-throughput drug screening assay with 126 human non-olfactory GPCRs. In a first-pass screen, we tested the activity of triphenol phosphate, bisphenol A, and diethyl phthalate, as well as three real-world mixtures of chemicals extracted from plastic food packaging covering all major polymer types. We found 11 GPCR-chemical interactions, of which the chemical mixtures exhibited the most robust activity at adenosine receptor 1 (ADORA1) and melatonin receptor 1 (MTNR1A). We further confirm that polyvinyl chloride and polyurethane products contain ADORA1 or MTNRA1 agonists using a confirmatory secondary screen and pharmacological knockdown experiments. Finally, an analysis of the associated gene ontology terms suggests that ADORA1 and MTNR1A activation may be linked to downstream effects on circadian and metabolic processes. This work highlights that signaling disruption caused by plastic chemicals is broader than that previously believed and demonstrates the relevance of nongenomic pathways, which have, thus far, remained unexplored.


Assuntos
Receptores Acoplados a Proteínas G , Transdução de Sinais , Humanos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Ensaios de Triagem em Larga Escala , Polímeros
17.
Int Immunopharmacol ; 130: 111693, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38428144

RESUMO

Oxidative stress and neuroinflammation are two major causes leading to early brain injury after subarachnoid hemorrhage (SAH). Nuclear factor E2-related factor 2 (Nrf2) is a critical transcription factor that contributes to antioxidant responses. Additionally, Nrf2 could inhibit transforming growth factor beta-activated kinase 1 (TAK1), which plays a vital role in microglial activation-mediated neuroinflammation. Neferine (NE) exhibits considerable protective effects in diverse disease models. However, the detailed effect and mechanism of NE on SAH remain unknown. Our data showed that NE treatment significantly reduced behavior and cognitive impairment, and brain edema in the early period after SAH. In addition, NE mitigated SAH-induced oxidative damage, neuroinflammation, and neural death. Moreover, NE inhibited M1 microglial polarization and enhanced M2 phenotype microglia both in vivo and in vitro. Further investigations revealed that NE enhanced the Nrf2-antioxidant response element (ARE) signaling pathway and suppressed TAK1-NF-κB signaling. In contrast, depletion of Nrf2 by ML385 suppressed Nrf2-ARE signaling, induced TAK1-NF-κB activation, and further promoted M1 microglial polarization. Additionally, ML385 abated the neuroprotective effects of NE against SAH. Notably, LPS also aggravated TAK1-NF-κB activation and reversed the beneficial effects of NE after SAH. In summary, NE provides protection after SAH by inhibiting oxidative stress and modulating microglial polarization through Nrf2 activation and TAK1-NF-κB suppression.


Assuntos
Benzilisoquinolinas , Microglia , Fator 2 Relacionado a NF-E2 , NF-kappa B , Doenças Neuroinflamatórias , Hemorragia Subaracnóidea , Masculino , Benzilisoquinolinas/farmacologia , Benzilisoquinolinas/uso terapêutico , Camundongos Endogâmicos C57BL , Microglia/patologia , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/etiologia , Fator 2 Relacionado a NF-E2/agonistas , NF-kappa B/metabolismo , Transdução de Sinais , Hemorragia Subaracnóidea/complicações , Modelos Animais de Doenças
18.
Int Immunopharmacol ; 130: 111778, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38432147

RESUMO

OBJECTIVE: To investigate the mechanism of action of fatty acid receptors, FFAR1 and FFAR4, on ulcerative colitis (UC) through fatty acid metabolism and macrophage polarization. METHODS: Dextran sulfate sodium (DSS)-induced mouse model of UC mice was used to evaluate the efficacy of FFAR1 (GW9508) and FFAR4 (GSK137647) agonists by analyzing body weight, colon length, disease activity index (DAI), and histological scores. Real-time PCR and immunofluorescence analysis were performed to quantify the levels of fatty acid metabolizing enzymes and macrophage makers. FFA-induced lipid accumulation in RAW264.7 cells was visualized by Oil Red O staining analysis, and cells were collected to detect macrophage polarization by flow cytometry. RESULTS: The combination of GW9508 and GSK137647 significantly improved DSS-induced UC symptoms, caused recovery in colon length, and decreased histological injury. GW9508 + GSK137647 treatment upregulated the expressions of CD206, lipid oxidation enzyme (CPT-1α) and anti-inflammatory cytokines (IL-4, IL-10, IL-13) but downregulated those of CD86, lipogenic enzymes (ACC1, FASN, SCD1), and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α). Combining the two agonists decreased FFA-induced lipid accumulation and increased CD206 expression in cell-based experiments. CONCLUSION: Activated FFAR1 and FFAR4 ameliorates DSS-induced UC by promoting fatty acid metabolism to reduce lipid accumulation and mediate M2 macrophage polarization.


Assuntos
Colite Ulcerativa , Ácidos Graxos não Esterificados , Macrófagos , Receptores Acoplados a Proteínas G , Animais , Camundongos , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metilaminas/farmacologia , Metilaminas/uso terapêutico , Camundongos Endogâmicos C57BL , Propionatos/farmacologia , Propionatos/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas
19.
Int Immunopharmacol ; 130: 111772, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38432148

RESUMO

Post-operative cognitive dysfunction (POCD) is a multi-etiological symptom mainly occurred in elderly people after surgery. The activation of retinoic acid receptor α (RARα), a transcriptional factor, was previously predicated to be negatively associated with the occurrence of POCD. However, the mechanisms underlying anti-POCD effects of RARα were still unclear. In this study, AM580, a selective agonist of RARα, and all-trans-retinoic acid (ATRA), a pan agonist of RAR, significantly alleviated cognitive dysfunction and increased the expression of RARα in elderly mice after surgery, which was decreased by RO41-5253, an antagonist of RARα. A bioinformatic study further predicted that the activation of RARα might produce anti-POCD effects via the restoration of synaptic proteins. Both agonists inhibited the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and the phosphorylation of nuclear factorkappa-B (NF-κB), leading to the prevention of microglial over-activation and pro-inflammatory cytokines secretion in the hippocampal regions of elderly mice after surgery. Moreover, AM580 and ATRA increased the expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), and the phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP-response element binding protein (CREB). All these results suggested that the activation of RARα prevented surgery-induced cognitive impairments via the inhibition of neuroinflammation by the reduction of the TLR4/Myd88/NF-κB pathway and the restoration of synaptic proteins by the activation of the BDNF/ERK/CREB pathway, providing a further support that RARα could be developed as a therapeutic target for POCD.


Assuntos
Benzoatos , NF-kappa B , Complicações Cognitivas Pós-Operatórias , Receptor alfa de Ácido Retinoico , Tetra-Hidronaftalenos , Animais , Camundongos , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Camundongos Endogâmicos ICR , Fator 88 de Diferenciação Mieloide/metabolismo , Doenças Neuroinflamatórias/prevenção & controle , NF-kappa B/metabolismo , Complicações Cognitivas Pós-Operatórias/prevenção & controle , Receptor alfa de Ácido Retinoico/agonistas , Transdução de Sinais , Tetra-Hidronaftalenos/farmacologia , Tetra-Hidronaftalenos/uso terapêutico , Receptor 4 Toll-Like/metabolismo , Tretinoína/farmacologia
20.
Chem Commun (Camb) ; 60(26): 3563-3566, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38465405

RESUMO

CPN-116 is a peptidic agonist that activates human neuromedin U receptor type 2 (NMUR2) but suffers from chemical instability due to inherent backbone isomerization on the Dap residue. To address this, a Leu-Dap-type (Z)-chloroalkene dipeptide isostere was synthesized diastereoselectively as a surrogate of the Leu-Dap peptide bond to develop a (Z)-chloroalkene analogue of CPN-116. The synthesized CPN-116 analogue is stable in 1.0 M phosphate buffer (pH 7.4) without backbone isomerization and can activate NMUR2 with similar potency to CPN-116 at nM concentrations (EC50 = 1.0 nM).


Assuntos
Neuropeptídeos , Humanos , Neuropeptídeos/química , Amidas/farmacologia , Peptídeos , Receptores de Neurotransmissores/agonistas
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