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1.
Nat Commun ; 15(1): 3882, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38719809

RESUMO

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.


Assuntos
Linfócitos T CD8-Positivos , Vacinas Anticâncer , Carboximetilcelulose Sódica/análogos & derivados , Células Dendríticas , Glioma , Interferons , Poli I-C , Polilisina/análogos & derivados , Humanos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Glioma/imunologia , Glioma/terapia , Feminino , Masculino , Pessoa de Meia-Idade , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Poli I-C/administração & dosagem , Poli I-C/farmacologia , Adulto , Receptores Toll-Like/agonistas , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Idoso , Vacinação , Monócitos/imunologia , Monócitos/efeitos dos fármacos , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamento farmacológico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Imunoterapia/métodos , Agonistas do Receptor Semelhante a Toll
2.
Mol Med ; 30(1): 58, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38720283

RESUMO

BACKGROUND: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. MATERIALS AND METHODS: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and ß-glycerophosphate (ß-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. RESULTS: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/ß-GP-induced VSMCs. In HG/ß-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/ß-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. CONCLUSION: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.


Assuntos
Proteínas Quinases Ativadas por AMP , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1 , Mitofagia , Transdução de Sinais , Calcificação Vascular , Animais , Mitofagia/efeitos dos fármacos , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Calcificação Vascular/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Camundongos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Masculino , Proteínas Quinases Ativadas por AMP/metabolismo , Humanos , Exenatida/farmacologia , Exenatida/uso terapêutico , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
3.
Nat Commun ; 15(1): 3965, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730017

RESUMO

Currently, there is no pesticide available for the selective control of the pine processionary moth (Thaumetopoea pityocampa-specific), and conventional methods typically rely on mechanical techniques such as pheromone traps or broad-spectrum larvicidal chemicals. As climate change increases the range and dispersion capacity of crop and forest pests, outbreaks of the pine processionary occur with greater frequency and significantly impact forestry and public health. Our study is carried out to provide a T. pityocampa-specific pesticide targeting the Allatostatin Type-C Receptor (AlstR-C). We use a combination of computational biology methods, a cell-based screening assay, and in vivo toxicity and side effect assays to identify, for the first time, a series of AlstR-C ligands suitable for use as T. pityocampa-specific insecticides. We further demonstrate that the novel AlstR-C targeted agonists are specific to lepidopteran larvae, with no harmful effects on coleopteran larvae or adults. Overall, our study represents an important initial advance toward an insect GPCR-targeted next-generation pesticide design. Our approach may apply to other invertebrate GPCRs involved in vital metabolic pathways.


Assuntos
Inseticidas , Larva , Mariposas , Animais , Mariposas/efeitos dos fármacos , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Proteínas de Insetos/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Humanos , Ligantes , Neuropeptídeos
4.
Nat Commun ; 15(1): 3933, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730243

RESUMO

As a strategy to improve the therapeutic success of chimeric antigen receptor T cells (CART) directed against solid tumors, we here test the combinatorial use of CART and IMSA101, a newly developed stimulator of interferon genes (STING) agonist. In two syngeneic tumor models, improved overall survival is observed when mice are treated with intratumorally administered IMSA101 in addition to intravenous CART infusion. Transcriptomic analyses of CART isolated from tumors show elevated T cell activation, as well as upregulated cytokine pathway signatures, in particular IL-18, in the combination treatment group. Also, higher levels of IL-18 in serum and tumor are detected with IMSA101 treatment. Consistent with this, the use of IL-18 receptor negative CART impair anti-tumor responses in mice receiving combination treatment. In summary, we find that IMSA101 enhances CART function which is facilitated through STING agonist-induced IL-18 secretion.


Assuntos
Interleucina-18 , Proteínas de Membrana , Receptores de Antígenos Quiméricos , Animais , Interleucina-18/metabolismo , Proteínas de Membrana/agonistas , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Humanos , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Feminino , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/tratamento farmacológico
5.
Rev Gastroenterol Peru ; 44(1): 71-74, 2024.
Artigo em Espanhol | MEDLINE | ID: mdl-38734915

RESUMO

Initially developed as medications for diabetes mellitus, GLP-1 agonists have gained much popularity in the treatment of obesity and weight loss. The present case describes a 69-year-old woman with a history of peptic ulcer and use of NSAIDs, who presented with abdominal pain and oral intolerance refractory to conventional management, for which an upper digestive endoscopy was performed, diagnosing severe gastroparesis. Asking more about the story, revealed surreptitious use of semaglutide. She continued with supportive therapy and the symptoms resolved spontaneously. The present case report aims to warn of the potential risks of the use of GLP-1 analogues in the context of endoscopy with sedation.


Assuntos
Gastroparesia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Peptídeos Semelhantes ao Glucagon , Redução de Peso , Humanos , Idoso , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/efeitos adversos , Redução de Peso/efeitos dos fármacos , Gastroparesia/tratamento farmacológico , Índice de Gravidade de Doença , Agonistas do Receptor do Peptídeo 1 Semelhante ao Glucagon
6.
J Immunother Cancer ; 12(5)2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702146

RESUMO

BACKGROUND: T cell checkpoint receptors are expressed when T cells are activated, and modulation of the expression or signaling of these receptors can alter the function of T cells and their antitumor efficacy. We previously found that T cells activated with cognate antigen had increases in the expression of PD-1, and this was attenuated in the presence of multiple toll-like receptor (TLR) agonists, notably TLR3 plus TLR9. In the current report, we sought to investigate whether combining TLR agonists with immune checkpoint blockade can further augment vaccine-mediated T cell antitumor immunity in murine tumor models. METHODS: TLR agonists (TLR3 plus TLR9) and immune checkpoint inhibitors (antibodies targeting PD-1, CTLA-4, LAG-3, TIM-3 or VISTA) were combined and delivered with vaccines or vaccine-activated CD8+T cells to E.G7-OVA or MyC-CaP tumor-bearing mice. Tumors were assessed for growth and then collected and analyzed by flow cytometry. RESULTS: Immunization of E.G7-OVA tumor-bearing mice with SIINFEKL peptide vaccine, coadministered with TLR agonists and αCTLA-4, demonstrated greater antitumor efficacy than immunization with TLR agonists or αCTLA-4 alone. Conversely, the antitumor efficacy was abrogated when vaccine and TLR agonists were combined with αPD-1. TLR agonists suppressed PD-1 expression on regulatory T cells (Tregs) and activated this population. Depletion of Tregs in tumor-bearing mice led to greater antitumor efficacy of this combination therapy, even in the presence of αPD-1. Combining vaccination with TLR agonists and αCTLA-4 or αLAG-3 showed greater antitumor than with combinations with αTIM-3 or αVISTA. CONCLUSION: The combination of TLR agonists and αCTLA-4 or αLAG-3 can further improve the efficacy of a cancer vaccine, an effect not observed using αPD-1 due to activation of Tregs when αPD-1 was combined with TLR3 and TLR9 agonists. These data suggest that optimal combinations of TLR agonists and immune checkpoint blockade may improve the efficacy of human anticancer vaccines.


Assuntos
Vacinas Anticâncer , Inibidores de Checkpoint Imunológico , Receptores Toll-Like , Animais , Camundongos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo , Feminino , Humanos , Linhagem Celular Tumoral , Agonistas do Receptor Semelhante a Toll
7.
Front Endocrinol (Lausanne) ; 15: 1343176, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38742200

RESUMO

Study objective: To investigate whether different timings of GnRH-a downregulation affected assisted reproductive outcomes in infertile women with moderate-to-severe intrauterine adhesions (IUAs) accompanied by adenomyosis. Design: A retrospective case series. Setting: An assisted reproductive technology center. Patients: The study reviewed 123 infertile women with moderate-to-severe IUAs accompanied by adenomyosis undergoing their first frozen-thawed embryo transfer (FET) cycles between January 2019 and December 2021. Measurements and main results: The majority of patients had moderate IUA (n=116, 94.31%). The average Basal uterine volume was 73.58 ± 36.50 cm3. The mean interval from operation to the first downregulation was 21.07 ± 18.02 days (range, 1-79 days). The mean duration of hormone replacement therapy (HRT) was 16.93 ± 6.29 days. The average endometrial thickness on the day before transfer was 10.83 ± 1.75 mm. A total of 70 women achieved clinical pregnancy (56.91%). Perinatal outcomes included live birth (n=47, 67.14%), early miscarriage (n=18, 25.71%), and late miscarriage (n=5, 7.14%). The time interval between uterine operation and the first downregulation was not a significant variable affecting live birth. Maternal age was the only risk factor associated with live birth (OR:0.89; 95% CI: 0.79-0.99, P=0.041). Conclusions: The earlier initiation of GnRH-a to suppress adenomyosis prior to endometrial preparation for frozen embryo transfer did not negatively impact repair of the endometrium after resection.


Assuntos
Adenomiose , Transferência Embrionária , Endométrio , Hormônio Liberador de Gonadotropina , Infertilidade Feminina , Nascido Vivo , Humanos , Feminino , Hormônio Liberador de Gonadotropina/agonistas , Adulto , Estudos Retrospectivos , Gravidez , Endométrio/efeitos dos fármacos , Endométrio/patologia , Nascido Vivo/epidemiologia , Infertilidade Feminina/terapia , Transferência Embrionária/métodos , Taxa de Gravidez , Coeficiente de Natalidade , Aderências Teciduais , Fertilização in vitro/métodos
8.
Med ; 5(5): 377-379, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38733969

RESUMO

The study by Hirschfield et al.1 demonstrated safety profile and clinically significant effectiveness of the peroxisome proliferator-activated receptor delta (PPARδ) agonist seladelpar in patients with primary biliary cholangitis, highlighting its plausible use as a second-line treatment to reduce disease activity and pruritus.


Assuntos
Cirrose Hepática Biliar , Prurido , Humanos , Prurido/tratamento farmacológico , Cirrose Hepática Biliar/tratamento farmacológico , PPAR delta/agonistas , PPAR delta/metabolismo
9.
BMJ Open Diabetes Res Care ; 12(3)2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38719507

RESUMO

INTRODUCTION: Studies have found that sodium-glucose cotransporter 2 inhibitors (SGLT2) and glucagon-like peptide 1 receptor agonists (GLP1) have cardiovascular benefits for patients with type 2 diabetes (DM2) and atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or heart failure (HF). The literature does not provide evidence specifically for patients with these conditions who are adding one of these medicines to two glucose-lowering medications (ie, as "third-step" therapy). We explored the effects of different third-step medications on cardiovascular outcomes in patients with diabetes and these comorbid conditions. Specifically, we compared third-step SGLT2 or GLP1 to third-step dipeptidyl peptidase-4 inhibitors (DPP4), insulin, or thiazolidinediones (TZD). RESEARCH DESIGN AND METHODS: We assembled a retrospective cohort of adults at five Kaiser Permanente sites with DM2 and ASCVD, CKD, or HF, initiating third-step treatment between 2016 and 2020. Propensity score weighted Poisson models were used to calculate adjusted rate ratios (ARRs) for all-cause mortality, incident major adverse cardiovascular event (MACE), and incident HF hospitalization in patients initiating SGLT2 or GLP1 compared with DPP4, insulin, or TZD. RESULTS: We identified 27 542 patients initiating third-step treatment with one or more of these conditions (19 958 with ASCVD, 14 577 with CKD, and 3919 with HF). ARRs for GLP1 and SGLT2 versus DPP4, insulin, and TZD in the patient subgroups ranged between 0.22 and 0.55 for all-cause mortality, 0.38 and 0.81 for MACE, and 0.46 and 1.05 for HF hospitalization. Many ARRs were statistically significant, and all significant ARRs showed a benefit (ARR <1) for GLP1 or SGLT2 when compared with DPP4, insulin, or TZD. CONCLUSIONS: Third-step SGLT2 and GLP1 are generally associated with a benefit for these outcomes in these patient groups when compared with third-step DPP4, insulin, or TZD. Our results add to evidence of a cardiovascular benefit of SGLT2 and GLP1 and could inform clinical guidelines for choosing third-step diabetes treatment.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Feminino , Masculino , Estudos Retrospectivos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Pessoa de Meia-Idade , Idoso , Hipoglicemiantes/uso terapêutico , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/epidemiologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glicemia/análise , Insuficiência Renal Crônica/epidemiologia , Seguimentos , Prognóstico , Insulina/uso terapêutico
10.
Alzheimers Res Ther ; 16(1): 95, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38693554

RESUMO

BACKGROUND: Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated endoplasmic reticulum (ER)- mitochondria signaling plays a key role in the neuronal cytopathology of Alzheimer's disease (AD). The natural psychedelic N, N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti-AD potential through protecting neuronal ER-mitochondrial interplay. METHODS: 3×TG-AD transgenic mice were administered with chronic DMT (2 mg/kg) for 3 weeks and then performed water maze test. The Aß accumulation in the mice brain were determined. The Sig-1r level upon DMT treatment was tested. The effect of DMT on the ER-mitochondrial contacts site and multiple mitochondria-associated membrane (MAM)-associated proteins were examined. The effect of DMT on calcium transport between ER and mitochondria and the mitochondrial function were also evaluated. RESULTS: chronic DMT (2 mg/kg) markedly alleviated cognitive impairment of 3×TG-AD mice. In parallel, it largely diminished Aß accumulation in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of 3×TG-AD transgenic mice. The hallucinogen reinstated the expression of multiple MAM-associated proteins in the brain of 3×TG-AD mice. DMT also prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. DMT modulated oxidative phosphorylation (OXPHOS) and ATP synthase in the in vitro model of AD. CONCLUSION: The anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the activation of Sig-1r. DMT has the potential to serve as a novel preventive and therapeutic agent against AD.


Assuntos
Doença de Alzheimer , Retículo Endoplasmático , Alucinógenos , Camundongos Transgênicos , Mitocôndrias , N,N-Dimetiltriptamina , Receptores sigma , Receptor Sigma-1 , Animais , Receptores sigma/metabolismo , Receptores sigma/agonistas , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Alucinógenos/farmacologia , N,N-Dimetiltriptamina/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Masculino
11.
Front Endocrinol (Lausanne) ; 15: 1379228, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38745956

RESUMO

Aims: Individuals with lipodystrophies typically suffer from metabolic disease linked to adipose tissue dysfunction including lipoatrophic diabetes. In the most severe forms of lipodystrophy, congenital generalised lipodystrophy, adipose tissue may be almost entirely absent. Better therapies for affected individuals are urgently needed. Here we performed the first detailed investigation of the effects of a glucagon like peptide-1 receptor (GLP-1R) agonist in lipoatrophic diabetes, using mice with generalised lipodystrophy. Methods: Lipodystrophic insulin resistant and glucose intolerant seipin knockout mice were treated with the GLP-1R agonist liraglutide either acutely preceding analyses of insulin and glucose tolerance or chronically prior to metabolic phenotyping and ex vivo studies. Results: Acute liraglutide treatment significantly improved insulin, glucose and pyruvate tolerance. Once daily injection of seipin knockout mice with liraglutide for 14 days led to significant improvements in hepatomegaly associated with steatosis and reduced markers of liver fibrosis. Moreover, liraglutide enhanced insulin secretion in response to glucose challenge with concomitantly improved glucose control. Conclusions: GLP-1R agonist liraglutide significantly improved lipoatrophic diabetes and hepatic steatosis in mice with generalised lipodystrophy. This provides important insights regarding the benefits of GLP-1R agonists for treating lipodystrophy, informing more widespread use to improve the health of individuals with this condition.


Assuntos
Modelos Animais de Doenças , Receptor do Peptídeo Semelhante ao Glucagon 1 , Resistência à Insulina , Lipodistrofia , Liraglutida , Camundongos Knockout , Animais , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos , Lipodistrofia/tratamento farmacológico , Lipodistrofia/metabolismo , Masculino , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Glicemia/metabolismo , Insulina/metabolismo , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Camundongos Endogâmicos C57BL
12.
Eur J Med Chem ; 271: 116462, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38691888

RESUMO

The G protein-coupled bile acid receptor 1 (GPBAR1) or TGR5 is widely distributed across organs, including the small intestine, stomach, liver, spleen, and gallbladder. Many studies have established strong correlations between TGR5 and glucose homeostasis, energy metabolism, immune-inflammatory responses, and gastrointestinal functions. These results indicate that TGR5 has a significant impact on the progression of tumor development and metabolic disorders such as diabetes mellitus and obesity. Targeting TGR5 represents an encouraging therapeutic approach for treating associated human ailments. Notably, the GLP-1 receptor has shown exceptional efficacy in clinical settings for diabetes management and weight loss promotion. Currently, numerous TGR5 agonists have been identified through natural product-based approaches and virtual screening methods, with some successfully progressing to clinical trials. This review summarizes the intricate relationships between TGR5 and various diseases emphasizing recent advancements in research on TGR5 agonists, including their structural characteristics, design tactics, and biological activities. We anticipate that this meticulous review could facilitate the expedited discovery and optimization of novel TGR5 agonists.


Assuntos
Receptores Acoplados a Proteínas G , Humanos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Estrutura Molecular , Desenvolvimento de Medicamentos , Obesidade/tratamento farmacológico , Animais , Diabetes Mellitus/tratamento farmacológico , Neoplasias/tratamento farmacológico
13.
Eur J Med Chem ; 271: 116439, 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38691886

RESUMO

Nucleotide-binding oligomerization domain 2 (NOD2) is a receptor of the innate immune system that is capable of perceiving bacterial and viral infections. Muramyl dipeptide (MDP, N-acetyl muramyl L-alanyl-d-isoglutamine), identified as the minimal immunologically active component of bacterial cell wall peptidoglycan (PGN) is recognized by NOD2. In terms of biological activities, MDP demonstrated vaccine adjuvant activity and stimulated non-specific protection against bacterial, viral, and parasitic infections and cancer. However, MDP has certain drawbacks including pyrogenicity, rapid elimination, and lack of oral bioavailability. Several detailed structure-activity relationship (SAR) studies around MDP scaffolds are being carried out to identify better NOD2 ligands. The present review elaborates a comprehensive SAR summarizing structural aspects of MDP derivatives in relation to NOD2 agonistic activity.


Assuntos
Acetilmuramil-Alanil-Isoglutamina , Proteína Adaptadora de Sinalização NOD2 , Proteína Adaptadora de Sinalização NOD2/metabolismo , Proteína Adaptadora de Sinalização NOD2/agonistas , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Acetilmuramil-Alanil-Isoglutamina/química , Relação Estrutura-Atividade , Humanos , Animais , Estrutura Molecular
14.
Bioconjug Chem ; 35(5): 693-702, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38700695

RESUMO

The development of oligomeric glucagon-like peptide-1 (GLP-1) and GLP-1-containing coagonists holds promise for enhancing the therapeutic potential of the GLP-1-based drugs for treating type 2 diabetes mellitus (T2DM). Here, we report a facile, efficient, and customizable strategy based on genetically encoded SpyCatcher-SpyTag chemistry and an inducible, cleavable self-aggregating tag (icSAT) scheme. icSAT-tagged SpyTag-fused GLP-1 and the dimeric or trimeric SpyCatcher scaffold were designed for dimeric or trimeric GLP-1, while icSAT-tagged SpyCatcher-fused GLP-1 and the icSAT-tagged SpyTag-fused GIP were designed for dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) receptor agonist. These SpyCatcher- and SpyTag-fused protein pairs were spontaneously ligated directly from the cell lysates. The subsequent icSAT scheme, coupled with a two-step standard column purification, resulted in target proteins with authentic N-termini, with yields ranging from 35 to 65 mg/L and purities exceeding 99%. In vitro assays revealed 3.0- to 4.1-fold increased activities for dimeric and trimeric GLP-1 compared to mono-GLP-1. The dual GLP-1/GIP receptor agonist exhibited balanced activity toward the GLP-1 receptor or the GIP receptor. All the proteins exhibited 1.8- to 3.0-fold prolonged half-lives in human serum compared to mono-GLP-1 or GIP. This study provides a generally applicable click biochemistry strategy for developing oligomeric or dual peptide/protein-based drug candidates.


Assuntos
Química Click , Peptídeo 1 Semelhante ao Glucagon , Peptídeo 1 Semelhante ao Glucagon/química , Humanos , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores dos Hormônios Gastrointestinais/química , Receptores dos Hormônios Gastrointestinais/metabolismo , Desenho de Fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/química , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas
15.
Nat Commun ; 15(1): 3962, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730247

RESUMO

Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting glucose (FG), hs-CRP, ferritin, diastolic BP and steatosis improved significantly, independent of diabetes status: most patients with prediabetes returned to normal FG levels. Significant adiponectin increases correlated with hepatic and CMH marker improvement; patients had an average weight gain of 2.5 kg, with 49% gaining ≥2.5% weight. Therapeutic benefits were similar regardless of weight change. Here, we show that effects of lanifibranor on liver histology in MASH are accompanied with CMH improvement, indicative of potential cardiovascular clinical benefits.


Assuntos
Chalconas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adiponectina/metabolismo , Adiponectina/sangue , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Chalconas/uso terapêutico , Chalconas/farmacologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Propionatos , Triglicerídeos/sangue , Triglicerídeos/metabolismo
17.
Front Endocrinol (Lausanne) ; 15: 1364503, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38715796

RESUMO

Obesity has become a global epidemic in the modern world, significantly impacting the global healthcare economy. Lifestyle interventions remain the primary approach to managing obesity, with medical therapy considered a secondary option, often used in conjunction with lifestyle modifications. In recent years, there has been a proliferation of newer therapeutic agents, revolutionizing the treatment landscape for obesity. Notably, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, liraglutide, and the recently approved dual GLP-1/GIP RAs agonist tirzepatide, have emerged as effective medications for managing obesity, resulting in significant weight loss. These agents not only promote weight reduction but also improve metabolic parameters, including lipid profiles, glucose levels, and central adiposity. On the other hand, bariatric surgery has demonstrated superior efficacy in achieving weight reduction and addressing overall metabolic imbalances. However, with ongoing technological advancements, there is an ongoing debate regarding whether personalized medicine, targeting specific components, will shape the future of developing novel therapeutic agents for obesity management.


Assuntos
Fármacos Antiobesidade , Cirurgia Bariátrica , Manejo da Obesidade , Obesidade , Humanos , Obesidade/terapia , Cirurgia Bariátrica/métodos , Manejo da Obesidade/métodos , Fármacos Antiobesidade/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Redução de Peso
18.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 40(4): 319-326, 2024 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-38710516

RESUMO

Objective To investigate the impact of the cannabinoid receptor agonist arachidonyl-2'-chloroethylamide (ACEA) on cognitive function in mice with sepsis-associated encephalopathy (SAE). Methods C57BL/6 mice were randomly divided into artificial cerebrospinal fluid (ACSF) and lipopolysaccharide (LPS) groups. The SAE model was established by intraventricular injection of LPS. The severity of sepsis in mice was assessed by sepsis severity score (MSS) and body mass changes. Behavioral paradigms were used to evaluate motor ability (open field test) and cognitive function (contextual fear conditioning test, Y-maze test). To evaluate the effects of ACEA intervention on SAE, mice were randomly assigned to ACSF group, ACEA intervention combined with ACSF group, LPS group, and ACEA intervention combined with LPS group. The dosage of ACEA intervention was 1.5 mg/kg. Real-time quantitative PCR was used to measure the mRNA expression levels of interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α) in mouse hippocampal tissues. Western blot analysis was used to assess the protein levels of IL-6 and TNF-α in the hippocampus. Nissl staining was performed to examine neuronal damage in the CA1 region of the mouse hippocampus. Behavioral paradigms were again employed to evaluate motor ability and cognitive function. Results Three days after intraventricular LPS injection, mice exhibited significant cognitive dysfunction, confirming SAE modeling. Compared to the control group, the LPS group showed significant increases in mRNA of inflammatory factors such as IL-6, TNF-α, and IL-1ß, together with significant increases in IL-6 and TNF-α protein levels in the hippocampus, a decrease in Nissl bodies in the CA1 region, and significant cognitive dysfunction. Compared to the LPS group, the ACEA intervention group showed a significant decrease in the mRNA of IL-6, TNF-α, and IL-1ß, a significant reduction in IL-6 and TNF-α protein levels, an increase in Nissl bodies, and improved cognitive function. Conclusion ACEA improves cognitive function in SAE mice by inhibiting the expression levels of inflammatory factors IL-6 and TNF-α.


Assuntos
Ácidos Araquidônicos , Camundongos Endogâmicos C57BL , Encefalopatia Associada a Sepse , Animais , Encefalopatia Associada a Sepse/tratamento farmacológico , Encefalopatia Associada a Sepse/metabolismo , Camundongos , Masculino , Ácidos Araquidônicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Lipopolissacarídeos/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Receptor CB1 de Canabinoide/genética , Receptor CB1 de Canabinoide/metabolismo , Receptor CB1 de Canabinoide/agonistas , Cognição/efeitos dos fármacos , Sepse/tratamento farmacológico , Sepse/complicações , Sepse/metabolismo
19.
Eur Rev Med Pharmacol Sci ; 28(8): 3073-3084, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38708466

RESUMO

OBJECTIVE: The aim of this study was to investigate and evaluate the risk of dyspepsia and anorexia in patients with type 2 diabetes mellitus (T2DM) induced by glucagon-like peptide 1 receptor agonist (GLP-1 RA) hypoglycemic drugs. MATERIALS AND METHODS: We searched papers in PubMed, Web of Science, Cochrane Library, Google Scholar, CNKI, Wanfang, Embase, and VIP databases, and the retrieval time limit was set from the establishment of the database to May 2023. Randomized Controlled Trials (RCTs) were collected in which the subjects were T2DM patients, the intervention was GLP-1RA compared with placebo or traditional hypoglycemic drugs, and the outcome indicators included dyspepsia and anorexia. A meta-analysis and a network meta-analysis were performed. RESULTS: The results of the traditional meta-analysis showed that the risk of dyspepsia and anorexia of total GLP-1 RA was 3.01 and 2.56 times that of placebo, respectively. All types of GLP-1RA were compared with placebo and the results also showed a trend towards increased risk of digestive system adverse events (DSAEs). Among all interventions included, liraglutide was the one with the highest risk of dyspepsia in patients with T2DM, and dulaglutide was the one with the highest risk of anorexia. CONCLUSIONS: The results of the two meta-analyses are consistent, and both clearly show that GLP-1RA can increase the risk of dyspepsia and anorexia in T2DM patients.


Assuntos
Anorexia , Diabetes Mellitus Tipo 2 , Dispepsia , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Dispepsia/tratamento farmacológico , Dispepsia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Anorexia/induzido quimicamente , Anorexia/tratamento farmacológico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Curr Rev Clin Exp Pharmacol ; 19(3): 225-233, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38708917

RESUMO

Farnesoid X receptor (FXR) was identified as an orphan nuclear receptor resembling the steroid receptor in the late '90s. Activation of FXR is a crucial step in many physiological functions of the liver. A vital role of FXR is impacting the amount of bile acids in the hepatocytes, which it performs by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting its enterohepatic circulation, thus protecting the hepatocytes against the toxic accumulation of bile acids. Furthermore, FXR mediates bile acid biotransformation in the intestine, liver regeneration, glucose hemostasis, and lipid metabolism. In this review, we first discuss the mechanisms of the disparate pleiotropic actions of FXR agonists. We then delve into the pharmacokinetics of Obeticholic acid (OCA), the first-in-class selective, potent FXR agonist. We additionally discuss the clinical journey of OCA in humans, its current evidence in various human diseases, and its plausible roles in the future.


Assuntos
Ácido Quenodesoxicólico , Ácido Quenodesoxicólico/análogos & derivados , Receptores Citoplasmáticos e Nucleares , Humanos , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Ácido Quenodesoxicólico/farmacologia , Ácido Quenodesoxicólico/uso terapêutico , Animais , Ácidos e Sais Biliares/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/efeitos dos fármacos
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