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Cellular senescence is an irreversible state of cell cycle arrest, characterized by a gradual decline in cell proliferation, differentiation, and biological functions. Cellular senescence is double-edged for that it can provoke organ repair and regeneration in physiological conditions but contribute to organ and tissue dysfunction and prime multiple chronic diseases in pathological conditions. The liver has a strong regenerative capacity, where cellular senescence and regeneration are closely involved. Herein, this review firstly introduces the morphological manifestations of senescent cells, the major regulators (p53, p21, and p16), and the core pathophysiologic mechanisms underlying senescence process, and then specifically generalizes the role and interventions of cellular senescence in multiple liver diseases, including alcoholic liver disease, nonalcoholic fatty liver disease, liver fibrosis, and hepatocellular carcinoma. In conclusion, this review focuses on interpreting the importance of cellular senescence in liver diseases and summarizes potential senescence-related regulatory targets, aiming to provide new insights for further researches on cellular senescence regulation and therapeutic developments for liver diseases.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Senescência Celular , Neoplasias Hepáticas/patologiaRESUMO
Surgical resection is the most common approach for the treatment of osteosarcoma. However, two major complications, including residual tumor cells and large bone defects, often arise from the surgical resection of osteosarcoma. Discovering new strategies for programmatically solving the two above-mentioned puzzles has become a worldwide challenge. Herein, a novel one-step strategy is reported for natural phenolic acid planted nanohybrids with desired physicochemical properties and steerable photothermal effects for efficacious osteosarcoma suppression and bone healing. Nanohybrids are prepared based on the self-assembly of chlorogenic acid and gold nanorods through robust Au-catechol interface actions, featuring precise nanostructures, great water solubility, good stability, and adjustable hyperthermia generating capacity. As expected, on the one hand, these integrated nanohybrids can severely trigger apoptosis and suppress tumor growth with strong hyperthermia. On the other hand, with controllable mild NIR irradiation, the nanohybrids promote the expression of heat shock proteins and induce prominent osteogenic differentiation. This work initiates a brand-new strategy for assisting osteosarcoma surgical excision to resolve the blockage of residual tumor cells elimination and bone regeneration.
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Neoplasias Ósseas , Hipertermia Induzida , Osteossarcoma , Humanos , Osteogênese , Ácido Clorogênico/farmacologia , Neoplasia Residual/terapia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/metabolismo , Regeneração Óssea , Neoplasias Ósseas/tratamento farmacológicoRESUMO
We investigated the role of zinc-finger protein 281 (ZNF281), a novel molecule, in ethanol-induced hepatocyte senescence and uncovered the potential mechanism. Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of ZNF281 in hepatocyte senescence. ZNF281 expression was upregulated in both alcohol-fed mice livers and ethanol-treated hepatocytes. Silence of ZNF281 in hepatocytes using siRNA mitigated ethanol-caused decrease in cell viability and increased release of aspartate aminotransferase, alanine transaminase, and lactate dehydrogenase. ZNF281 siRNA reduced senescence-associated ß-galactosidase-positive cells under ethanol exposure, abolished cell cycle arrest at G0/G1 phase, and diminished senescence-associated secretory phenotype and proinflammatory cytokines (IL-1ß and IL-6) release. At molecular level, ZNF281 deficiency altered the expression profile of senescence-associated proteins including p53, p21, p16, high mobility group AT-hook 1, and phospho-histone H2A.X and telomerase-associated regulatory factors including telomerase reverse transcriptase, telomeric repeat binding factor 1 (TRF1), and TRF2. ZNF281 knockdown promoted hepatocyte recovery from ethanol-induced mitochondrial dysfunction and ROS production, which was correlated with rescuing HK2-PINK1/Parkin signalling-mediated mitophagy. Mechanistically, ZNF281 directly bound to 5'-GGCGGCGGGCGG-3' motif within HK2 promoter region and transcriptionally repressed HK2 expression. Systematic ZNF281 knockdown by adeno-associated virus encoding ZNF281 shRNA protected mice from alcohol feeding-caused hepatocyte injury and senescence. This study provides a novel factor ZNF281 as a driver of hepatocyte senescence during alcoholic liver disease.
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Hepatopatias Alcoólicas , Mitofagia , Camundongos , Animais , Hepatócitos/metabolismo , Hepatopatias Alcoólicas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Etanol , Proteínas Quinases/metabolismo , RNA Interferente Pequeno/metabolismo , Senescência CelularRESUMO
For Codonopsis Radix polysaccharides (CRPs), oral administration is generally considered the most convenient route for patients. However, the details of its absorption and transport mechanisms remain unclear. In this study, we aimed to evaluate the oral absorption of CPA (an inulin-type fructan extracted from CRPs) in mice and Caco-2 cells. It was labeled with fluorescein isothiocyanate, and the fluorescence derivative (FCPA) was used to trace the behavior of CPA. The results showed that FCPA could be absorbed after oral administration and has a wide tissue distribution, including in the stomach, intestine, kidneys, and liver. FCPA was poorly absorbed, and its internalization was time- and energy-dependent, as well as dependent on cholesterol- and dynamin-mediated endocytosis. Confocal laser scanning microscopy showed successful cellular internalization of FCPA from the cytoplasm to the nucleus. In addition, we found that FCPA was trafficked to endosomes and lysosomes, and that tubulin was required for its intracellular transport. These findings add new details to our knowledge of the internalization and transport mechanisms of CPA, which may prove useful to the development and application of oral formulations of CRPs.
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Codonopsis , Polissacarídeos , Animais , Células CACO-2 , Codonopsis/química , Endocitose , Humanos , Camundongos , Polissacarídeos/farmacologiaRESUMO
Codonopsis Radix (CR) is an important traditional Chinese medicine used for the treatment of spleen deficiency syndrome (SDS). Codonopsis pilosula polysaccharides (CPP) in CR are considered to be responsible for tonifying the spleen function; however, the mechanisms of the polysaccharides have remained unclear. This study aimed to investigate the treatment mechanisms of CPP in SDS mice using a combinational strategy of 16S rRNA gene sequencing and targeted metabolomics. Here, studies demonstrated that CPP had invigorating effect in vivo in Sennae Folium-induced SDS in mice by organ indexes, D-xylose determination, gastrointestinal hormones levels and goblet cells observation. Antibiotic treatment revealed that the intestinal microbiota was required for the invigorating spleen effect of CPP. Furthermore, gut microbiota analysis found that CPP significantly enriched probiotic Lactobacillus and decreased the abundance of some opportunistic pathogens, such as Enterococcus and Shigella. The metabolic profile analysis of the colonic content revealed that 25 chemicals were altered significantly by CPP, including amino acids, organic acids, fatty acids, carbohydrates and carnitine etc., which are mainly related to "energy conversion" related processes such as amino acids metabolism, tricarboxylic acid cycle, and nitrogen metabolism. Spearman's correlation assays displayed there were strong correlations among biochemical indicators-gut microbiota-metabolomics. In summary, these results provided a new perspective for CPP improving SDS by regulating energy metabolism related bacteria and pathways.
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The aim of this work has been to establish and validate a simple and efficient method to detect the concentration of inulin-type fructan CPA from the roots of Codonopsis pilosula (Franch.) Nannf. in biosamples, and then apply it to evaluate the pharmacokinetics behavior, distribution character in tissue and excretion in mice. In this work, fluorescein isothiocyanate (FITC) was used to label CPA. Then FCPA was intravenously and orally administered to mice at different doses. In both i.v and p.o administration, FCPA concentration slowly declined in the circulatory system with a much longer T1/2 and MRT. After p.o administration, the area under the time curve (AUC0-∞) was dose-dependently increased. Taken together, FCPA showed poor absorption and wide tissue distribution. These pharmacokinetic results yield helpful insights into the pharmacological actions of FCPA.
Assuntos
Codonopsis , Frutanos , Administração Intravenosa , Animais , Inulina , Camundongos , Raízes de PlantasRESUMO
Hepatocyte necroptosis is a core pathogenetic event during alcoholic liver disease. This study was aimed to explore the potential of tetramethylpyrazine (TMP), an active hepatoprotective ingredient extracted from Ligusticum Wallichii Franch, in limiting alcohol-triggered hepatocyte necroptosis and further specify the molecular mechanism. Results revealed that TMP reduced activation of receptor-interacting protein kinase 1 (RIPK1)/RIPK3 necrosome in ethanol-exposed hepatocytes and phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which thereby diminished necroptosis and leakage of damage-associated molecular patterns. Suppression on mitochondrial translocation of p-MLKL by TMP contributed to recovery of mitochondrial function in ethanol-damaged hepatocytes. TMP also disrupted necroptotic signal loop by interrupting mitochondrial reactive oxygen species (ROS)-dependent positive feedback between p-MLKL and RIPK1/RIPK3 necrosome. Further, TMP promoted clearance of impaired mitochondria in ethanol-incubated hepatocytes via restoring PINK1/parkin-mediated mitophagy. Ubiquinol-cytochrome c reductase core protein 2 (UQCRC2) was downregulated in ethanol-exposed hepatocytes, which was restored after TMP treatment. In vitro UQCRC2 knockdown lowered the capacities of TMP in reducing mitochondrial ROS accumulation, relieving mitochondria damage, and enhancing PINK1/parkin-mediated mitophagy in ethanol-exposed hepatocytes. Analogously, systematic UQCRC2 knockdown interrupted the actions of TMP to trigger autophagic signal, repress necroptotic signal, and protect against alcoholic liver injury, inflammation, and ROS overproduction. In conclusion, this work concluded that TMP rescued UQCRC2 expression in ethanol-challenged hepatocytes, which contributed to necroptosis inhibition by facilitating PINK1/parkin-mediated mitophagy. These findings uncovered a potential molecular pharmacological mechanism underlying the hepatoprotective action of TMP and suggested TMP as a promising therapeutic candidate for alcoholic liver disease.
Assuntos
Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Hepatopatias Alcoólicas , Mitofagia , Necroptose , Hepatócitos/enzimologia , Humanos , Hepatopatias Alcoólicas/tratamento farmacológico , Proteínas Quinases/genética , PirazinasRESUMO
Receptor-interacting protein kinase (RIPK) 3-dependent necroptosis plays a critical role in alcoholic liver disease. RIPK3 also facilitates steatosis, oxidative stress, and inflammation. Pterostilbene (PTS) has favorable hepatoprotective activities. The present study was aimed to reveal the therapeutic effects of PTS on ethanol-induced hepatocyte necroptosis and further illustrate possible molecular mechanisms. Human hepatocytes LO2 were incubated with 100 mM ethanol for 24 h to mimic alcoholic hepatocyte injury. Results showed that PTS at 20 µM reduced damage-associated molecular patterns (DAMPs) release, including IL-1α and high-mobility group box 1 (HMGB1), and blocked necroptotic signaling, evidenced by decreased RIPK1 and RIPK3 expression. Trypan blue staining visually showed that PTS reduced nonviable hepatocytes after ethanol exposure, which was counteracted by adenovirus-mediated ectopic overexpression of RIPK3 but not RIPK1. Besides, PTS inhibited ethanol-induced hepatocyte steatosis via restricting lipogenesis and enhancing lipolysis, decreased oxidative stress via rescuing mitochondrial membrane potential, reducing oxidative system, and enhancing antioxidant system, and relieved inflammation evidenced by decreased expression of proinflammatory factors. Notably, RIPK3 overexpression diminished these protective effects of PTS. Subsequent work indicated that PTS suppressed the expression and nuclear translocation of nuclear factor of activated T-cells 4 (NFATc4), an acetylated protein, in ethanol-exposed hepatocytes, while NFATc4 overexpression impaired the negative regulation of PTS on RIPK3 and DAMPs release. Further, PTS rescued sirtuin 2 (SIRT2) expression, and SIRT2 knockdown abrogated the inhibitory effects of PTS on nuclear translocation and acetylation status of NFATc4 in ethanol-incubated hepatocytes. In conclusion, PTS attenuated RIPK3-dependent hepatocyte necroptosis after ethanol exposure via SIRT2-mediated NFATc4 deacetylation.
Assuntos
Hepatócitos/efeitos dos fármacos , Hepatopatias Alcoólicas/tratamento farmacológico , Necroptose/efeitos dos fármacos , Estilbenos/farmacologia , Antioxidantes/metabolismo , Células Cultivadas , Etanol/toxicidade , Técnicas de Silenciamento de Genes , Hepatócitos/patologia , Humanos , Hepatopatias Alcoólicas/fisiopatologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Fatores de Transcrição NFATC/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Sirtuína 2/genética , Sirtuína 2/metabolismoRESUMO
BACKGROUND: Hepatocyte senescence is a core event that mediates the occurrence and development of alcoholic liver disease. Nuclear factor of activated T-cells 4 (NFATc4) is a key driver of nonalcoholic steatohepatitis. However, little was known about the implication of NFATc4 for alcoholic liver disease. This study was aimed to investigate the role of NFATc4 in hepatocyte senescence and further elucidate the underlying mechanism. METHODS: Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of NFATc4 in hepatocyte senescence. RESULTS: NFATc4 was induced in ethanol-incubated hepatocytes. NFATc4 knockdown recovered cell viability and reduced the release of aspartate transaminase, alanine transaminase, and lactic dehydrogenase from ethanol-incubated hepatocytes. NFATc4 knockdown protected mice from alcoholic liver injury and inflammation. NFATc4 knockdown counteracted ethanol-induced hepatocyte senescence, evidenced by decreased senescence-associated ß-galactosidase positivity and reduced p16, p21, HMGA1, and γH2AX, which was validated in in vivo studies. Peroxisome proliferator-activated receptor (PPAR)γ was inhibited by NFATc4 in ethanol-treated hepatocytes. PPARγ deficiency abrogated the inhibitory effects of NFATc4 knockdown on hepatocyte senescence, oxidative stress, and hepatic steatosis in mice with alcoholic liver disease. CONCLUSIONS: This work discovered that ethanol enhanced NFATc4 expression, which further triggered hepatocyte senescence via repression of PPARγ.
Assuntos
Senescência Celular/efeitos dos fármacos , Etanol/efeitos adversos , Etanol/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/fisiopatologia , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/farmacologia , Animais , Células Cultivadas/efeitos dos fármacos , Humanos , Hepatopatias Alcoólicas/metabolismo , Camundongos , Modelos AnimaisRESUMO
Meiogyne oligocarpa sp. nov. (Annonaceae) is described from Yunnan Province in Southwest China. It is easily distinguished from all previously described Meiogyne species by the possession of up to four carpels per flower, its bilobed, sparsely hairy stigma, biseriate ovules and cylindrical monocarps with a beaked apex. A phylogenetic analysis was conducted to confirm the placement of this new species within Meiogyne. Meiogyne oligocarpa represents the second species of Meiogyne in China: a key to the species of Meiogyne in China is provided to distinguish it from Meiogyne hainanensis. Paraffin sectioning was undertaken to study the anatomy of the corrugations on the inner petals of Meiogyne oligocarpa to verify whether they are glandular.
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Background: Emerging evidence suggests that gut microbiota plays a vital role in the occurrence of multiple endocrine disorders including polycystic ovary syndrome (PCOS). Shaoyao-Gancao Decoction (SGD), a classical Chinese prescription, has been widely used in the treatment of PCOS for decades. In previous studies, we found that SGD treatment could effectively reduce ovarian inflammation in PCOS rats. However, whether the anti-inflammation effect of SGD involves the regulation of the gut microbiota remains elusive. Methods: Letrozole-induced PCOS rat models were established, and the therapeutic effects of SGD were evaluated. Specifically, body weight, serum hormone concentrations, estrus phase and ovary histopathology were assessed. Then the structure of gut microbiota was determined by 16s rRNA sequencing. Additionally, the serum levels of pro-inflammatory cytokines and LPS were measured by ELISA kits. The key gene and protein expressions of TLR4/NF-κB signaling pathway were detected by quantitative real-time PCR and western blot. Results: SGD could effectively reduce body weight, regulate estrous cycles and ameliorate hyperandrogenism in PCOS rats. In addition, SGD treatment decreased releases of pro-inflammatory cytokines, enhanced the expressions of tight junction (occludin and claudin1), and then prevented a translocation of LPS into bloodstream. SGD could significantly reduce the ratio of Firmicutes to Bacteroidetes, decrease the abundance of LPS-producing pathogens Proteobateria and enrich the abundance of Butyricicoccus, Coprococcus, Akkermansia Blautia and Bacteroides in PCOS rats. Furthermore, SGD blunted the key gene and protein expressions of TLR4/NF-κB signaling pathway both in vivo and in LPS-induced RAW264.7 cells. Conclusion: SGD administration could ameliorate the inflammatory response in PCOS rats by remodeling gut microbiome structure, protecting gut barrier, and suppressing TLR4/NF-κB signaling pathway.
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Meiogyne kwangtungensis is a rare species endemic to Hainan, China, known just from two fruiting collections made in the 1930s. Although it was published under the name Meiogyne in 1976, it was suggested that it might be better placed within Pseuduvaria or Mitrephora. For decades, this species was never collected again, thus its true generic affinity remained unresolved due to the lack of flowers. During a field exploration in Hainan, we re-discovered this species and collected a flowering specimen for the first time. The flower immediately confirmed its affinity with Pseuduvaria. Phylogenetic analyses of five chloroplast regions (psbA-trnH, trnL-F, matK, rbcL, and atpB-rbcL; ca. 4.2 kb, 70 accessions) also unambiguously placed Meiogyne kwangtungensis in the Pseuduvaria clade (PP = 1.00, ML BS = 99%). Morphologically, it is most similar to P. multiovulata which is endemic to Myanmar and Thailand, both with often-paired flowers, long pedicels and short peduncles, and often 1-2 monocarps. However, it differs in having smaller flowers with kidney-shaped glands on the inner petals, fewer stamens and carpels, smaller ovoid monocarps with an apicule and fewer seeds. On the basis of the combined molecular phylogenetic and morphological data, we propose a new combination, Pseuduvaria kwangtungensis (P.T.Li) Qing L.Wang & B.Xue. A full description including floral characters and a color plate are provided here for this species. A key to species in the genus Pseuduvaria in China is also provided.
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To investigate the beneficial effects of oridonin, a diterpenoid compound isolated from Rabdosia rubescens, on the inflammatory response in TNBS-induced post-inflammatory irritable bowel syndrome (PI-IBS) model and the underlying mechanism. Using the PI-IBS rat model and Caco-2 cell lines, we found that intestinal barrier function reflected by lactulose/mannitol (L/M) ratio and tight junction protein level was significantly ameliorated by oridonin. We also demonstrated that oridonin abrogated inflammation through inhibiting the phosphorylation of NF-κBp65 as well as its downstream gene (iNOS, COX-2, IL-1ß, and IL-6) level. Molecular docking studies confirmed the good binding activity between oridonin and PXR. In Caco-2 cell lines, oridonin markedly inhibited LPS-induced NF-κB activation in a PXR-dependent manner. Meanwhile, PXR and its target genes CYP3A4 and P-gp were induced by oridonin, which was associated with the decreased expression of NF-κB and the recovery of intestinal barrier. This study indicated that the therapeutic effect of oridonin on experimental PI-IBS through repairing intestinal barrier function may be closely associated with the regulatory role of PXR/NF-κB signaling pathway. Oridonin may serve as a PXR ligand for the development of drugs in the therapy for PI-IBS.
Assuntos
Anti-Inflamatórios/uso terapêutico , Diterpenos do Tipo Caurano/uso terapêutico , Inflamação/tratamento farmacológico , Síndrome do Intestino Irritável/tratamento farmacológico , NF-kappa B/metabolismo , Receptor de Pregnano X/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Biomarcadores/metabolismo , Western Blotting , Células CACO-2 , Diterpenos do Tipo Caurano/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/fisiopatologia , Síndrome do Intestino Irritável/etiologia , Síndrome do Intestino Irritável/metabolismo , Masculino , Permeabilidade , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Resultado do Tratamento , Ácido TrinitrobenzenossulfônicoRESUMO
Postinflammatory irritable bowel syndrome (PI-IBS) is a common functional gastrointestinal disorder, which is characterized by abdominal pain, low-grade inflammation, and visceral hypersensitivity. Shaoyao-Gancao decoction (SGD) has been used to improve the clinical symptoms of abdominal spasmodic pain accompanying acute gastroenteritis, but the underlying therapeutic mechanism has not been fully elucidated. In the present study, a rat model of PI-IBS was established via rectal administration of TNBS. Rats were scored daily for 28 days using disease activity index (DAI). Abdominal withdrawal reflex (AWR) was used to measure the pain threshold. After SGD (6.25, 12.5, and 25 g/kg/d) treatment for 14 days, rat colonic tissue was collected for histopathological grading, enterochromaffin (EC) cell count, and 5-HT content measurement. RT-qPCR and western blot analyses were employed to detect the gene and protein level of tryptophan hydroxylase (TPH), serotonin reuptake transporter (SERT), and transient receptor potential vanilloid 1 (TRPV1). To further validate the effect of SGD on TRPV1, another experiment was performed in cells. The results revealed that visceral hyperalgesia, reflected by increased DAI, AWR, pathological injury score, 5-HT content, and EC cell count in PI-IBS rats, was significantly ameliorated by SGD. In cells, SGD markedly inhibited the expression and function of TRPV1. Moreover, the expression levels of TPH were also repressed by SGD. The findings of the present study indicated that the therapeutic effect of SGD on visceral hyperalgesia may be closely associated with the regulatory role of TRPV1 and 5-HT signaling pathways.
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The genus Polyalthiopsis Chaowasku (Annonaceae) was a poorly known monotypic genus from Vietnam that was recently segregated from the highly polyphyletic genus Polyalthia s.l. The sister clade relationship between Polyalthiopsis and Miliusa was not well established in previous study. The phylogenetic position of two Polyalthia spp. from China, P. chinensis S.K.Wu ex P.T.Li and P. verrucipes C.Y.Wu ex P.T.Li, remains unresolved and is shown here to be phylogenetically affiliated with Polyalthiopsis. Phylogenetic analyses of six chloroplast regions (matK, ndhF, psbA-trnH, rbcL, trnL-F and ycf1; ca.7.3 kb, 60 accessions) unambiguously placed Polyalthia chinensis and P. verrucipes in the same clade with Polyalthiopsis floribunda (PP = 1, MPBS = 97%); the entire clade is sister to Miliusa with weak to strong support (PP = 1, MPBS = 54%). Polyalthia chinensis and P. verrucipes share several diagnostic characters with Polyalthiopsis floribunda, including the raised midrib on the upper surface of the leaf in vivo, conspicuous foliar glands when dried, petiole with transverse striations when dried and axillary inflorescences. The two species differ from Polyalthiopsis floribunda in having fewer flowers per inflorescence, longer linear petals and two ovules per carpel. On the basis of the combined molecular phylogenetic and morphological data, we propose two new combinations, Polyalthiopsis chinensis (S.K.Wu ex P.T.Li) B.Xue & Y.H.Tan and Polyalthiopsis verrucipes (C.Y.Wu ex P.T.Li) B.Xue & Y.H.Tan. The protologue of Polyalthia verrucipes did not include a description of the flowers, which we provide here. An updated description for the genus Polyalthiopsis and a key to species in the genus Polyalthiopsis is also provided.
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A simple and sensitive liquid chromatography with tandem mass spectrometry method was developed for simultaneous quantification of paeoniflorin, albiflorin, oxypaeoniflorin, liquiritin, liquiritigenin, glycyrrhetinic acid, and glycyrrhizin in rat plasma after oral administration of Shaoyao-Gancao decoction, which is traditionally used in the treatment of polycystic ovary syndrome. The plasma samples were pretreated with methanol as precipitant. The method exhibited good linearity (correlation coefficient (R2 ) > 0.99) with lower quantification limits of 0.595-4.69 ng/mL for all analytes. Intra- and interbatch precision, accuracy, recovery, and stability of the method were all within accepted criteria. The results showed that the pharmacokinetic behaviors of the seven compounds were altered in the pathological status of polycystic ovary syndrome. Furthermore, a total of 36 metabolites were structurally identified based on their accurate masses and fragment ions. The major metabolic pathway involves phase I metabolic reactions (such as hydroxylation), phase II metabolic reactions (such as sulfation and glucuronidation conjugation) as well as the combined multiple-step metabolism. This study is the first report on the pharmacokinetic and metabolic information of Shaoyao-Gancao decoction in both normal and model rats, which would provide scientific evidences for the bioactive chemical basis of herbal medicines and also promote the clinical application of Shaoyao-Gancao decoction for treating polycystic ovary syndrome.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Administração Oral , Animais , Hidrocarbonetos Aromáticos com Pontes/sangue , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Hidrocarbonetos Aromáticos com Pontes/farmacocinética , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Flavanonas/sangue , Flavanonas/metabolismo , Flavanonas/farmacocinética , Glucosídeos/sangue , Glucosídeos/metabolismo , Glucosídeos/farmacocinética , Ácido Glicirretínico/sangue , Ácido Glicirretínico/metabolismo , Ácido Glicirretínico/farmacocinética , Ácido Glicirrízico/sangue , Ácido Glicirrízico/metabolismo , Ácido Glicirrízico/farmacocinética , Monoterpenos/sangue , Monoterpenos/metabolismo , Monoterpenos/farmacocinética , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em TandemRESUMO
Shaoyao-Gancao Decoction (SGD) has been widely used for the treatment of gynopathy. The present study aimed to evaluate the therapeutic effect and potential mechanism of SGD on hyperandrogenism in polycystic ovary syndrome (PCOS) rats. In the present work, SGD was orally administrated to the PCOS rats at the dose of 12.5, 25, and 50 g/kg/d for 14 consecutive days. UPLC-MS/MS was performed to identify the main chemical components of SGD. Body weight, ovarian weight, cystic dilating follicles, and serum levels of steroid hormones were tested to evaluate the therapeutic effect of SGD. In order to further clarify the underlying mechanism, we also measured mRNA and the protein levels of NF-κB, NF-κB p65, P-NF-κB p65, and IκB by RT-qPCR and Western blotting techniques. Our results showed that SGD treatment significantly alleviated hyperandrogenism in PCOS rats as evidenced by reduced serum levels of T and increased E2 and FSH levels. In addition, SGD effectively reduced the phosphorylation of NF-κB p65 and increased the expression of IκB. Results of the present study demonstrated that SGD could ameliorate hyperandrogenism in PCOS rats, and the potential mechanism may relate to the NF-κB pathway.
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Medicamentos de Ervas Chinesas/administração & dosagem , Hiperandrogenismo/tratamento farmacológico , NF-kappa B/genética , Síndrome do Ovário Policístico/tratamento farmacológico , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperandrogenismo/induzido quimicamente , Hiperandrogenismo/genética , Hiperandrogenismo/patologia , Quinase I-kappa B/genética , Letrozol/toxicidade , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/patologia , Ratos , Fator de Transcrição RelA/genéticaRESUMO
The enterohepatic circulation of bile acids (BAs) critically depends on BA transporters and enzymes, which can be affected by inflammatory bowel disease. Diarrhea in colitis is believed to result in part from BA malabsorption. The work aimed to investigate whether diarrhea in colitis was associated with the expression of BA transporters, enzymes, and nuclear receptors. RT-qPCR and Western blot techniques were used to evaluate the gene and protein levels of Cyp7a1, Asbt, SHP, FXR, Ostß in a 2,4,6-trinitrobenzenesulfonic-acid-induced rat model of colitis. The total BAs (TBAs) levels were assayed using ELISA kits, and the individual BAs were measured by LC-MS/MS. Results showed that the fecal excretions of TBAs were significantly increased by 1.6-fold in acute stage of colitis. In ileum, Asbt was significantly decreased; however, there was a compensatory increase in Cyp7a1 level in liver. Moreover, FXR has a decreased tendency and the downstream target gene SHP was downregulated. Contrary to acute stage, molecular changes were completely reversible during the remission phase. Our results indicated that the expression of Asbt and Cyp7a1 were altered in acute colitis, which performed vital roles in maintaining BA homeostasis. Early medical manipulation of BA transporters and enzymes may help prevent diarrhea.
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Ácidos e Sais Biliares/metabolismo , Colite/metabolismo , Diarreia/metabolismo , Doença Aguda , Animais , Colesterol 7-alfa-Hidroxilase/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/fisiologia , Homeostase/fisiologia , Íleo/metabolismo , Fígado/metabolismo , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Ratos , Ratos Sprague-Dawley , Simportadores/metabolismoRESUMO
Alphonsea glandulosa sp. nov. is described from Yunnan Province in south-west China. It is easily distinguished from all previously described Alphonsea species by the possession of glandular tissue at the base of the adaxial surface of the inner petals. Nectar was observed throughout the flowering period, including the pistillate phase and subsequent staminate phase. Small curculionid beetles were observed as floral visitors and are inferred to be effective pollinators since they carry pollen grains. A phylogenetic analysis was conducted to confirm the placement of this new species within Alphonsea and the evolution of the inner petal glands and specialized pollinator reward tissues throughout the family.
Assuntos
Annonaceae/classificação , Annonaceae/genética , Annonaceae/anatomia & histologia , Evolução Biológica , China , DNA de Cloroplastos , DNA de Plantas , Frutas , Especificidade de Órgãos , Fenótipo , Filogenia , Pólen/ultraestrutura , Análise de Sequência de DNARESUMO
The aim of this present study was to investigate the effect of oridonin on visceral hyperalgesia and colonic serotonin availability in a rat model of trinitrobenzenesulfonic acid-induced postinflammatory irritable bowel syndrome (PI-IBS). Rats were randomly divided into five groups: normal control, PI-IBS model, PI-IBS+low-dose oridonin (5 mg/kg), PI-IBS+median-dose oridonin (10 mg/kg), and PI-IBS+high-dose oridonin (20 mg/kg). Rats in control and model groups were orally administered with water by gavage, whereas rats in oridonin-treated groups were orally administered with different dosages of oridonin, and drugs were given for 14 consecutive days. Compared with the control group, the pain threshold pressure was significantly reduced in PI-IBS rats. The colonic enterochromaffin (EC) cell number, serotonin content, and the protein expression of tryptophan hydroxylase (TPH) were markedly increased and the protein expression of serotonin reuptake transporter was significantly decreased in PI-IBS rats. The spleen index in PI-IBS rats was decreased, and the levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-4, and IL-13 in the colon of PI-IBS rats were also markedly decreased. Oridonin treatment dose dependently increased pain threshold pressure, and markedly decreased colon EC cell numbers, TPH expression, and serotonin content in PI-IBS rats. Oridonin treatment also significantly increased the spleen index as well as the levels of TNF-α, IFN-γ, IL-4, and IL-13 in the colon of PI-IBS rats. Results of this study demonstrate that the analgesic effect of oridonin in PI-IBS rats is associated with reduced colonic EC cell hyperplasia and 5-HT availability, the regulatory effect of oridonin on colonic cytokine production may be correlated with its effect on colonic EC cell number.