RESUMO
The angiotensin II type 2 receptor (AT2R) is a well-established component of the renin-angiotensin system and is known to counteract classical activation of this system and protect against organ damage. Pharmacological activation of the AT2R has significant therapeutic benefits, including vasodilation, natriuresis, anti-inflammatory activity, and improved insulin sensitivity. However, the precise biological functions of the AT2R in maintaining homeostasis in liver tissue remain largely unexplored. In this study, we found that the AT2R facilitates liver repair and regeneration following acute injury by deactivating Hippo signaling and that interleukin-6 transcriptionally upregulates expression of the AT2R in hepatocytes through STAT3 acting as a transcription activator binding to promoter regions of the AT2R. Subsequently, elevated AT2R levels activate downstream signaling via heterotrimeric G protein Gα12/13-coupled signals to induce Yap activity, thereby contributing to repair and regeneration processes in the liver. Conversely, a deficiency in the AT2R attenuates regeneration of the liver while increasing susceptibility to acetaminophen-induced liver injury. Administration of an AT2R agonist significantly enhances the repair and regeneration capacity of injured liver tissue. Our findings suggest that the AT2R acts as an upstream regulator in the Hippo pathway and is a potential target in the treatment of liver damage.
Assuntos
Via de Sinalização Hippo , Interleucina-6 , Regeneração Hepática , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases , Receptor Tipo 2 de Angiotensina , Transdução de Sinais , Animais , Masculino , Camundongos , Acetaminofen , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Interleucina-6/metabolismo , Fígado/metabolismo , Fígado/efeitos dos fármacos , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/fisiologia , Camundongos Knockout , Proteínas Serina-Treonina Quinases/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Proteínas de Sinalização YAP/metabolismoRESUMO
This study established a rat model of obesity by using a high-fat diet(HFD) to explore the effect of polymethoxylated flavonoids on glucose and lipid metabolism in the model rats and decipher the role and mechanism of polymethoxylated flavonoids in mitigating obesity. Thirty normal SD rats were selected and randomized into normal, model, ezetimibe(0.1 mg·kg~(-1)), and polymethoxylated flavonoids(62.5 mg·kg~(-1) and 125 mg·kg~(-1)) groups based on the body weight. Except the normal group receiving a conventional diet, the other groups received a HFD. Rats were administrated with corresponding doses of drugs by gavage. During the administration period, the body weight of each group of rats was regularly weighed, and the serum lipid and glucose levels were measured by a fully automated biochemical analyzer. Islet homeostasis and serum levels of obesity factors were measured by ELISA. The 16S rRNA high-throughput sequencing was employed to study the gut microbiota. Hematoxylin-eosin staining was employed to observe the histomorphology of white fat, brown fat, and pancreas. After the wet weights of white fat and brown fat were measured, the organ index was calculated. Immunohistochemistry and Western blot were employed to determine the protein levels. The results showed that polymethoxylated flavonoids reduced the body weight and Lee's index and improved blood lipid levels of the model rats. Polymethoxylated flavonoids reduced blood glucose and insulin secretion, increased insulin responsiveness, and alleviated insulin resistance. In addition, polymethoxylated flavonoids regulated the serum levels of obesity factors and reduced the weights and indexes of white fat and brown fat, the diameter of white adipocytes, and the number of fat vacuoles in brown fat and pancreatic islet cells. The intervention with polymethoxylated flavonoids increased the diversity of gut microbiota in the model rats, increasing the beneficial bacteria associated with glucose and lipid metabolism and reduced the harmful bacteria at the genus level. In addition, polymethoxylated flavonoids up-regulated the protein levels of glucose transporter 4(GLUT4), phosphorylated AMP-activated protein kinase(p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α), and uncoupling protein 1(UCP1). In summary, polymethoxylated flavonoids may increase the body utilization of glucose and lipids by regulating the homeostasis of insulin, the serum levels of obesity factors, the diversity of gut microbiota, and the expression of mitochondrial metabolism-related proteins in brown adipocytes, thereby mitigating obesity in rats.
Assuntos
Dieta Hiperlipídica , Flavonoides , Metabolismo dos Lipídeos , Obesidade , Ratos Sprague-Dawley , Animais , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ratos , Metabolismo dos Lipídeos/efeitos dos fármacos , Flavonoides/farmacologia , Flavonoides/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Masculino , Glucose/metabolismo , Modelos Animais de Doenças , Humanos , Glicemia/metabolismo , Glicemia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Microbioma Gastrointestinal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacosRESUMO
Camellia perpetua has the excellent characteristic of flowering multiple times throughout the year, which is of great importance to solve the problem of "short flowering period" and "low fresh flower yield" in the yellow Camellia industry at present. Observations of flowering phenology have demonstrated that most floral buds of C. perpetua were formed by the differentiation of axillary buds in the scales at the base of the terminal buds of annual branches. However, the molecular mechanism of flowering in C. perpetua is still unclear. In this study, we conducted a comparative transcriptomic study of the terminal buds and their basal flower buds in March (spring) and September (autumn) using RNA-seq and found that a total of 11,067 genes were significantly differentially expressed in these two periods. We identified 27 genes related to gibberellin acid (GA) synthesis, catabolism, and signal transduction during floral bud differentiation. However, treatment of the terminal buds and axillary buds of C. perpetua on annual branch with GA3 did not induce floral buds at the reproductive growth season (in August) but promoted shoot sprouting. Moreover, 203 flowering genes were identified from the C. perpetua transcriptome library through homology alignment, including flowering integrators LEAFY (LFY) and UNUSUAL FLORAL ORGANS (UFO), as well as MADS-box, SQUAMOSA PROMOTER BINDING PROTEIN-box (SBP-box), and TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) genes, which were specifically upregulated in floral buds and were likely involved in flowering in C. perpetua. The floral inhibitor CperTFL1b was identified and cloned from C. perpetua, and its expression level was specifically regulated in terminal buds in autumn. Ectopic overexpression of CperTFL1b delayed flowering time and produced abnormal inflorescence and floral organs in Arabidopsis, suggesting that CperTFL1b inhibits flowering. In conclusion, this study deepens our understanding of the molecular mechanism of blooms throughout the year in C. perpetua and provides a helpful reference for cultivating new varieties of yellow Camellia with improved flowering traits.
Assuntos
Camellia , Transcriptoma , Camellia/genética , Perfilação da Expressão Gênica , RNA-Seq , Flores , Regulação da Expressão Gênica de PlantasRESUMO
Laminin subunit alpha 4 (LAMA4),a member of the laminin family,is present in the intercellular matrix of adult tissues as a major component of basement membrane.LAMA4 is involved in the adhesion of cells and can bind to corresponding integrins to activate relevant signaling pathways,playing an essential role in the growth,proliferation,and migration of cells.It has been demonstrated that LAMA4 is associated with the occurrence and development of a variety of diseases including tumors,and the expression of LAMA4 can be used as a biomarker of tumor diagnosis and prognosis.This paper summarizes the current research progress in LAMA4 with the focus on the relationship between LAMA4 and diseases,especially tumor,with a view to provide new directions for the future research.
Assuntos
Matriz Extracelular , Laminina , Adulto , HumanosRESUMO
This study aims to examine the effect of superfine powder and aqueous extract of Polygonati Rhizomaon on natural perimenopausal syndrome in rats and explore the underlying mechanism. To be specific, a total of 60 female SD rats(14-15 months old) with estrous cycle disorder were screened by the vaginal smear and randomized into model control group, ß-estradiol 3-benzoate group(0.1 mg·kg~(-1)), superfine powder of Polygonati Rhizoma group(0.25, 0.5 g·kg~(-1)) and aqueous extract of Polygonati Rhizoma group(0.25, 0.5 g·kg~(-1)), and another 10 female SD rats(14-15 months old) were selected as the youth control group. The administration lasted 6 weeks. Then the perimenopausal syndrome-related indexes such as body temperature, microcirculatory blood flow of face and ear, vertigo period, salivary secretion, grip force, and bone strength were determined and open field test was conducted. The immune system-related indexes such as the wet weight and index of thymus and spleen, percentage of T lymphocytes and subgroups in peripheral blood, and hematological indexes were measured. In addition, the ovary-related indexes such as estrous cycle, the wet weight and index of uterus and ovary, ovarian tissue morphology, and cell apoptosis were determined. Moreover, hypothalamus-pituitary-ovary axis(HPO)-related indexes such as serum sex hormone levels, cytochrome P450 family 11 subfamily A member 1(CYP11A1), cytochrome P450 family 19 subfamily A member 1(CYP19A1), and cytochrome P450 family 17 subfamily A member 1(P450 17A1) in ovarian tissue were measured. The results showed that the superfine powder and aqueous extract of Polygonati Rhizoma significantly decreased body temperature(anal, facial and dorsal temperature), microcirculatory blood flow in the ear, and vertigo period, increased salivary secretion, grip force, bone strength, total distance and total speed in the open field test, wet weight and index of thymus and spleen, lymphocyte ratio, CD3~+ level, and CD4~+/CD8~+ ratio, reduced neutrophil number and ratio, estrous cycle disorder ratio, and number of ovarian apoptotic cells, raised wet weight and index of uterus, wet weight of ovary, levels of inhibin B(INHB), estradiol(E_2), anti-müllerian hormone(AMH), and ovarian CYP11A1 and CYP19A1, decreased follicle-stimulating hormone(FSH) and luteinizing hormone(LH) content, and improved ovarian tissue morphology. It is suggested that the superfine powder and aqueous extract of Polygonati Rhizoma can improve the symptoms associated with natural perimenopausal syndrome in rats and enhance ovarian function and immune function. The mechanism is that they regulate HPO axis function by increasing estrogen synthesis.
Assuntos
Enzima de Clivagem da Cadeia Lateral do Colesterol , Perimenopausa , Feminino , Animais , Ratos , Ratos Sprague-Dawley , Microcirculação , Pós , Citocromo P-450 CYP1A1RESUMO
This study aimed to investigate the therapeutic effect of Yunkang Oral Solution on the improvement of spleen deficiency and pregnancy outcomes in pregnant mice with spleen deficiency syndrome induced by irregular diet and over consumption of cold and bitter foods. To simulate human irregular diet and over consumption of cold and bitter foods leading to spleen deficiency, the pregnant mice with spleen deficiency syndrome were prepared using an alternate-day fasting and high-fat diet combined with oral administration of Sennae Folium. During the experiment, spleen deficiency-related indicators and diarrhea-related parameters were measured. Gastric and intestinal motility(gastric emptying rate and intestinal propulsion rate) were evaluated. The levels of serum ghrelin, growth hormone(GH), gastrin(Gas), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-c), chorionic gonadotropin ß(ß-CG), progesterone(P), and estradiol(E_2) were measured. Intestinal barrier function in pregnant mice with spleen deficiency syndrome was assessed. Conception rate, ovarian coefficient, litter-bearing uterine coefficient, number of live fetuses, average fetal weight, and fetal length were calculated. The results showed that Yunkang Oral Solution significantly improved spleen deficiency-related indicators and diarrhea in pregnant mice with spleen deficiency syndrome, increased gastric emptying rate and intestinal propulsion rate, elevated the levels of gastrointestinal hormones(ghrelin, GH, and Gas) in the serum, and reduced lipid levels(TC and LDL-c), thereby improving lipid metabolism disorders. It also improved colonic tissue morphology, increased the number of goblet cells, and promoted the mRNA and protein expression of occludin and claudin-1 in colonic tissues, thereby alleviating intestinal barrier damage. Yunkang Oral Solution also regulated the levels of pregnancy hormones(ß-CG, P, and E_2) in the serum of pregnant mice with spleen deficiency syndrome. Moreover, it increased the conception rate, ovarian coefficient, litter-bearing uterine coefficient, number of live fetuses, average fetal weight, and fetal length. These findings suggest that Yunkang Oral Solution can improve spleen deficiency-related symptoms in pregnant mice before and during pregnancy, regulate pregnancy-related hormones, and improve pregnancy outcomes.
Assuntos
Grelina , Baço , Gravidez , Feminino , Camundongos , Humanos , Animais , Peso Fetal , LDL-Colesterol , DiarreiaRESUMO
Breast cancer is one of the most frequent malignancies in females. The molecular mechanism of how breast cancer development and recurrence still need to be explored. Peroxisome gamma coactivator-1ß (PGC-1ß) was engaged in cancer energy metabolism and tumor genesis. However, the mechanisms of PGC-1ß in breast cancer have not been fully understood. In this study, PCG-1ß overexpressed and knockdown vectors were transferred into MCF-7 cells. With the association-quantitative connection analysis, the different expressions of mRNAs and proteins were examined. Additionally, the terms on differentially expressed mRNAs and proteins were enriched by GO and KEGG. Based on the results, 1872 differentially expressed genes were identified in the up-regulated of PGC-1ß group, and 1318 genes were found in the down-regulated of PGC-1ß cells. With the label-free technique, 221 differentially expressed proteins were screened in PGC-1ß up-regulated group, and 459 proteins were identified in PGC-1ß down-regulated group. Correlation analysis showed that 49 significantly expressed mRNA-protein pairs in OV vs CT groups and 25 paired in SI vs CT groups. Combined analysis of transcriptome and proteome demonstrated that PGC-1ß plays a important role in cancer energy metabolism and boosting the pace of chemical processes in the proliferation of breast cancer cells. Additional investigation about PGC-1ß and energy metabolism in cancer cells may shed fresh light on the growth and treatment of breast cancer cells.
Assuntos
Neoplasias da Mama , Proteínas de Ligação a RNA , Feminino , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Peroxissomos/metabolismo , RNA Mensageiro/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Células MCF-7RESUMO
The present study evaluated the effect of Shenqi Jiangtang Granules(SJG) combined with western medicine on the adverse pregnancy outcomes in women with gestational diabetes mellitus(GDM). PubMed, Web of Science, CNKI, Wanfang, and VIP were searched for clinical randomized controlled trials(RCTs) of SJG combined with western medicine against GDM. The included RCTs were assessed for risks using the assessment criteria recommended by the Cochrane handbook for systematic reviews of interventions. Meta-analysis was performed using Stata 12.0 and RevMan 5.3. Nineteen RCTs were included, with 1 647 patients involved, including 824 cases treated with western medicine alone, and 823 cases treated with SJG combined with western medicine. The course of treatment ranged from 2 to 12 weeks. As revealed by Meta-analysis results, compared with western medicine treatment alone, SJG combined with western medicine could reduce the incidence of postpartum hemorrhage(OR=0.23, 95%CI[0.10, 0.53], P=0.000 6), gestational hypertension(OR=0.24, 95%CI[0.13, 0.45], P<0.000 01), polyhydramnios(OR=0.24, 95%CI[0.12, 0.45], P<0.000 1), premature rupture of membranes(OR=0.20, 95%CI[0.09, 0.45], P<0.000 1), cesarean section(OR=0.40, 95%CI[0.29, 0.55], P<0.000 01), macrosomia(OR=0.19, 95%CI[0.08, 0.47], P<0.000 3), neonatal asphyxia(OR=0.22, 95%CI[0.12, 0.40], P<0.000 01), premature delivery(OR=0.19, 95%CI[0.12, 0.30], P<0.000 01), proteinuria(OR=0.19, 95%CI[0.06, 0.58], P=0.004) and hypoglycemia(OR=0.28, 95%CI[0.16, 0.50], P<0.000 1). The funnel plots and Egger's test showed that except macrosomia, there was no significant publication bias in the results of other indicators. Therefore, as indicated by the findings, SJG combined with western medicine can reduce the incidence of adverse pregnancy outcomes in GDM patients. However, due to the uneven quality of the included trials, the clinical application of this protocol requires caution.
Assuntos
Diabetes Gestacional , Cesárea , Diabetes Gestacional/tratamento farmacológico , Medicamentos de Ervas Chinesas , Feminino , Macrossomia Fetal , Humanos , Recém-Nascido , Gravidez , Resultado da Gravidez , Revisões Sistemáticas como AssuntoRESUMO
Dendrobium officinale can serve as Chinese medicinal material effective in nourishing yin, clearing heat, and producing fluid, and is used to treat throat diseases, but its active substances and mechanism are not clear. To clarify the active fraction and underlying mechanism of D. officinale against chronic pharyngitis(CP), the present study induced a CP model in rats by pepper water combined with low-concentration ammonia, and crude polysaccharides of D. officinale(DOP), non-polysaccharides of D. officinale(DON), and total extract of D. officinale(DOT)(0.33 g·kg~(-1), calculated according to the crude drug) were administered by gavage for six weeks. The changes in oral secretions and pharyngeal conditions of rats with CP were observed and rated. The hematological indicators were determined by an automatic hematology analyzer. The serum levels of pro-inflammatory factors, such as tumor necrosis factor-alpha(TNF-α), interleukin 1ß(IL-1ß), and interleukin 6(IL-6), and T-lymphocyte cytokines, including interferon γ(IFN-γ), interleukin 4(IL-4), interleukin 17(IL-17), and transforming growth factor ß1(TGF-ß1) were detected by the enzyme-linked immunosorbent assay(ELISA). The proportions of CD3~+, CD4~+, and CD8~+cells in peripheral blood T lymphocyte subsets were determined by the flow cytometry. The histomorphological changes of the pharynx were observed by hematoxylin-eosin(HE) staining. The protein expression of nuclear factor-κB P65(NF-κB P65), cyclooxygenase-2(COX-2), F4/80, and monocyte chemoattractant protein-1(MCP-1) in the pharynx were detected by immunohistochemistry and Western blot. The results showed that DOP and DON could significantly relieve pharyngeal lesions, reduce white blood cells(WBC) and lymphocytes(LYMP), decrease the levels of pro-inflammatory factors TNF-α, IL-6, and IL-1ß, and inhibit the protein expression of NF-κB P65, COX-2, F4/80, and MCP-1 in the pharynx. DOP was superior in reducing oral secretions and serum IL-17 level and inferior in increasing CD4~+/CD8~+ratio to DON. It is suggested that both polysaccharides and non-polysaccharides of D. officinale have anti-PC effects and the anti-inflammatory mechanism may be related to the regulation of T lymphocyte distribution and inhibition of the inflammatory signaling pathways mediated by NF-κB P65. The anti-inflammatory effect of DOP may be related to the regulation of Th17/Treg balance, while that of DON may be related to the regulation of the Th/Tc ratio.
Assuntos
Dendrobium , Faringite , Amônia/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Ciclo-Oxigenase 2 , Dendrobium/química , Interleucina-17/uso terapêutico , Interleucina-6 , NF-kappa B/metabolismo , Faringite/tratamento farmacológico , Extratos Vegetais/química , Polissacarídeos/farmacologia , Ratos , Fator de Necrose Tumoral alfa , ÁguaRESUMO
The organization of molecular motors in supramolecular assemblies to allow the amplification and transmission of motion and collective action is an important step toward future responsive systems. Metal-coordination-driven directional self-assembly into supramolecular metallacycles provides a powerful strategy to position several motor units in larger structures with well-defined geometries. Herein, we present a pyridyl-modified molecular motor ligand (MPY) which upon coordination with geometrically distinct di-Pt(II) acceptors assembles into discrete metallacycles of different sizes and shapes. This coordination leads to a red-shift of the absorption bands of molecular motors, making these motorized metallacycles responsive to visible light. Photochemical and thermal isomerization experiments demonstrated that the light-driven rotation of the motors in the metallacycles is similar to that in free MPY in solution. CD studies show that the helicity inversions associated with each isomerization step in the rotary cycle are preserved. To explore collective motion, the trimeric motor-containing metallacycle was aggregated with heparin through multiple electrostatic interactions, to construct a multi-component hierarchical system. SEM, TEM, and DLS measurements revealed that the photo- and thermal-responsive molecular motor units enabled selective manipulation of the secondary supramolecular aggregation process without dissociating the primary metallacycle structures. These visible-light-responsive metallacycles, with intrinsic multiple rotary motors, offer prospects for cooperative operations, dynamic hierarchical self-assembled systems, and adaptive materials.
RESUMO
In this study, we aimed to explore the effects of iguratimod (IGU) combined with methotrexate (MTX) and hydroxychloroquine (HCQ) on bone mineral density (BMD) in patients with rheumatoid arthritis (RA). 76 patients who received IGU combined with MTX and HCQ were included in this retrospective study. After 48 weeks treatment of IGU combined with MTX and HCQ, the BMD at the L1-L4 (p <0.01), left femoral neck (p <0.01) and left total hip (p <0.01) were significantly increased. Especially, the BMD at left femoral neck was significantly increased from baseline to week 24 (p <0.05). With regard to inflammatory reaction, there were statistically significant reductions in the RF (p <0.05), CRP (p <0.05), ESR (p <0.01), anti-CCP (p <0.01) from baseline to week 48. The most common adverse events were gastrointestinal reaction and transaminase elevation. The combination of IGU, MTX and HCQ could significantly improve the BMD and restrain inflammatory reaction. No additional adverse events were noticed in our research. This study provides valuable information for treatment of osteopenia in patients with RA.
Assuntos
Artrite Reumatoide , Metotrexato , Artrite Reumatoide/tratamento farmacológico , Densidade Óssea , Cromonas , Quimioterapia Combinada , Humanos , Hidroxicloroquina/efeitos adversos , Estudos Retrospectivos , SulfonamidasRESUMO
The aim of this paper was to study the improvement effect of ethanol extract from Citri Reticulatae Pericarpium(CRP) on triglyceride of hyperlipidemia model rats, and to explore the possible mechanism. SD rats were randomly divided into normal group, model group, positive control group, and high, medium and low-dose CRP ethanol extract groups, with 10 rats in each group. During the experiment, except for the normal group that was fed with distilled water and ordinary feed, rats in the other groups were given different concentrations of alcohol and fed with high-sugar and fat diets. All rats were given free diets. While being modeled, each group was administered with 0.01 mL·g~(-1) by gavage once a day for six weeks. Blood samples were collected after two weeks, four weeks and six weeks of drug treatment. After the completion of the experiment, blood, liver and adipose tissue were collected. Triglyceride(TG), alanine aminotransferase(ALT), aspartate aminotransferase(AST), alkaline phosphatase(ALP) in serum, TG in liver tissue and TG in fecal were detected. Free fatty acid(FFA) and triglyceride-related hydrolase, such as adipose tiglyceride lipase(ATGL), lipoprotein lipase(LPL), hepatic lipase(HL), hormone-sensitive triglyceride lipase(HSL) were detected by ELISA. The mRNA expressions of peroxisome proliferators-activated receptors(PPARγ), sterol regulatory element binding protein 1 c(SREBP-1 c) and farnesoid X receptor(FXR) were determined by RT-PCR. Compared with the model group, each administration group could reduce TG levels in serum and liver to varying degrees, reduce serum ALT, AST, ALP activities, significantly reduce free fatty acid content in serum, significantly increase triglyceride metabolism-related enzymes, including fat ATGL, LPL and liver HL content, and significantly reduced the content of fat HSL. According to the study of transcriptional regulation genes relating to triglyceride metabolism, extract from CRP could significantly increase the mRNA expressions of PPARγ and FXR. In conclusion, ethanol extract from CRP could ob-viously reduce the TG level of hyperlipidemia model rats, and might reduce plasma TG content by increasing PPARγ-LPL/ATGL and FXR-HL triglyceride hydrolysis pathways.
Assuntos
Hiperlipidemias , Animais , Etanol , Hiperlipidemias/tratamento farmacológico , Hiperlipidemias/genética , Fígado , Extratos Vegetais , Ratos , Ratos Sprague-Dawley , TriglicerídeosRESUMO
Dendrobii officinalis, with a definite effect of nourishing Yin and clearing heat, has been a folk habit for drinking after being mixed with water. Because its superfine powder has the advantages of high dissolution and convenient drinking, we observed the effect of D. officinalis superfine powder on metabolic hypertension model rats and its possible mechanism in this experiment, which can be used as a reference for its clinical application for hypertension. The overeating greasy-induced metabolic hypertension model was established with high-fat, high-sugar and high-purine diet. These rats were orally administered with 400 mg·kg~(-1) and 200 mg·kg~(-1) of D. officinalis superfine powder for 20 consecutive weeks. During this period, blood pressure, blood lipid, blood glucose, insulin and other related indexes of glucose and lipid metabolism were monitored; the levels of lipopolysaccharide(LPS), C-reactive protein(CRP), interleukin 6(IL-6) and other inflammatory mediators were measured; the levels of nitric oxide(NO) and endothelin-1(ET-1) were detected, and the histomorphological and ultrastructural changes of aorta were observed. In addition, the expression of LPS/TLR4 pathway-related molecules in aorta was determined. The results showed that long-term administration of D. officinalis superfine powder significantly reduced the levels of systolic blood pressure(SBP), diastolic blood pressure(DBP) and mean arterial pressure(MBP) in metabolic hypertension model rats, decreased the levels of total cholesterol(TC), triglyceride(TG), low density lipoprotein cholesterol(LDL-c), glucose(Glu), and insulin(INS) levels in blood, increased the contents of high density lipoprotein cholesterol(HDL-c),decreased the LPS, CRP, IL-6 and ET-1 levels in blood and increased NO content. Furthermore, it improved the abnormality of aortic histomorphology and endothelial ultrastructure, and inhibited the protein expression of TLR4, myeloid differentiation factor(MyD88), IL-6, interleukin-1 ß(IL-1ß), and tumor necrosis factor-α(TNF-α) as well as mRNA expression of TNF-α and IL-1ß in aorta. In conclusion, D. officinalis superfine powder may improve the abnormal function and structure of blood vessels by inhibiting the activation of LPS/TLR4 pathway, thus playing a role against metabolic hypertension.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hipertensão , Animais , Dendrobium/química , Hiperfagia , Hipertensão/induzido quimicamente , Hipertensão/tratamento farmacológico , Interleucina-6 , Pós , Ratos , Fator de Necrose Tumoral alfaRESUMO
This study aims to investigate the preventive effect of Dendrobium officinale in LPS-induced intestinal mucosal damage. Forty SPF-grade C57 BL/6 J male mice were randomly divided into normal group(NC), model group(LPS), and two superfine powder groups of Dendrobium officinale(DOF)(DOF-L, 0.30 g·kg~(-1)and DOF-H, 0.60 g·kg~(-1), respectively), with 10 mice in each group. DOF superfine powder suspension was given via oral administration to mice for 7 days, while the mice in NC and LPS groups received the same volume of saline for 7 days. On the eighth day, the mice in LPS group and DOF treatment groups were injected with LPS(5 mg·kg~(-1)) by intraperitoneal injection to establish the intestinal mucosal injury model, while the mice in NC group were injected with the same volume of sterile saline in the same manner. Six hours after injection with LPS or saline, plasma and the intestinal tissue were collected. The diamine oxidase(DAO) and D-lactate levels in plasma were detected with a biochemical method. The levels of proinflammatory factors interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) in plasma were detected by ELISA. The histomorphology and ultrastructure of mouse ileum tissues were observed by hematoxylin-eosin(HE) staining in optical microscope and transmission electron microscope(TEM). The expression and distribution of tight junction(TJ) proteins claudin-1, occludin and F4/80 were detected by immunohistochemistry while the protein expression levels of Toll-like receptor 4(TLR-4) and nuclear factor kappa B p65(NF-κB p65) in jejunum were detected by Western blot. The experimental results showed that continuous intragastric administration of D. officinale superfine powder for 7 days obviously alleviated the damage and ultrastructural changes of intestinal mucosa induced by LPS; significantly decreased DAO and D-lactate levels in plasma in model group(P<0.05); up-regulated the protein expression of claudin-1 and occludin in ileum tissues; down-regulated the protein expression of TLR-4 and NF-κB p65 in jejunum tissues(P<0.01); significantly decreased TNF-α and IL-6 levels in plasma(P<0.05); and decreased the infiltration of F4/80~+ macrophage cells. Our results suggested that D. officinale had significant protective effects on LPS-induced intestinal mucosal damage and reduced intestinal permeability. The mechanism might be related to its effects of inhibiting inflammation via TLR-4/NF-κB p65, and up-regulating the expression of tight junction proteins.
Assuntos
Dendrobium , Lipopolissacarídeos , Animais , Mucosa Intestinal , Masculino , Camundongos , NF-kappa B , Pós , Fator de Necrose Tumoral alfa/genéticaRESUMO
AIMS: To determine deficiencies in the Food and Drug Administration (FDA)'s guidance for assessing acarbose bioequivalence (BE) and to explore optimal pharmacodynamic (PD) metrics for better evaluation of acarbose BE. METHODS: Three clinical trials with branded acarbose were conducted in healthy subjects, including a pilot study (Study I, n = 11, 50 and 100 mg), a 2×2 crossover BE study (Study II, n = 36, 100 mg) and a 4×4 Williams study (Study III, n = 16, 50/100/150 mg). Serum glucose concentrations were measured by the glucose oxidase method. RESULTS: In Study I, compared with 50 mg acarbose, only 100 mg acarbose had a significantly lower Cmax0-4h than that of sucrose administration alone (7.96 ± 0.83 mmol/L vs 6.78 ± 1.02 mmol/L, P < .05). In Study II, the geometric mean ratios of the test formulation to the reference formulation (both formulations were the branded drug) for FDA PD metrics, ΔCmax0-4h and ΔAUC0-4h , were 0.903 and 0.776, respectively, and the 90% confidence intervals were 67.44-120.90 and 53.65-112.13, respectively. The geometric mean ratios (confidence interval) for possible optimal evaluation PD metrics (Cmax0-2h and AUC0-2h ) were 1.035 (94.23-112.68) and 0.982 (89.28-107.17), respectively. Further, Cmax0-2h and AUC0-2h also met the sensitivity requirements for BE evaluation in Study III. CONCLUSION: Considering the mechanisms of action of acarbose, the PD effect was shown to be dose independent during the 2-4 hours postadministration of acarbose. Hence PD metrics based on the serum glucose concentration from 0 to 2 hours (Cmax0-2h and AUC0-2h ) are more sensitive than the FDA-recommended PD metrics for acarbose BE evaluation from 0-4 hours (ΔCmax0-4h and ΔAUC0-4h ). The trial has been registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn, ChiCTR1800015795, ChiCTR-IIR-17013918, ChiCTR-IIR-17011903). All subjects provided written informed consent before screening.
Assuntos
Acarbose , Área Sob a Curva , Estudos Cross-Over , Humanos , Projetos Piloto , Comprimidos , Equivalência TerapêuticaRESUMO
The aim of this paper was to study the effect of Wubi Shanyao Pills on sexual dysfunction in rats with kidney-Yang deficiency and to investigate its possible mechanism. Adenine(100 mg·kg~(-1)) was administered to male SD rats for 8 weeks to establish kidney-Yang deficiency model, and at the same time, Wubi Shanyao Pills(2, 1, 0.5 g·kg~(-1)) were administered to rats for 8 weeks. The syndrome manifestation of kidney-Yang deficiency was observed in rats and the scores of symptoms were evaluated. Sexual behavior indexes(incubation period and times of capture, straddle and ejaculation) were measured by mating experiment. The levels of serum testosterone(T), estradiol(E_2), follicle stimulating hormone(FSH), luteinizing hormone(LH), and gonadotropin releasing hormone(GnRH) were measured by radioimmunoassay. The wet weights of testis and seminal vesicle were measured. The content of fructose in seminal plasma was detected by UV spectrophotometry. The pathological changes of testis and epididymis were observed by HE staining. The expression levels of transforming growth factor(TGF-ß1) and cytochrome P450 aromatase(CYP19) in testis were detected by immunohistochemistry and Western blot. The results showed that Wubi Shanyao Pills could significantly reduce the score of kidney-Yang deficiency syndrome, improve the symptoms of kidney-Yang deficiency syndrome, shorten capture, straddle and ejaculation latency, increase capture and straddle times, increase serum T, LH, FSH, E_2 and GnRH levels, increase the wet weight of testis and seminal vesicle and fructose content in seminal plasma, improve the pathological structure of testis and epididymis, and inhibit the expression of TGF-ß1 and increase CYP19 in testis of the model rats. Therefore, Wubi Shanyao Pills can significantly improve sexual dysfunction in rats with kidney-Yang deficiency, and its mechanism may be related to regulating the low function of hypothalamus pituitary gonad(HPG) axis and improving the disorder of sex hormone secretion. In addition, it may be also related to inhibiting the expression of testicular TGF-ß1, increasing the expression of CYP19 protein, and then regulating the amount of T converted to E_2.
Assuntos
Adenina , Deficiência da Energia Yang , Animais , Hormônio Foliculoestimulante , Hormônio Liberador de Gonadotropina , Hormônio Luteinizante , Masculino , Ratos , Ratos Sprague-Dawley , Testículo , TestosteronaRESUMO
Designing artificial molecular machines to execute complex mechanical tasks, like coupling rotation and translation to accomplish transmission of motion, continues to provide important challenges. Herein, we demonstrated a novel molecular machine comprising a second-generation light-driven molecular motor and a bistable [1]rotaxane unit. The molecular motor can rotate successfully even in an interlocked [1]rotaxane system through a photoinduced cis-to -trans isomerization and a thermal helix inversion, resulting in concomitant transitional motion of the [1]rotaxane. The transmission process was elucidated via 1H NMR, 1H-1H COSY, HMQC, HMBC, and 2D ROESY NMR spectroscopies, UV-visible absorption spectrum, and density functional theory calculations. This is the first demonstration of a molecular motor to rotate against the appreciably noncovalent interactions between dibenzo-24-crown-8 and N-methyltriazolium moieties comprising the rotaxane unit, showing operational capabilities of molecular motors to perform more complex tasks.
RESUMO
Based on pharmacodynamics-component correlation analysis,the best effective part of hyperlipidemia of Pericarpium Citri Reticulatae( PCR) was screened out to confirm the possible constituents with the lipid regulating effect,in order to provide a basis for the development of new drugs. Hyperlipidemia rats induced by fat emulsion were used to screen out the best hypolipidemic parts of PCR with TC,LDL-c as the index. HPLC-ESI-MS were used to analyze common constituents of the different solvent extracts from PCR. The constituents were classified and identified based on the retention time,m/z and UV spectra. And the HPLC-DAD were used to determine the contents of flavonoids( narirutin,hesperidin,didymin,nobiletin,tangeretin,3,5,6,7,8,3',4'-heptemthoxyflavone).Correlation analysis was conducted on the constituents and efficacy with the method of SPSS ANOVA bivariate correlation. Five extracts could significantly decrease the content of TC,LDL-c of hyperlipemia rats induced by fat emulsion,and the best effective part were95% ethanol and ethyl acetate. There were 19 common peaks in five different solvent extracts from PCR,and 17 flavonoids were identified and classified,including 10 polymethoxyflavonoids and 7 other flavonoids. According to the raw material quantity,the order of content of flavonones arranged from high to low: n-butyl alcohol part> 95% ethanol part> water part> ethyl acetate part> petroleum ether part; and the order of PMFs arranged from high to low: n-butyl alcohol part≈95% ethanol part≈ethyl acetate part > petroleum ether part > water part. The decreased percentage of TC,LDL-c was positively correlated with 10 common PMFs constituents,which suggested that PMFs may be the effective components for reducing blood lipid.
Assuntos
Citrus/química , Medicamentos de Ervas Chinesas/farmacologia , Hipolipemiantes/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Flavonoides/farmacologia , RatosRESUMO
Previous studies of Dendrobium officinale on anti-hypertension effect always focused only on the blood pressure,while polysaccharides of D. officinale( DOP) have been traditionally considered as one of the main effective substances. This study aimed to evaluate the effect of ethanol extract from D. officinale( DOE) on blood pressure,Glu and lipid profile in metabolic hypertensive rats induced by comprehensive dietary factors,and elucidate the composition of effective fractions from DOE. A metabolic hypertension model of rat induced by high-sugar,high-fat diet and alcohol drinking was adopted to evaluate the effect of DOE on hypertension and other metabolic disorders. Blood pressure,Glu and lipid profile were detected to find the features and differences of DOE and DOP on metabolic hypertension. Furthermore,DOE was separated with three different common solvents according to the polarity. Along with blood pressure,Glu,UA and lipid profile,hemorheology,oxidative index and aortas structure changes were adopted to evaluate the comprehensive effects of the most effective fractions on metabolic hypertension. Finally,HPLC-DAD-MS was adopted to identify the components of the most effective fraction. The SBP and Glu of models were decreased significantly after administration of DOE and DOP for 6 weeks,while TG in DOE groups also reduced dramatically. The DOE was separated with ether,n-butanol respectively and named NAF,NBF and NCF. SBP,TG,Glu,UA of model rats were decreased significantly after 4 weeks administration with NBF. The level of MDA in serum was down-regulated,while GSH-Px and T-AOC were up-regulated obviously after 12 weeks.And the blood viscosity also obviously decreased,with less collagen deposition of aortas by Masson's trichrome staining. NBF was mainly composed of phenols and flavone C-glycosides,whose aglycone was apigenin,and monosaccharide was connected to C-6 and C-8. Ethanol extract from D.officinale has an positive effect in alleviating hypertension and metabolic disorders in metabolic hypertension. Medium polarity fraction was the effective fraction of alcohol extraction from D. officinale,and mainly composed of phenols and flavone C-glycosides.
Assuntos
Dendrobium , Hipertensão/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Pressão Sanguínea , Etanol , Extratos Vegetais/farmacologia , RatosRESUMO
BACKGROUND/AIMS: Heat stress could cause huge losses for Lentinula edodes in China and other Asian cultivation areas. Yet our understanding of mechanism how to defend to heat stress is incomplete. METHODS: Using heat-tolerant and heat-sensitive strains of L. edodes, we reported a combined proteome and transcriptome analysis of L. edodes response to 40 °C heat stress for 24 h. Meanwhile, the effect of LeDnaJ on the thermotolerance and IAA (indoleacetic acid) biosynthesis in L. edodes was analyzed via the over-expression method. RESULTS: The proteome results revealed that HSPs (heat shock proteins) such as Hsp40 (DnaJ), Hsp70, Hsp90 and key enzymes involved in tryptophan and IAA metabolism process LeTrpE, LeTrpD, LeTam-1, LeYUCCA were more highly expressed in S606 than in YS3357, demonstrating that HSPs and tryptophan as well as IAA metabolism pathway should play an important role in thermotolerance. Over-expression of LeDnaJ gene in S606 strains showed better tolerance to heat stress. It was also documented that intracellular IAA accumulation of S606 (8-fold up) was more than YS3357 (2-fold up), and exogenous IAA enhanced L. edodes tolerance to heat stress. CONCLUSION: Our data support the interest of LeTrpE, LeDnaJ, tryptophan and IAA could play a pivotal role in enhancing organism thermotolerance.