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1.
Gerontology ; 69(4): 428-449, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36470214

RESUMO

INTRODUCTION: Senile osteoporosis is one of the most common age-related diseases worldwide. Glucagon like peptide-2 (GLP-2), a naturally occurring gastrointestinal peptide, possesses therapeutic effects on bone loss in postmenopausal women and ovariectomized rats. However, the role of GLP-2 in senile osteoporosis and underlying mechanisms has not been explored. METHODS: GLP-2 was subcutaneously injected into the 6-month-old male senile osteoporosis model of senescence-accelerated mouse prone 6 (SAMP6) mice for 6 weeks. SAMP6 subjected to normal saline and senescence-accelerated mouse resistant 1 served as control groups. Micro-computed tomography was performed to evaluate the bone mass and microarchitecture of the mice. Osteoblastic and osteoclastic activities were determined by biochemical, quantitative real-time PCR, histological, and histomorphometric analyses combined with hematoxylin-eosin, toluidine blue, and tartrate-resistant acid phosphatase staining. We also examined the proteins and structure of intestinal tight junction using immunohistochemical assay as well as a transmission electron microscope. Serum inflammation marker levels were measured using ELISA. Additionally, anti-oxidative enzymes GPX-4 and SOD-2 and receptors of GLP-2 and vitamin D expression in the ileum and colon were detected under immunofluorescence staining. RESULTS: Six-week GLP-2 treatment attenuated bone loss in SAMP6 mice, as evidenced by increased bone mineral density, improved microarchitecture in femora, and enhanced osteogenic activities. In contrast, the activity of osteoclastic activity was not obviously inhibited. Moreover, GLP-2 ameliorated tight junction structure and protein expression in the intestinal barrier, which was accompanied by the reduction of TNF-α level. The expression of receptors of intestinal GLP-2 and vitamin D in the ileum was elevated. Furthermore, the oxidative stress in the intestines was improved by increasing the GPX-4 and SOD-2 signaling. CONCLUSION: Our findings suggest that GLP-2 could ameliorate age-associated bone loss, tight junction structure, and improved antioxidant enzyme activity in the gut in SAMP6 mice. Amelioration of gut barrier dysfunction may potentially contribute to improving bone formation and provide evidence for targeting the entero-bone axis in the treatment of senile osteoporosis.


Assuntos
Peptídeo 2 Semelhante ao Glucagon , Osteoporose , Camundongos , Masculino , Feminino , Ratos , Animais , Microtomografia por Raio-X/métodos , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Modelos Animais de Doenças , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Osteoporose/patologia , Envelhecimento , Vitamina D , Superóxido Dismutase
2.
Exp Gerontol ; 125: 110661, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31319131

RESUMO

Old people are spectacularly susceptible to acute lung injury (ALI) and the accompanying complications. An acute aggravated inflammatory response is a characteristic feature of ALI, and inflammasomes play a critical role in the inflammatory response. Metformin has been shown to be an effective anti-inflammatory agent in ALI. However, the mechanism of this regulation still remains poorly understood. In this study, 18- to 19-month-old male mice were treated by intratracheal instillation of lipopolysaccharide (LPS) or PBS with or without metformin pretreatment. We found that the metformin pretreatment alleviated the lung injury and decreased the levels of TNF-a, IL-1ß and IL-6 in the bronchoalveolar lavage fluid (BALF) and in lung tissues, as well as the levels of NLRP3, NLRC4 and cleaved caspase-1 associated with LPS-induced ALI in old mice. Furthermore, the in vitro study showed metformin dose-dependently suppressed NLRC4 inflammasome expression. Metformin activated AMPK by phosphorylation; thus, we investigated the role of AMPK in NLRC4 activation. The results demonstrated that the efficacy of metformin was reduced when using the AMPK pharmacological inhibitor compound C or AMPKα1 expression was knocked down in RAW 264.7 cells. In conclusion, our data indicated that metformin may inhibit NLRC4 inflammasome activation in LPS-induced ALI in old mice through AMPK signaling, and further understanding of the AMPK/NLRC4 axis may provide a novel therapeutic strategy for LPS-induced ALI in the future.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Lesão Pulmonar Aguda/prevenção & controle , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Lesão Pulmonar Aguda/metabolismo , Fatores Etários , Animais , Citocinas/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inflamassomos/efeitos dos fármacos , Inflamassomos/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Células RAW 264.7
3.
Life Sci ; 226: 47-56, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30959027

RESUMO

AIMS: In this study, we evaluate the effects of glucagon-like peptide 2 (GLP-2) on bone microarchitecture, bone turnover markers (BTMs) and inflammation markers in ovariectomized (OVX) rats. MATERIAL AND METHODS: In total, 31 Sprague-Dawley rats were divided into the following three groups: sham (control sham-operated with vehicle, n = 7), OV (OVX with vehicle, n = 12), and GLP-2 (OVX with GLP-2, n = 12). Intervention began at the 12th week after surgery and lasted for 4 weeks. The dosage of the GLP-2 was 160 µg/kg/d through subcutaneous injections, and normal saline was used as the vehicle agent. After 4 weeks of treatment, serum BTM and inflammation marker levels were measured by ELISA, and femora samples were analyzed by qRT-PCR, micro-CT, histology and histomorphometry. KEY FINDINGS: After 4 weeks of treatment, serum TRAcP-5b and RANKL levels as well as the CTX-1/P1NP ratio in the GLP-2 group decreased, and ALP activity, P1NP level, and OPG/RANKL ratio increased significantly; qRT-PCR analysis showed that mRNA levels of RANKL decreased, and Runx2, ALP, and Col-1 levels as well as the OPG/RANKL ratio increased significantly in the GLP-2 group compared with the OV group. In bone histology analysis, GLP-2 significantly decreased the AV/MV, Oc.N and Oc.S but increased the Ob.N, BFR and MAR. Analysis with µ-CT showed that the BMD, BV/TV, Tb.N and Conn.D increased significantly in the GLP-2 group compared with the OV group. The levels of serum inflammation markers TNF-α, IL-1ß and IL-6 decreased, and TGF-ß levels increased in the GLP-2 group compared with the OV group. SIGNIFICANCE: GLP-2 may have a positive impact on osteoporosis by promoting bone formation, inhibiting bone resorption and decreasing circulatory inflammation in ovariectomized rats.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Osteoporose/tratamento farmacológico , Animais , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Feminino , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Osteogênese/efeitos dos fármacos , Osteoporose/metabolismo , Osteoporose/patologia , Osteoprotegerina/metabolismo , Ovariectomia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Microtomografia por Raio-X
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