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Diquat (DQ) poisoning has garnered attention in recent years, primarily due to the rising incidence of cases worldwide, coupled with the absence of a viable antidote for its treatment. Despite the fact that diquat monopyridone (DQ-M) has been identified as a significant metabolite of DQ, the enzyme responsible for its formation remains unknown. In this study, we have identified aldehyde oxidase (AOX) as a vital enzyme involved in DQ oxidative metabolism. The metabolism of DQ to DQ-M was significantly inhibited by AOX inhibitors including raloxifene and hydralazine. The source of oxygen incorporated into DQ-M was proved to be from water through a H218O incubation experiment which further corroborated DQ-M formation via AOX metabolism. The product of DQ-M in vitro generated by fresh rat tissues co-incubation was consistent with its AOX expression. The result of the molecular docking analysis of DQ and AOX protein showed that DQ is capable of binding to AOX. Furthermore, the cytotoxicity of DQ was significantly higher than DQ-M at the same concentration tested in six cell types. This work is the first to uncover the involvement of aldehyde oxidase, a non-cytochrome P450 enzyme, in the oxidative metabolic pathway of diquat, thus providing a potential target for the development of detoxification treatment.
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Aldehído Oxidasa , Diquat , Ratas , Animales , Diquat/farmacología , Aldehído Oxidasa/química , Aldehído Oxidasa/metabolismo , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Redes y Vías Metabólicas , Sistema Enzimático del Citocromo P-450/metabolismoRESUMEN
This study aims to explore anti-obesity and lipid-lowering mechanism of Corydalis Bungeanae Herba(CB) based on intestinal microflora and metabolomics. Specifically, high-fat high-sugar diet(HFHS, 10 weeks) was used to induce obesity in rats. Then the model rats were randomized into the model group, low-dose(0.18 g·kg~(-1)), medium-dose(0.9 g·kg~(-1)), and high-dose(1.8 g·kg~(-1)) CBH groups, and orlistat group(0.03 g·kg~(-1)), 12 in each group. Rats which received normal diet were used as control. The body weight and feed intake of rats were recorded every week. After 6 weeks of administration, rats were killed and gastric emptying and small intestinal propulsion were examined. Enzyme-linked immunosorbent assay(ELISA) was employed to analyze serum indexes, and liver and perirenal fat were collected for haematoxilin-eosin(HE) staining. Rat feces and serum were gathered for 16 S rDNA sequencing and metabolomics analysis and Spearman's correlation analysis was performed to explore the correlation between differential microflora and differential metabolites. The result showed that CBH extract decreased body weight, feed intake, and serum cholecystokinin(CCK), triglyceride(TG), and total cholesterol(TC), delayed gastric emptying, and reduced fat accumulation in liver and perirenal adiposity as compared with rats in the model group. In addition, Lachnospiraceae and Sutterellaceaecan significantly decreased in the model group, but CBH extract up-regulated their abundance. Moreover, the abundance of Prevotellaceae was significantly raised by HFHS, but CBH decreased it. Glutaric acid, glyceric acid, hippuric acid, malic acid, glyceric acid, oxoglutaric acid, fumaric acid/succinic acid, oxoglutaric acid/isocitric acid, D-glucuronic acid, cholic acid were the main deferentially expressed metabolites and significantly correlated with Sutterellaceae and Prevotellaceae. These key metabolites and microbiota mainly involved in tricarboxylic acid(TCA) cycle, glucose metabolism, amino acid metabolism, and energy metabolism. This study proved that CBH can efficiently improve body weight and blood lipids, reduce adipocyte volume, and positively regulate the intestinal microflora and serum metabolites, thereby achieving the anti-obesity and lipid-owering effect.
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Corydalis , Microbioma Gastrointestinal , Animales , Peso Corporal , Dieta Alta en Grasa/efectos adversos , Lípidos , Metabolómica , Obesidad/tratamiento farmacológico , Extractos Vegetales/farmacología , RatasRESUMEN
BACKGROUND: Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB. METHODS: We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA. RESULTS: When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death. CONCLUSIONS: The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.
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Leonurine hydrochloride (LH) is a synthetic chemical compound derived from leonurine that can be extracted from Leonurus sibiricus and possesses antioxidant, anti-apoptosis, and neuroprotective activities. In previous studies, LH has been demonstrated to attenuate osteoclast activity and prevent bone loss. However, it is unknown whether LH accelerates bone formation and promotes osteogenic differentiation. We systematically examined the effects of LH on ovariectomized-induced osteoporotic mice and the MC3T3-E1 osteoblastic cell line. The results revealed that LH enhanced differentiation of MC3T3-E1 cells, with a dose-dependent increase in alkaline phosphatase (ALP) activity. Moreover, LH upregulated osteogenesis-related gene expression, including osterix, alpha 1 type 1 collagen, runt-related transcription factor 2 (Runx2) and ALP, as shown by quantitative reverse transcription-polymerase chain reaction analysis. At the same time, elevated expression of low-density lipoprotein receptor-related protein 5 and ß-catenin mRNA was detected in the Wnt/ß-catenin pathway. A western blot analysis revealed that LH dose-dependently increased the expression of Runx2 and ß-catenin, and promoted phosphorylation of glycogen synthase kinase-3ß in vitro. The in vivo results showed that administering LH (15â¯mg/kg/d) for 8 weeks alleviated destruction of the trabecular microstructure caused by osteoporosis. LH increased the bone mineral density and trabecular number, decreased trabecular separation according to a micro-computed tomography scan. In addition, LH enhanced the expression of ß-catenin and Runx2 in vivo. In conclusion, LH promoted osteogenic differentiation and bone formation in vivo and in vitro, which alleviated osteoporosis through activation of the Wnt/ß-catenin pathway.
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Ácido Gálico/análogos & derivados , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Animales , Densidad Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Femenino , Ácido Gálico/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Ratones Endogámicos C57BL , Osteoblastos/metabolismo , Osteoporosis/patología , Osteoporosis/prevención & control , Ovariectomía , beta Catenina/metabolismoRESUMEN
To establish the high performance liquid chromatography (HPLC) fingerprint for Digeda-4 decoction (DGD-4D), determine the contents of aesculetin, geniposide, picroside â , picroside â ¡ and ellagicacid in DGD-4D, and provide the scientific foundation for quality control of DGD-4D. The analysis was performed on Diamonsil(2) C18 (4.6 mm×250 mm,5 µm) column, with methanol-0.1% phosphoric acid aqueous solution as mobile phase for gradient elution. The flow rate was 1.0 mL·min⻹; injection size was 10 µL; temperature was maintained at 30 °C, and the detection wavelength was set at 254 nm. The common mode of DGD-4D HPLC fingerprint was established, and the hidden information was analyzed by Chemometrics. Chromatographic peaks for DGD-4D were identified by HPLC and quantitative analysis was conducted for characteristic peaks. There were 17 common peaks in the fingerprints and the similarity of the fingerprints was over 0.9 in all 15 batches. The samples were broadly divided into four kinds by principal component analysis and clustering analysis. Four marker compounds were verified by partial least squares discriminant analysis, and No. 9, 12 and 14 peaks were identified as geniposide, picroside â ¡, and picroside â respectively. The average recoveries were in the range of 95.91%-97.31%. The HPLC fingerprint method for content determination is reliable, accurate, rapid, simple, and reproducible, and can be used as one of the effective methods to control the quality of DGD-4D.
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Medicamentos Herbarios Chinos/análisis , Medicamentos Herbarios Chinos/normas , Cromatografía Líquida de Alta Presión , Cinamatos , Glucósidos Iridoides , Iridoides , Metanol , Análisis de Componente Principal , Control de CalidadRESUMEN
Curcumin, an active component of the rhizomes of Curcumin longa L., possesses broad anti-inflammation and anti-cancer properties. Curcumin was previously reported to be capable of protecting ovariectomized rats against osteoporosis. However, the effect of curcumin on glucocorticoid-induced osteoporosis (GIO) is not yet clear. The present study investigated the effects of curcumin on dexamethasone (Dex)-induced osteoporosis in vivo and Dex-induced osteoblast apoptosis in vivo and in vitro. The GIO rat model was induced by subcutaneous injection of Dex for 60 days and verified to be successful as evidenced by the significantly decreased bone mineral density (BMD) determined using dual X-ray absorptiometry. Subsequently, curcumin administration (100 mg/kg) for 60 days obviously increased BMD and bone-alkaline phosphatase, decreased carboxy-terminal collagen cross links, enhanced bone mechanical strength, and improved trabecular microstructure, thereby alleviating Dex-induced osteoporosis. Mechanically, curcumin remarkably reversed Dex-induced femoral osteoblast apoptosis in vivo. In cultured primary osteoblasts, pretreatment with curcumin concentration-dependently decreased the number of Dex-induced apoptotic osteoblasts by down-regulating the ratio of Bax/Bcl-2 as well as the levels of cleaved caspase-3 and cleaved poly ADP-ribose polymerase (PARP). Moreover, curcumin pretreatment activated extracellular signal regulated kinase (ERK) signalling in Dex-induced osteoblasts by up-regulating the expression level of p-ERK1/2. Taken together, our study demonstrated that curcumin could ameliorate GIO by protecting osteoblasts from apoptosis, which was possibly related to the activation of the ERK pathway. The results suggest that curcumin may be a promising drug for prevention and treatment of GIO.
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Curcumina/farmacología , Citoprotección/efectos de los fármacos , Glucocorticoides/efectos adversos , Osteoblastos/efectos de los fármacos , Osteoblastos/patología , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Animales , Apoptosis/efectos de los fármacos , Curcumina/uso terapéutico , Dexametasona/efectos adversos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Osteoblastos/metabolismo , Osteoporosis/metabolismo , Osteoporosis/patología , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVE: To study the chemical constituents of traditional Mongolian medicine Usnea longissima. METHODS: The compounds were isolated and purified by the methods of solvent extraction and chromatographic technique, and their structures were identified on the basis of the analyses of spectral data. RESULTS: Three compounds were obtained and identified as 4-hydroxy-2-[ (2-hydroxy-4-methoxy-6-methylbenzoyl) oxy]-6-methylbenzoic acid (1), dibutyl phthalate (2) and diisobutyl phthalate (3). CONCLUSION: Compound 1 is a new compound and named as isoevernic acid, compounds 2 and 3 are isolated from Usnea longissima for the first time.
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Medicina Tradicional Mongoliana , Fitoquímicos/análisis , Plantas Medicinales/química , Usnea/químicaRESUMEN
OBJECTIVE: To study the chemical constituents of Mongolian medicine Halenia corniculata. METHODS: Positive phase and reversed phase silica gel, as well as Sephadex LH-20 methods were used to separate and purify. The structure of the isolated constituents was identified according to the NMR spectroscopy data and the literature data. RESULTS: Nine compounds were isolated from 95% ethanol extracts of petroleum ether part of Halenia corniculata and identified as: 1-hydroxy-2,3,4,6-tetramethoxyxanthone (1), 1-hydroxy-2,3, 5-trimethoxyxanthone (2) 1-hydroxy-3,7-dimethoxyxanthone (3), 1-hydroxy-3,5,6,7,8-pentamethoxyxanthone (4), 1-hydroxy-2,3,4, 7-tetramethoxyxanthone (5), 1-hydroxy-3,5-dimethoxyxanthone (6),1-hydroxy-2,3,4,5,7-pentamethoxyxanthone (7), palmitic acid (8) and ß-sitosterol (9). CONCLUSION: Compounds 3, 4 and 8 are isolated from this genus for the first time, Compound 1 is isolated from this plant for the first time.
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Gentianaceae/química , Fitoquímicos/análisis , Extractos Vegetales/química , Alcanos , Medicina Tradicional Mongoliana , Fitoquímicos/aislamiento & purificación , Sitoesteroles/análisis , Sitoesteroles/aislamiento & purificación , Solventes , Xantonas/análisis , Xantonas/aislamiento & purificaciónRESUMEN
Background: Trichosporon asahii (T. asahii) is part of the cutaneous fungal microbiota in humans and can cause lethal opportunistic infection. During infection, microorganisms can adapt to their environment by adjusting gene expression and cellular activities. Objectives: Investigation of the microevolutionary changes in T. asahii during chronic infection. Methods: Two T. asahii strains were isolated from a chronic trichosporonosis patient between a 15-year interval, and the microevolutionary changes were compared by the immune response of dendritic cell (DC), mice survival model, and transcriptome sequencing analysis. Results: Compared with the primary T. asahii strain, the microevolved strain induced much lower expression of TNF-α by mice bone marrow-derived DC and had a much superior survival rate, a total of 2212 significantly differentially expressed genes were identified in the microevolved strain, and functional analysis showed significance in the downregulated transcription and metabolic process, especially the valine, leucine, and isoleucine degradation pathways, which were associated with pathogenicity and virulence; hence, the results were highly consistent with the decreased immunogenicity and virulence of the microevolved strain. Conclusions: These results demonstrated that the microevolution during chronic infection could induce changes in immunogenicity, virulence, and transcriptome, which might lead T. asahii to coexist with the host.
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BACKGROUND: In clinical practice, some patients might not be able or unwilling to provide a thorough history of medication and poison exposure. The aim of this study was to use toxicological analysis to examine the clinical characteristics of patients with acute poisoning whose exposure history was uncertain from a toxicological analysis perspective. METHODS: This was a retrospective and descriptive study from an institute of poisoning. Patient registration information and test reports spanning the period from April 1, 2020 to March 31, 2022, were obtained. Patients with uncertain exposure histories and who underwent toxicological analysis were included. Clinical manifestations and categories of toxics were analyzed. RESULTS: Among the 195 patients with positive toxicological analysis results, the main causes of uncertain exposure history was disturbance of consciousness (62.6%), unawareness (23.6%) and unwillingness or lack of cooperation (13.8%). The predominant clinical manifestations were disturbed consciousness (62.6%), followed by vomiting and nausea (14.4%) and liver function abnormalities (8.7%). A comparison of clinical manifestations between patients with positive and negative (n=99) toxicological analyses results revealed significantly different proportions of disturbances in consciousness (63% vs. 21%), dizziness (1.5% vs. 5.1%), multi-organ failure (1.5% vs. 7.1%), and local pain (0 vs 4%). The main categories of substances involved were psychiatric medications (23.1%), sedatives (20.5%), insecticides (13.8%), and herbicides (12.8%). CONCLUSION: The clinical manifestations of acute poisoning in patients with an uncertain exposure history are diverse and nonspecific, and toxicological analysis plays a pivotal role in the diagnosis and differential diagnosis of such patients.
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Objective: This article aims to discuss a novel surgical strategy, referred to as unilateral bi/multi-portal endoscopy (UME), which used a uniaxial spinal endoscope instead of an arthroscope in the traditional unilateral biportal endoscopy (UBE) surgical procedure in our study of the treatment of complicated lumbar degenerative diseases. Methods: This retrospective study included 42 patients diagnosed with high-migrated lumbar disc herniation and bilateral spinal stenosis who underwent UME surgery from January 2021 to December 2021. Patients included 20 men and 22 women, with an average age of 55.97±14.92 years. The average follow-up period was 13.19 months. The demographic data, operation time (min), and complications were recorded and analyzed. The visual analogue scale (VAS), Oswestry Disability Index (ODI) scores were used to evaluate the surgical outcomes. Three-dimensional CT scans and MRI were conducted to evaluate the radiographic improvement. Results: A total of 26 patients were diagnosed with lumbar disc herniation and 16 with lumbar spinal stenosis. All 42 patients underwent UME surgery and achieved satisfactory outcomes. The operation time was 154.46±46.09 min. The average follow-up time was 13.19±1.33 months. The preoperative back pain (VAS-Back) and the last follow-up VAS-Back were 3.84±1.00 and 0.70±0.46, respectively (P < 0.05). The preoperative leg pain (VAS-Leg) and the last follow-up VAS-Leg were 6.46±1.08 and 1.03±0.64, respectively (P <0.05). Significant differences existed between preoperative ODI scores (58.70±11.22%) and the last follow-up ODI scores (9.24±3.04%; P<0.05). All patients achieved significant pain relief and functional improvement after the surgery. No severe complications occurred, except for two cases of postoperative dysesthesia and one case suffered from vertebral compression fractures induced by a postoperative accidental injury. Symptoms of numbness disappeared within one week with treatment using dexamethasone and neurotrophic drugs. The vertebral fracture case recovered with percutaneous kyphoplasty treatment. Conclusion: This study suggests that UME is a promising treatment strategy for high-migrated disc herniation and bilateral spinal stenosis.
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Fracturas por Compresión , Desplazamiento del Disco Intervertebral , Fracturas de la Columna Vertebral , Estenosis Espinal , Masculino , Humanos , Femenino , Anciano , Desplazamiento del Disco Intervertebral/complicaciones , Desplazamiento del Disco Intervertebral/diagnóstico por imagen , Desplazamiento del Disco Intervertebral/cirugía , Estudios Retrospectivos , Estenosis Espinal/complicaciones , Estenosis Espinal/cirugía , Vértebras Lumbares/diagnóstico por imagen , Vértebras Lumbares/cirugía , Endoscopía/métodos , Endoscopios , Dolor , Resultado del TratamientoRESUMEN
BACKGROUND: Lomatogonium rotatum (LR) is traditionally used in Mongolian folk medicine as a hypoglycemic agent, but its evidence-based pharmacological effects and me-chanisms of action have not been fully elucidated. AIM: To emphasize the hypoglycemic action mechanism of LR in a type 2 diabetic rat model and examine potential biomarkers to obtain mechanistic understanding regarding serum metabolite modifications. METHODS: A high-fat, high-sugar diet and streptozotocin injection-induced type 2 diabetic rat model was established. The chemical composition of the LR was identified by high performance liquid chromatography. LR extract administrated as oral gavage at 0.5 g/kg, 2.5 g/kg, and 5 g/kg for 4 wk. Anti-diabetic effects of LR extract were evaluated based on histopathological examination as well as the measurement of blood glucose, insulin, glucagon-like peptide 1 (GLP-1), and lipid levels. Serum metabolites were analyzed using an untargeted metabolomics approach. RESULTS: According to a chemical analysis, swertiamarin, sweroside, hesperetin, coumarin, 1.7-dihydroxy-3,8-dimethoxyl xanthone, and 1-hydroxy-2,3,5 trimethoxanone are the principal active ingredients in LR. An anti-diabetic experiment revealed that the LR treatment significantly increased plasma insulin and GLP-1 levels while effectively lowering blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and oral glucose tolerance test compared to the model group. Furthermore, untargeted metabolomic analysis of serum samples detected 236 metabolites, among which 86 were differentially expressed between the model and the LR group. It was also found that LR considerably altered the levels of metabolites such as vitamin B6, mevalonate-5P, D-proline, L-lysine, and taurine, which are involved in the regulation of the vitamin B6 metabolic pathway, selenium amino acid metabolic pathway, pyrimidine metabolic pathway, and arginine and proline metabolic pathways. CONCLUSION: These findings indicated that LR may have a hypoglycemic impact and that its role may be related to changes in the serum metabolites and to facilitate the release of insulin and GLP-1, which lower blood glucose and lipid profiles.
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BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) as a substitute for iliac crest bone graft (ICBG) has been increasingly widely used in lumbar fusion. It has been proven non-inferior in fusion success and clinical outcomes when compared with ICBG. However, increasingly, some potentially uncommon and serious complications associated with the use of rhBMP-2 have been of great concern to surgeons. The purpose of this study was to determine whether rhBMP-2 could be considered an effective and, more importantly, a relatively safe substitute for ICBG in lumbar fusion. METHODS: Randomized controlled trials that compared rhBMP-2 with ICBG for lumbar fusion were identified by computer and manual searching. The risk of bias and clinical relevance of the included studies were assessed. Publication bias was explored using funnel plot and statistical tests (Egger's test and Begg's test). Meta-analyses were performed using the Cochrane systematic review methods. RESULTS: Ten randomized controlled trials (1,342 patients) met the inclusion criteria. Compared with ICBG, the use of rhBMP-2 significantly decreased the risk of fusion failure at all time intervals (6 months: p < 0.0001, RR = 0.55, 95 % CI = 0.42-0.72; 12 months: p = 0.0003, RR = 0.53, 95 % CI = 0.37-0.75; 24 months: p < 0.00001, RR = 0.31, 95 % CI = 0.21-0.46) and the rate of reoperation (p = 0.0001, RR = 0.52, 95 % CI = 0.37-0.72). There was no statistical difference in clinical improvement on the Oswestry Disability Index, although a favorable trend in the rhBMP-2 group was found (p = 0.12, RR = 0.73, 95 % CI = 0.49-1.08). Subgroup analyses stratified by the type of surgical procedure yielded similar results. Owing to the different data formats, meta-analysis on adverse events was not performed. CONCLUSION: RhBMP-2 was superior to the ICBG for achieving fusion success and avoiding reoperation. However, evidence from the Food and Drug Administration document and subsequent independent studies has demonstrated that original, industry-sponsored trials underestimated rhBMP-2-related adverse events. There are still security risks in the use of rhBMP-2.
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Proteína Morfogenética Ósea 2/uso terapéutico , Ilion/trasplante , Vértebras Lumbares/cirugía , Fusión Vertebral/métodos , Factor de Crecimiento Transformador beta/uso terapéutico , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/uso terapéuticoRESUMEN
Few studies have examined the association between handgrip strength and BMD in specific subgroups. Therefore, we examined the associations of handgrip strength with BMD aged ≥ 40 years and found that handgrip strength is associated with BMD which is independent of BMI, physical activity, and other potential confounders. PURPOSE: Previous studies have revealed that handgrip strength is a measure of muscular fitness and is associated with fracture and bone mineral density (BMD) in adolescents and adults, with conflicting results. In addition, few studies have examined the association between handgrip strength in predefined subgroups such as sex, age, and physical activity in a whole population. METHODS: We examined the associations of handgrip strength with BMD in 2720 adults (1359 men and 1361 women) aged ≥ 40 years (mean age, 58.6 ± 11.8 years) from the National Health and Nutrition Examination Survey (NHANES) 2013-2014. NHANES collects data via household interviews and direct standardized physical examinations conducted in specially equipped mobile examination centers. The date of final data collection was 2014 and the present data analysis was conducted in January to February 2020. RESULTS: Handgrip strength was significantly associated with total femur (r = 0.482, P < 0.001) and femoral neck BMD (r = 0.427, P < 0.001) among all participants, respectively. After adjustment for age, sex, race, body mass index (BMI), physical activity, smoking, history of diabetes, history of hypertension, and history of high cholesterol, each unit (1 SD) of BMI-adjusted handgrip strength was positively associated with 0.026 g/cm2 increase in total femur BMD (P < 0.001) and 0.027 g/cm2 increase in femoral neck BMD (P < 0.001). There was a significant increasing trend in total femur and femoral BMD as handgrip strength increased from the lowest quartile to the highest quartile (P for trend < 0.001). For subgroup analysis, there were no significant interaction effects of handgrip strength with BMD between predefined subgroups (all P > 0.05). CONCLUSIONS: High level of handgrip strength is associated with increased BMD. The association is independent of BMI, physical activity, and other potential confounders.
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Densidad Ósea , Fuerza de la Mano , Absorciometría de Fotón , Adolescente , Adulto , Anciano , Femenino , Fémur , Humanos , Masculino , Persona de Mediana Edad , Encuestas NutricionalesRESUMEN
BACKGROUND: Sulongga-4 (SL-4) is a herbal formula used in traditional Mongolian medical clinics for the treatment of peptic ulcers and gastroenteritis, even though its pharmacological mechanism has not been well characterized. AIM: To evaluate the protective effect and identify the mechanisms of action of SL-4 on gastroduodenal ulcer induced by pyloric ligation (PL) in rats. METHODS: PL was performed to induce gastric and duodenal ulcers in rats, which were then treated with oral SL-4 (1.3, 2.6, or 3.9 g/kg per day) for 15 d. PL-induced gastroduodenal ulceration. Therapeutic effects were characterized by pathological and histological evaluations and inflammatory indicators were analyzed by enzyme-linked immunosorbent assay. Microarray analyses were conducted to identify gene expression profiles of gastroduodenal tissue in PL rats with or without SL-4 treatment. The candidate target genes were selected and verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: SL-4 decreased histopathological features in the PL-induced ulcerated rats. SL-4 significantly (P < 0.05) decreased expression of tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, endotoxin, platelet-activating factor, and increased prostaglandin E2 and epidermal growth factor in ulcer tissue. Microarray analysis was used to identify a panel of candidate target genes for SL-4 acting on PL-induced ulceration. Genes included some complement and coagulation cascade and retinol metabolism pathways that are closely associated with inflammatory responses and gastric mucosal protective mechanisms. qRT-PCR showed that altered expression of the selected genes, such as CYP2b2, UGT2b1, A2m, and MASP1 was consistent with the microarray results. CONCLUSION: SL-4 exerts protective effects against PL-induced gastroduodenal ulcers via reducing inflammatory cytokines and elevating expression of gastric acid inhibitory factors. Downregulation of CYP2b2 and UGT2b1 genes in retinol metabolism and upregulation of A2m and MASP1 genes in the complement and coagulation cascades pathways are possibly involved in SL-4-mediated protection against gastroduodenal ulcer.
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Úlcera Péptica , Úlcera Gástrica , Animales , Mucosa Gástrica , Medicina Tradicional Mongoliana , Ratas , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/prevención & controlRESUMEN
Polo-like kinase 4 (PLK4) is a member of the serine/threonine protein kinase family involved in cell-cycle regulation and cellular response to stresses. However, the alteration of PLK4 in response to endoplasmic reticulum (ER) stress has not been well described. In the present study, we focused on the regulation of PLK4 regulation in response to ER stress. PLK4 expression was dramatically reduced under ER stress induced by brefeldin A (BFA), tunicamycin (TM), or thapsigargin (TG) and down regulation of PLK4 expression was dependent on activating transcription factor 6 (ATF6) and CCAAT/enhancer-binding protein ß (C/EBPß). Luciferase activity analysis of the truncated PLK4 promoter indicated that region from -1343 to -1250 of the PLK4 promoter was sensitive to BFA or TG. Additionally, ChIP and ChIP Re-IP assays showed that ATF6 and C/EBPß were assembled on the same region of Plk4 promoter. Notably, we identified one C/EBPß responsive element at position -1284, to which ATF6 or C/EBPß binding was enhanced by BFA or TG under in vitro and in vivo conditions. Finally, overexpression of PLK4 inhibits apoptosis and promotes cell proliferation in response to ER stress. In summary, these results demonstrated that ER stress plays a crucial role in PLK4 expression. ATF6 may upregulate DNA-binding affinities after BFA treatment, via recruiting C/EBPß to the upstream promoter of PLK4. These findings may contribute to the understanding of the molecular mechanism of PLK4 regulation.
Asunto(s)
Factor de Transcripción Activador 6/metabolismo , Neoplasias Óseas/genética , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Estrés del Retículo Endoplásmico/genética , Regulación Neoplásica de la Expresión Génica , Osteosarcoma/genética , Proteínas Serina-Treonina Quinasas/genética , Apoptosis , Neoplasias Óseas/enzimología , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Proliferación Celular , Humanos , Mutagénesis , Osteosarcoma/enzimología , Osteosarcoma/metabolismo , Regiones Promotoras Genéticas , Proteínas Serina-Treonina Quinasas/metabolismo , Elementos de Respuesta , Transcripción GenéticaRESUMEN
Osteosarcoma (OS) is the most common primary malignancy of bone that mostly affects children, adolescents, and young people. Despite advances have been made in multimodal therapy of OS, the long-term survival rate has reached a plateau, and the main obstacles are bad response to chemotherapy and gained chemoresistance. In this study, we tested the therapeutic effect of a newly reported drug, DMAMCL, on OS. Five human OS cell lines (143B, MNNG, MG63, Saos-2, U-2OS), and the mouse fibroblast cell line (NIH3T3) and human retinal epithelial cell (ARPE19) were used. The anti-tumor effect of DMAMCL was studied by MTS assay or IncuCyte-Zoom (in vitro), and Xenograft-mice-model (in vivo). Changes of cell cycle, apoptotic cells, caspase3/7 activities, and stemness after DMAMCL treatment were investigated. BAX siRNAs were used to knockdown the expression of BAX. Expressions of CyclinB1, CDC2, BCL-2 family, PARP, CD133, and Nanog were measured by Western Blotting. DMAMCL-induced dose-dependent OS cell death in vitro, and suppressed tumor growth and extended the survival of xenograft-bearing mice. DMAMCL-induced G2/M phase arrest in vitro, and apoptosis both in vitro and in vivo. Down-regulation of BAX expression attenuated the DMAMCL-induced OS cell death in vitro. We also found that DMAMCL inhibited the stemness in OS cells. These results indicated that DMAMCL possess therapeutic value in OS and may be a promising candidate for the new drug discovery for OS therapy.
Asunto(s)
Células Madre Neoplásicas/patología , Osteosarcoma/patología , Sesquiterpenos de Guayano/farmacología , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Ratones , Células 3T3 NIH , Células Madre Neoplásicas/efectos de los fármacos , Análisis de Supervivencia , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a predominant DNA sensor inducing the activation of the innate immune responses that produce proinflammatory cytokines and type I interferons, which has been well-investigated in mammals. However, chicken cGAS (chcGAS), which participates in avian innate immunity, has not been well-investigated. Here, we cloned the complete open reading frame sequence of chcGAS. Multiple sequence alignment and phylogenetic analysis revealed that chcGAS was homologous to mammalian cGAS. The chcGAS mRNA was highly expressed in the bone marrow and ileum. The subcellular localization of chcGAS was mainly in the cytoplasm, and partial co-localization was observed in the endoplasmic reticulum. Through overexpression and RNA interference, we demonstrated that chcGAS responded to exogenous dsDNA, HS-DNA, and poly(dA:dT), and to self dsDNA from the DNA damage response, thereby triggering the activation of STING/TBK1/IRF7-mediated innate immunity in both chicken embryonic fibroblasts and chicken liver cancer cells. Furthermore, downregulation of chcGAS enhanced the infection of fowl adenovirus serotype 4 in LMH cells. Our results demonstrated that chcGAS was an important cytosolic DNA sensor activating innate immune responses and may shed light on a strategy for preventing infectious diseases in the poultry industry.
Asunto(s)
Adenoviridae/inmunología , Pollos/inmunología , Pollos/virología , Citosol/metabolismo , ADN/metabolismo , Inmunidad Innata , Nucleótidos Cíclicos/metabolismo , Serogrupo , Secuencia de Aminoácidos , Animales , Línea Celular , Daño del ADN , Etopósido/farmacología , Perfilación de la Expresión Génica , Factor 7 Regulador del Interferón/metabolismo , Interferón beta/metabolismo , Interleucina-1beta/metabolismo , Nucleótidos Cíclicos/química , Filogenia , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Transducción de Señal/efectos de los fármacos , Fracciones Subcelulares/metabolismoRESUMEN
Severe cold exercise involves the irisin response, and may be related to body composition. We aimed to investigate changes in circulating irisin after ice swimming (IS), as well as to evaluate the correlation between body composition and the change in irisin caused by IS (Δirisin). 81 ice swimmers were recruited to perform IS activities. Blood samples were drawn 30 min before and 30 min after IS, and the serum levels of irisin and the ice swimmers' body composition were measured. As results, circulating irisin declined significantly during the recovery period following IS exercise (P < 0.001). The afternoon baseline circulating irisin level and Δirisin in response to IS were correlated with body fat characteristics rather than muscle parameters in ice swimmers. Δirisin subgroup analyses showed that the Δirisin ascending group (Δirisin+) subjects had a higher fat composition and higher basal irisin levels than the Δirisin descending group (Δirisin-). Furthermore, the decrease in irisin was negatively correlated with fat components in Δirisin- subjects, whereas no correlation was observed between the increase in irisin and body composition in Δirisin + subjects. Finally, a non-linear association analysis suggested that body fat indicators had obvious curvilinear relationships with Δirisin. In conclusion, IS caused a significant decrease in irisin. Statistical and curvilinear associations suggested that the correlation between fat tissue and Δirisin caused by IS is dimorphic and the underlying mechanisms may be due to the different metabolic states of subjects.