RESUMO
To elucidate the precise upstream and downstream regulatory mechanisms of inflammatory factors in osteoporosis (OP) progression and to establish a causal relationship between inflammatory factors and OP. We conducted bidirectional Mendelian randomization (MR) analyses using data for 41 cytokines obtained from three independent cohorts comprising 8293 Finnish individuals. Estimated bone mineral density (eBMD) data were derived from 426,824 UK Biobank White British individuals (55% female) and fracture data from 416,795 UK Biobank participants of European ancestry. The inverse variance-weighted method was the primary MR analysis approach. We employed other methods as complementary approaches for mutual corroboration. To test for pleiotropy and heterogeneity, we used the MR-Egger regression, MR-pleiotropy residual sum and outlier global test, and the Cochrane Q test. Macrophage inflammatory protein (MIP)-1α and interleukin (IL)-12p70 expression associated negatively and causally with eBMD (ß = -0.017 [MIP-1α], ß = -0.011 [IL-12p70]). Conversely, tumor necrosis factor-related apoptosis-inducing ligand was associated with a decreased risk of fractures (Odds Ratio: 0.980). Additionally, OP influenced the expression of multiple inflammatory factors, including growth-regulated oncogene-α, interferon-gamma, IL-6, beta nerve growth factor, and IL-2. Finally, we discovered complex bidirectional causal relationships between IL-8, IL-10, and OP. Specific inflammatory factors may contribute to OP development or may be causally affected by OP. We identified a bidirectional causal relationship between certain inflammatory factors and OP. These findings provide new perspectives for early prediction and targeted treatment of OP. Larger cohort studies are necessary in the future to further validate these findings.
Assuntos
Densidade Óssea , Citocinas , Inflamação , Análise da Randomização Mendeliana , Osteoporose , Humanos , Análise da Randomização Mendeliana/métodos , Feminino , Osteoporose/genética , Citocinas/metabolismo , Inflamação/genética , Masculino , Densidade Óssea/genética , Pessoa de Meia-Idade , Idoso , Estudos de CoortesRESUMO
Fecal samples from 20 healthy adults were collected for in vitro fermentation experiments to investigate the effects of combined probiotics on the utilization of grape seed extract in humans. After fermenting for 24 h, short-chain fatty acids, metabolites, and gut microbiota composition were analyzed. Short-chain fatty acids in the grape seed extract probiotics group were significantly higher than those in the grape seed extract group. Probiotics significantly enhanced the conversion and utilization of catechins and epicatechins in grape seed extract group and increased the production of 3-hydroxyphenylacetic acid. The 16S rRNA sequencing results revealed that compound probiotics significantly increased the relative abundance of Lacticaseibacillus, HT002, Bifidobacterium, and Lactobacillus and reduced that of Escherichia-Shigella. Our findings showed considerable individual variability in the metabolic utilization of grape seed extract in humans. The consumption of probiotics appears to significantly enhance the utilization.
Assuntos
Extrato de Sementes de Uva , Probióticos , Adulto , Humanos , Polifenóis , RNA Ribossômico 16S , Ácidos Graxos Voláteis/metabolismoRESUMO
To verify the role of myricetin in alleviating the symptoms of type 2 diabetes and regulating the intestinal flora, we established a type 2 diabetes mouse model. After being fed a high-fat and high-sugar diet for six weeks, mice were intraperitoneally injected with streptozotocin (80 mg/kg body weight [BW]) 2-3 times. Type 2 diabetes mice were randomly divided into type 2 diabetes control (T2DM) and myricetin intervention groups. Water and food intake, fasting blood glucose (FBG), and BW were monitored weekly. After six weeks of myricetin administration, superoxide dismutase (SOD) levels and blood lipid content were measured. Furthermore, 16S rRNA sequencing was used to detect the gut microbiota composition. FBG and blood lipid levels of T2DM mice were significantly reduced upon myricetin treatment, while SOD levels were increased. Myricetin improved polydipsia, polyphagia, polyuria, and weight loss in T2DM mice. In addition, the signature type 2 diabetes microflora was established by analyzing the microflora structure of healthy mice, type 2 diabetes mice, and mice treated with myricetin. Results showed that type 2 diabetes disrupted the mice intestinal flora, and myricetin intervention normalized the intestinal flora. In conclusion, our results indicate that myricetin alleviates type 2 diabetes in mice and regulates the intestinal microflora.
Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica , Flavonoides , Microbioma Gastrointestinal/fisiologia , Lipídeos , Camundongos , RNA Ribossômico 16S , Superóxido DismutaseRESUMO
To confirm whether 17ß-estradiol (E2) activates mammalian target of rapamycin (mTOR) signaling pathway in chondrocytes and in what way activates mTOR. Human immortalized chondrocytes cell lines TC28a2 and C28/I2 were subjected to incubate with or without E2, LY294002 (the inhibitor of PI3K), rapamycin (the inhibitor of mTOR), or E2 in combination with LY294002 or rapamycin. Thereafter, protein levels of S6K1, p-S6K1, protein kinase B (AKT), and p-AKT were determined by Western blot analysis. Matrix metallopeptidase (MMP) 3 or MMP13 mRNA levels were evaluated by quantitative real-time PCR (qRT-PCR). Co-immunoprecipitation and Western blot analysis were performed to verify the interaction between ERα and mTOR. Both p-S6K1 and p-AKT protein levels in TC28a2 and C28/I2E2 cells were significantly increased by incubation with E2 (0.5 h and 1 h) (P < 0.05). Rapamycin did not affect the levels of p-AKT, but were significantly reduced by LY294002 or E2 in combination with LY294002. The levels of p-S6K1 were significantly decreased by incubation with LY294002, but the effect could be reversed by E2 in combination with LY294002. Rabbit anti-mTOR antibody was able to immunoprecipitate ERα after incubation with E2. Moreover, E2 inhibited the mRNA levels of MMP3 and MMP13 by mTOR pathway. E2 actives mTOR in chondrocytes through AKT-dependent and independent ways.
Assuntos
Condrócitos/efeitos dos fármacos , Estradiol/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular , Condrócitos/enzimologia , Ativação Enzimática , Receptor alfa de Estrogênio/agonistas , Receptor alfa de Estrogênio/metabolismo , Humanos , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
OBJECTIVE: Injection of insulin-like growth factor-1 (IGF-1) can prevent bone loss in sciatic nerve transaction rats. We try to investigate the action mechanism of IGF-1 on bone formation. METHODS: A total of 40 adult male Spragne-Dawley rats were divided into two groups (experimental group and control group) with 20 animals in each. Sciatic neurectomy was performed to model disuse osteoporosis in all rats. IGF-1 was administered in experimental group with the dose of 100 microgramme/kilogram per day for 3 days. Meanwhile, the rats in control group were treated with saline. Bone mineral density was measured by dual-energy X-ray absorptiometry 4 and 6 weeks after neurectomy respectively. Expression of Osterix and Runx2 was determined by reverse transcription-polymerase chain reaction (RT-PCR) assay. RESULTS: There was a significant increase in the bone mineral density of experimental group compared with control group. There was a significant decrease in the level of receptor activator of nuclear factor-kappaB-ligand but an increase in the level of osteoprotegerin 4 and 6 weeks after neurectomy in the experimental group compared with control one. The expression of Osterix and Runx2 was up-regulated in the bone marrow of experimental group compared with control group. CONCLUSION: IGF-1 can increase bone formation by stimulation of osteoblast number and activity, and reduce bone resorption by restriction of differentiation of osteoclast, suggesting that IGF-1 may improve the therapeutic efficacy for disuse osteoporosis.