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1.
Toxicol Appl Pharmacol ; 398: 115032, 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32387182

RESUMO

BACKGROUND AND PURPOSE: Irinotecan-induced diarrhea (IID) results from intestinal damages by its active metabolite SN-38. Alleviation of these damages has focused on lowering luminal SN-38 concentrations. However, it is unclear if the enteric bioavailability of SN-38 is mostly dependent on luminal SN-38 concentrations. EXPERIMENTAL APPROACH: Irinotecan (50 mg/kg, i.p. once daily for 6 days) was administered to female wildtype FVB, Mdr1a (-/-), Mrp2 (-/-) and Bcrp1 (-/-) mice for pharmacokinetic (PK), toxicokinetic (TK) and biodistribution studies. Plasma PK/TK profiles and tissues drug distribution were determined after first or sixth daily doses, along with activities of blood and gut esterases and intestinal Ugts. Caco-2 cells and bile-cannulate mice were used to further investigate intestinal and biliary disposition of irinotecan and its metabolites. KEY RESULTS: Significant differences in IID severity were observed with the susceptible rank of Bcrp1(-/-) > wildtype FVB > Mdr1a(-/-) > Mrp2(-/-). This rank order did not correlate with biliary excretion rates of SN-38/SN-38G. Rather, the severity was best correlated (R = 0.805) with the intestinal ratio of Css SN-38/SN-38G, a measure of gut Ugt activity. On the contrary, IID was poorly correlated with plasma AUC ratio of SN-38/SN-38G (R = 0.227). Increased intestinal esterase activities due to repeated dosing and gut efflux transporter functionality are the other key factors that determine SN-38 enteric exposures. CONCLUSION AND IMPLICATIONS: Intestinal SN-38 exposure is mainly affected by intestinal Ugt activities and blood esterase activities, and strongly correlated with severity of IID. Modulating intestinal SN-38 concentration and gut Ugt expression should be the focus of future studies to alleviate IID.

2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(2): 157-163, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32314714

RESUMO

Objective To investigate the effect of matrine on gastric mucosal injury induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in rats and its mechanism. Methods A total of 75 Wister rats were randomly divided into a control group, a model group and three matrine-treated groups (100, 150 and 200 mg/kg). Except for the control group, the other groups were treated with MNNG to establish the models of gastric mucosal injury in the rats. After the models were successfully established, the rats in the three matrine-treated groups were administrated 100, 150, 200 mg/kg matrine, respectively, for successive 45 days. After the last administration, the body mass, daily intake of drinking water and dietary of rats were measured. And then the tissue samples were collected after the rats were sacrificed. The levels of interleukin 1ß (IL-1ß), IL-4, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were measured by ELISA in gastric mucosa. HE staining was used to observe the pathological changes of gastric mucosa tissue. Immunohistochemical staining was performed to evaluate the expression of vascular endothelial growth factor C (VEGF-C) and vascular endothelial growth factor receptor 3 (VEGFR3) in gastric mucosa. The protein levels of Bcl2, BAX, caspase-3, cytochrome C (Cyt-C), Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and nuclear factor κB p65 (NF-κB p65) were determined by Western blotting. Results The body mass, daily intake of drinking water and dietary increased in matrine-treated rats in comparison with the model group. In addition, compared with the model group, matrine significantly reduced the expression levels of VEGF-C, VEGFR3, BAX, caspase-3, Cyt-C, TLR4, MyD88 and NF-κB p65, and increase Bcl2 protein level in the gastric mucosa tissues. Conclusion Matrine can reduce gastric mucosal damage induced by MNNG in rats, which is related to the down-regulation of VEGF-C/VEGFR3 and NF-κB/TLR4 signaling pathway.

3.
Alcohol Alcohol ; 55(3): 264-277, 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32232424

RESUMO

AIMS: To investigate the effect of ethanol intake on the whole enterohepatic circulation (EHC) of bile acids (BAs) and, more importantly, on pharmacokinetics of irinotecan. METHODS: The present study utilized a mouse model administered by gavage with 0 (control), 240 mg/100 g (30%, v/v) and 390 mg/100 g (50%, v/v) ethanol for 6 weeks, followed by BA profiles in the whole EHC (including liver, gallbladder, intestine and plasma) and colon using ultra-high performance liquid chromatography with tandem mass spectrometry analysis. Pharmacokinetic parameters of irinotecan were measured after administration of irinotecan (i.v. 5 mg/kg) on alcohol-treated mice. RESULTS: The results showed that compared with the control group, concentrations of most free-BAs, total amount of the three main forms of BAs (free-BA, taurine-BA and glycine-BA) and total BAs (TBAs) in 50% ethanol intake group were significantly increased, which are mostly attributed to the augmentation of free-BAs and taurine-BAs. Additionally, the TBAs in liver and gallbladder and the BA pool were markedly increased in the 30% ethanol intake group. Importantly, ethanol intake upregulated the expression of BA-related enzymes (Cyp7a1, Cyp27a1, Cyp8b1 and Baat) and transporters (Bsep, Mrp2, P-gp and Asbt) and downregulated the expression of transporter Ntcp and nuclear receptor Fxr in the liver and ileum, respectively. Additionally, 50% ethanol intake caused fairly distinct liver injury. Furthermore, the AUC0-24 h of irinotecan and SN38 were significantly reduced but their clearance was significantly increased in the disrupted EHC of BA by 50% ethanol intake. CONCLUSIONS: The present study demonstrated that ethanol intake altered the expression of BA-related synthetases and transporters. The BA levels, especially the toxic BAs (chenodeoxycholic acid, deoxycholic acid and lithocholic acid), in the whole EHC were significantly increased by ethanol intake, which may provide a potential explanation to illuminate the pathogenesis of alcoholic liver injury. Most importantly, chronic ethanol consumption had a significant impact on the pharmacokinetics (AUC0-24 h and clearance) of irinotecan and SN38; hence colon cancer patients with chronic alcohol consumption treated with irinotecan deserve our close attention.

4.
J Pharm Biomed Anal ; 185: 113226, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32163851

RESUMO

Aconitum carmichaelii Debeaux is a widely used herbal medicine, which has anti-inflammatory and analgesic activities. However, due to its high toxicity, poisoning incidents often occur all over the world. To systematically understand the pharmacokinetics (PK) and tissue distribution of A. carmichaelii, 18 representative alkaloids, including 8 amine- (ADA), 4 monoester- (MDA) and 6 diester-type (DDA) diterpenoid alkaloids, were simultaneously quantified by ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UHPLC-QQQ-MS) with dynamic multiple reaction monitoring (MRM) mode. PK results suggested that benzoylmesaconine, mesaconitine, 10-OH-aconitine and aconitine had lower bioavailability, which might relate to the substitution at C-3. In tissue distribution, alkaloids present higher concentrations in the liver, kidney, and only songorine, neoline and benzoyldeoxyaconine were detected in the brain. Moreover, the concentrations of extremely toxic DDAs in high-dose group were much higher than that of low-dose group, indicating that these DDAs might be the main reason for the toxicity of Aconitum. The results also suggested that benzoyldeoxyaconine and deoxyaconitine should be determined for the quality control of A. carmichaelii due to their high concentrations in both herbal extract and tissues. The systematic investigation into these 18 representative alkaloids could basically illuminate the PK and distribution of A. carmichaelii in rats, and provide some information for clinical studies.

5.
J Asian Nat Prod Res ; : 1-8, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32162545

RESUMO

Two new phenolic glycosides (1-2), along with six existing compounds (3-8), were isolated from the ethanolic extract of Ilex pubescens roots, a traditional folk medicine. These structures were determined using HR-ESI-MS, IR, UV, and NMR (including 1 D, 2 D-NMR). The anti-inflammatory activities of three phenolic glycosides (1-3) were evaluated in the human HepG2 cell lines. The results showed that compound 3 could induce P-gp and BCRP expression through the Nrf2-mediated pathway.

6.
Atherosclerosis ; 297: 64-73, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-32078831

RESUMO

BACKGROUND AND AIMS: Atherosclerosis is a serious cardiovascular disease, featuring inflammation, abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). During atherosclerosis, inflammation may cause low pH. T-cell death-associated gene 8 (Tdag8) is a proton-sensing receptor, however, the role of Tdag8 in VSMCs remains unknown. This study aimed to investigate the potential effects of Tdag8 in VSMCs during atherosclerosis. METHODS: We examined the expression of Tdag8 in an atherosclerotic model of high-fat-diet-fed ApoE-/- mice, while the role and mechanism of Tdag8 in phenotype transformation, proliferation and migration of VSMCs were investigated in a series of in vivo and in vitro experiments. RESULTS: We first found that Tdag8 expression at the mRNA and protein level was significantly increased in atherosclerotic ApoE-/- mice. Immunofluorescence staining showed that Tdag8 was primarily distributed in PCNA-positive VSMCs and the phenotype of VSMCs switching from contractile phenotype to synthetic phenotype. Additionally, the protein level of Tdag8 was upregulated in FBS-treated VSMCs. VSMCs proliferation and migration were inhibited by Tdag8 silencing and increased by Tdag8 overexpression. Further mechanistic studies showed that cAMP level was increased in Tdag8-overexpressing VSMCs and ApoE-/- mice. However, the PKA inhibitor H-89 reversed Tdag8-induced VSMC proliferation and migration. CONCLUSIONS: The results demonstrate that Tdag8 mediated phenotype transformation, proliferation and migration of VSMCs via the cAMP/PKA signaling pathway, thus partially contributing to atherosclerosis.

7.
Biochem Pharmacol ; 172: 113753, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31837310

RESUMO

Glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGTs), is a crucial substance metabolism and elimination process that mostly occurs in the liver to protect the body from toxic substances and maintain homeostasis. The reaction functions well in a uridine diphosphate glucuronic acid (UDPGA) -dependent manner in vivo. However, the mechanism for recognizing UDPGA or analog has not been reported so far. Here, through X-ray crystallography, we present a 1.78 Å cocrystal structure of the C-terminal domain of UDP-glucuronosyltransferase 2B15 (2B15CTD, K284-H451) bound by tartrate, which reveals the detailed recognition mechanism of UDPGA analog at the active site. Using surface plasmon resonance techniques, protein thermal shift studies, and limited proteolysis, we determine that tartrate stabilizes the conformation of 2B15CTD thermodynamically. The biochemical analysis further elucidates that two residues, S312 and T374, are essential for the interactions between 2B15CTD and tartrate. We also investigate the pharmacological effects of tartrate on UGTs based on the cocrystal structure of UGT2B15 and experiments performed in vitro and in vivo. In brief, the LC-MS/MS analysis shows that tartrate has a significant inhibitory effect towards UGT2B15 (Ki = 91 µM), and oral administration of tartrate to FVB mice can reduce the relative plasma concentration of glucuronide. These results reveal an unexpected physiological role of tartrate in the maintenance of UGTs function. Therefore, tartrate is a potential inhibitor of UGTs, and the excess tartrate in the diet may disturb body homeostasis and inhibit the metabolism of UGT substrates by interfering with glucuronidation.

8.
Pharmacol Res ; 152: 104586, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31877350

RESUMO

Visceral obesity is the excess deposition of visceral fat within the abdominal cavity that surrounds vital organs. Visceral obesity is directly associated with metabolic syndrome, breast cancer and endometrial cancer. In visceral obese subjects, signal transducer and activator of the transcription 3 (STAT3) in adipocytes is constitutively active. In this study, we aimed to screen for dietary herbal compounds that possess anti-visceral obesity effect. Apigenin is abundant in fruits and vegetables. Our data show that apigenin significantly reduces body weight and visceral adipose tissue (VAT), but not subcutaneous (SAT) and epididymal adipose tissues (EAT), of the high fat diet (HFD)-induced obese mice. Mechanistic studies show that HFD increases STAT3 phosphorylation in VAT, but not in SAT and EAT. Further studies suggest that apigenin binds to non-phosphorylated STAT3, reduces STAT3 phosphorylation and transcriptional activity in VAT, and consequently reduces the expression of STAT3 target gene cluster of differentiation 36 (CD36). The reduced CD36 expression in adipocytes reduces the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) which is the critical nuclear factor in adipogenesis. Our data show that apigenin reduces CD36 and PPAR-γ expressions and inhibits adipocyte differentiation; overexpression of constitutive active STAT3 reverses the apigenin-inhibited adipogenesis. Taken together, our data suggest that apigenin inhibits adipogenesis via the STAT3/CD36 axis. Our study has delineated the mechanism of action underlying the anti-visceral obesity effect of apigenin, and provide scientific evidence to support the development of apigenin as anti-visceral obesity therapeutic agent.

9.
Anal Chem ; 91(22): 14458-14466, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31613596

RESUMO

LC-MS-based untargeted metabolomics have been proven to be an extremely promising technique to discover biomarkers and explore the mechanisms underlying diseases, which, however, relies heavily on sample pretreatment for metabolite extraction. In the present study, a systematic and pragmatic evaluation of eight protocols employing conventional metabolites extraction strategies, protein precipitation (PPT), and liquid-liquid extraction (LLE), with and without proteinase K (PK) incubation, was performed simultaneously, using human plasma and a mixture of 39 endogenous metabolite standards. These protocols were as follows: (1) PPT with methanol, (2) PPT with acetonitrile, (3) PPT with 2-propanol, (4) two-step LLE of CH2Cl2-MeOH, followed by MeOH-H2O, (5) PK incubation combining two-step LLE of CH2Cl2-MeOH followed by MeOH-H2O, (6) two-step LLE of CHCl3-MeOH, followed by MeOH-H2O, (7) PK incubation combining two-step LLE of CHCl3-MeOH, followed by MeOH-H2O, (8) PK incubation combining MeOH-EtOH PPT. The results suggested that two-step LLE produced broader metabolome coverage than protein precipitation, and the addition of proteinase K enhanced the extraction performance further. Taken together, PK incubation combining two-step LLE of CHCl3-MeOH, followed by MeOH-H2O, was determined to be the most suitable extraction method, because of its broad metabolome coverage, high reproducibility, and satisfactory recovery. Next, the developed optimal sample preparation method was applied successfully to profile the plasma metabolome of colorectal adenoma and uncover its potential mechanism for significant differential changes in linoleic acid and phospholipid metabolism.

10.
Curr Cancer Drug Targets ; 19(7): 551-560, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31509102

RESUMO

BACKGROUND: Diarrhea is a severe side effect of irinotecan, a pro-drug of SN-38 used for the treatment of many types of cancers. Pre-clinical and clinical studies showed that decreasing the colonic exposure of SN-38 can mitigate irinotecan-induced diarrhea. OBJECTIVE: The purpose of this study is to evaluate the anti-diarrhea potential of Xiao-Chai-Hu-Tang (XCHT), a traditional Chinese herbal formula, against irinotecan-induced diarrhea by determining if and how XCHT alters the disposition of SN-38. METHODS: LC-MS/MS was used to quantify the concentrations of irinotecan and its major metabolites (i.e., SN-38, SN-38G). An Intestinal perfusion model was used to determine the effect of XCHT on the biliary and intestinal secretions of irinotecan, SN-38, and SN-38G. Pharmacokinetic (PK) studies were performed to determine the impact of XCHT on the blood and fecal concentrations of irinotecan, SN-38, and SN-38G. RESULTS: The results showed that XCHT significantly inhibits both biliary and intestinal excretions of irinotecan, SN-38, and SN-38G (range: 35% to 95%). PK studies revealed that the fecal concentrations of irinotecan and SN-38 were significantly decreased from 818.35 ± 120.2 to 411.74 ± 138.83 µg/g or from 423.95 ± 76.44 to 245.63 ± 56.72 µg/g (p<0.05) by XCHT, respectively, suggesting the colonic exposure of SN-38 is significantly decreased by XCHT. PK studies also showed that the plasma concentrations of irinotecan, SN-38, and SN-38G were not affected by XCHT. CONCLUSION: In conclusion, XCHT significantly decreased the exposure of SN-38 in the gut without affecting its plasma level, thereby possessing the potential of alleviating irinotecan-induced diarrhea without negatively impacting its therapeutic efficacy.

11.
Food Funct ; 10(9): 6062-6073, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31486445

RESUMO

Depression is a mental disorder that brings severe burdens to patients and their families. Neuroinflammation and neurotrophins are involved in depression. Lotus plumule is a nutritional food with medicinal values. In the present study, we tried to clarify the anti-depressive effect and molecular mechanism of lotus plumule. Network pharmacological analysis, behavior tests, qRT-PCR and western blotting were used. We found 7 potential active components and 91 targets from the TCMSP database. KEGG analysis suggested that lotus plumule significantly affected nitrogen metabolism, calcium signaling, and inflammatory mediator regulation signaling pathways. Consistent with those effects, total alkaloids of lotus plumule (TLA) and active alkaloids differently suppressed the nitric oxide (NO) production and pro-inflammatory mediators. TLA and higenamine significantly ameliorated LPS-induced depression-like behavior, increased BDNF levels, suppressed microglia activation, and inhibited the expression of ER stress-related proteins. Meanwhile, TLA and higenamine activated microglia autophagy by increasing the beclin-1 and LC3B-II expression. Additionally, in the presence of autophagy inhibitor 3-MA, TLA and higenamine did not reduce the LPS-induced NO production or pro-inflammatory mediators. Collectively, TLA and higenamine attenuated LPS-induced depression-like behavior by regulating BDNF-mediated ER stress and autophagy. Therefore, drinking tea of lotus plumule may provide a potential strategy for preventing depression.


Assuntos
Alcaloides/administração & dosagem , Depressão/tratamento farmacológico , Lotus/química , Extratos Vegetais/administração & dosagem , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/induzido quimicamente , Depressão/metabolismo , Depressão/psicologia , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Sementes/química
12.
Chin J Nat Med ; 17(9): 707-712, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31526506

RESUMO

Four new 3, 4-seco-labdane diterpenoids, nudiflopenes J-M, were isolated from the leaves of Callicarpa nudiflora along with six known compounds. The structures of these diterpenoids were determined by comprehensive spectroscopic analysis. All the isolated compounds were evaluated for their inhibitory effects on NO production in LPS-stimulated RPMs and RAW264.7 cells. The results suggest that nudiflopenes J-M and other four known compounds showed significant inhibitory effects against NO production comparable to the positive control dexamethasone.


Assuntos
Anti-Inflamatórios/farmacologia , Callicarpa/química , Diterpenos/farmacologia , Medicamentos de Ervas Chinesas/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Células Cultivadas , Diterpenos/química , Diterpenos/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Estrutura Molecular , Óxido Nítrico/metabolismo , Folhas de Planta/química , Células RAW 264.7 , Ratos
13.
Biomaterials ; 223: 119469, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31520886

RESUMO

Checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, have been proven as a promising type of immunotherapy in a number of cancers, but the relatively low response rates limit their scope of clinical application. Here, we report the use of cascade chemo-photodynamic therapy (chemo-PDT) with reactive oxygen species (ROS)-sensitive lipid-polymer hybrid nanoparticles TKHNP-C/D to potentiate the antitumor efficacy of anti-PD-L1 antibody (aPD-L1). Under light irradiation, TKHNP-C/D not only induced photodynamic therapy (PDT) but also boosted intracellular DOX release via the rapid degradation of its hydrophobic core, promoting an efficient cascade of chemo-PDT to inhibit tumor growth by a single treatment. More importantly, the cascade chemo-PDT could evoke anticancer immune responses and efficiently synergize with aPD-L1 to generate an abscopal effect, which could simultaneously inhibit primary and distant tumor growth.

14.
Anal Biochem ; 587: 113446, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31545947

RESUMO

The effect of sample containers made of different materials on the MS-based analysis of oligonucleotides remains unknown. Here, we evaluated five types of sample containers on the MS signal stability of oligonucleotide, and they were normal glass insert, silanized glass insert with three different silanization techniques, and polypropylene sample vial. Also, we attempted to tackle signal stability issue by varying modifiers in dissolution solvent. Our results showed that sample containers made of different materials can significantly influence the MS signal stability of oligonucleotide at low concentration. Triethylamine (TEA) evidently improved both the signal stability and intensity of oligonucleotide.

15.
J Ethnopharmacol ; 245: 112147, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31401319

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ilex pubescens (I. pubescens), which is well known in Chinese as Mao-Dong-Qing, is widely used in traditional Chinese medicine. This plant is distributed in the wild in southern China, and the roots and stems are used for clearing heat, detoxifying, activating blood circulation and dispelling stasis. Moreover, it is used for treating wind-heat cold, lung-heat asthma, swelling and pain of pharynxes and gingivae, thoracic obstruction and cardiodynia with pungent, stroke, hemiplegia, thromboangiitis obliterans, burn, scald and central retinitis. AIMS OF THE REVIEW: This paper aims to provide a critical summary of the current studies on I. pubescens. The progress in research on the botany, traditional uses, phytochemistry, pharmacology and toxicology of the plant is discussed. We mainly focus on the phytochemical and pharmacological investigations of I. pubescens. Furthermore, perspectives for possible future studies on I. pubescens are also discussed. MATERIALS AND METHODS: A systematic review was conducted on the studies of I. pubescens performed during the past 40 years with resources including the Chinese Pharmacopoeia and literature databases such as PubMed, Science Direct, Wiley, CNKI (China National Knowledge Infrastructure), SciFinder, Web of Science, Google Scholar and Baidu Scholar. RESULTS: To date, more than 200 compounds have been isolated and identified from the plant, a substantial proportion of which were reported to be triterpenes. Biological effects such as protective effects against cardio-cerebrovascular diseases, anti-thrombosis, anti-inflammatory and anti-tumour activities were also investigated in in vitro and in vivo research. Therapeutic effects are attributed to the bioactivities of the naturally occurring compounds in this herb. Furthermore, toxicological studies on I. pubescens are relatively scarce, and it is worthy of further research. CONCLUSIONS: This review summarizes the results from current studies of I. pubescens, which is one of the valuable medicinal sources from traditional herbs. Some conventional uses have been evaluated by pharmacological investigation. In addition, unresolved issues include molecular mechanisms underlying bioactivities, pharmacokinetics, toxicology and efficacy, which are still being studied and explored before achieving integration into clinical medicines.


Assuntos
Ilex , Animais , Etnobotânica , Etnofarmacologia , Humanos , Medicina Tradicional Chinesa , Compostos Fitoquímicos/análise , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico , Compostos Fitoquímicos/toxicidade , Fitoterapia , Preparações de Plantas/química , Preparações de Plantas/farmacologia , Preparações de Plantas/uso terapêutico , Preparações de Plantas/toxicidade
16.
Microbiome ; 7(1): 107, 2019 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-31315667

RESUMO

BACKGROUND: Early treatment is key for optimizing the therapeutic success of drugs, and the current initiating treatment that blocks the progression of bone destruction during the pre-arthritic stages remains unsatisfactory. The microbial disorder in rheumatoid arthritis (RA) patients is significantly reversed with effective treatment. Modulating aberrant gut microbiomes into a healthy state is a potential therapeutic approach for preventing bone damage. RESULTS: By using metagenomic shotgun sequencing and a metagenome-wide association study, we assessed the effect of Lactobacillus casei (L. casei) on the induction of arthritis as well as on the associated gut microbiota and immune disorders in adjuvant-induced arthritis (AIA) rats. Treatment of AIA rats with L. casei inhibited joint swelling, lowered arthritis scores, and prevented bone destruction. Along with the relief of arthritis symptoms, dysbiosis in the microbiome of arthritic rats was significantly reduced after L. casei intervention. The relative abundance of AIA-decreased Lactobacillus strains, including Lactobacillus hominis, Lactobacillus reuteri, and Lactobacillus vaginalis, were restored to normal and Lactobacillus acidophilus was upregulated by the administration of L. casei to the AIA rats. Moreover, L. casei downregulated the expression of pro-inflammatory cytokines, which are closely linked to the effect of the L. casei treatment-associated microbes. Functionally, the maintenance of the redox balance of oxidative stress was involved in the improvement in the L. casei-treated AIA rats. CONCLUSION: A single bacterium, L. casei (ATCC334), was able to significantly suppress the induction of AIA and protect bones from destruction in AIA rats by restoring the microbiome dysbiosis in the gut, indicating that using probiotics may be a promising strategy for treating RA, especially in the early stage of the disease.

17.
Phytomedicine ; 63: 152968, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31280140

RESUMO

BACKGROUND: Gastric cancer has a high morbidity and is a leading cause of cancer-related mortality worldwide. Helicobacter pylori (H. pylori) infection is commonly found in the early stage of gastric cancer pathogenesis, which induces chronic gastritis. Artemisinin (ART) and its derivatives (ARTS, artesunate and DHA, dihydroartemisinin), a new class of potent antimalarials, have been reported to exert both preventive and anti-gastric cancer effects. However, the underlying mechanisms of the chemopreventive effects of ART and its derivatives in H. pylori infection induced-gastric cancer are not fully elucidated. PURPOSE: We investigated the effects of H. pylori infection in gastric cancer; and the preventive mechanisms of ART, ARTS and DHA. METHODS: The H. pylori growth was determined by the broth macro-dilution method, and its adhesion to gastric cancer cells was evaluated by using the urease assay. The protein and mRNA levels, reactive oxygen species (ROS) production, as well as the production of inflammatory cytokines were evaluated by Western blot, real-time PCR, flow cytometry and ELISA, respectively. Moreover, an in vivo MNU (N-methyl-N-nitroso-urea) and H. pylori-induced gastric adenocarcinoma mouse model was established for the investigation of the cancer preventive effects of ART and its derivaties, and the underlying mechanisms of action. RESULTS: ART, DHA and ARTS inhibited the growth of H. pylori and gastric cancer cells,suppressed H. pylori adhesion to the gastric cancer cells, and reduced the H. pylori-enhanced ROS production. Moreover, ART, DHA and ARTS significantly reduced tumor incidence, number of tumor nodules and tumor size in the mouse model. Among these three compounds, DHA exerted the most potent chemopreventive effect. Mechanistic studies showed that ART and its derivatives potently inhibited the NF-κB activation. CONCLUSION: ART, DHA and ARTS have potent preventive effects in H. pylori-induced gastric carcinogenesis. These effects are, at least in part, attributed to the inhibition of NF-κB signaling pathway. Our findings provide a molecular justification of using ART and its derivatives for the prevention and treatment of gastric cancer.


Assuntos
Anticarcinógenos/farmacologia , Artemisininas/farmacologia , Infecções por Helicobacter/complicações , Helicobacter pylori/efeitos dos fármacos , Neoplasias Gástricas/prevenção & controle , Animais , Artesunato/farmacologia , Aderência Bacteriana/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Helicobacter pylori/patogenicidade , Humanos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
18.
J Chromatogr A ; 1603: 160-164, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31272732

RESUMO

An environmentally benign and cost-effective method was designed for isolating and purifying condensed arenes from acetone-extractable portion (AEP) of a high-temperature coal tar through a high pressure preparative chromatograph (HPPC) with different packings, including silica gel, octadecyl silane, octyl bonded silica gel, and diol bonded silica gel. In total, 196 compounds were detected with a gas chromatograph/mass spectrometer from AEP and its eluates. From the eluates, naphthalene, anthracene, phenanthrene, fluoranthene, and pyrene were successfully isolated and purified, and their structures were confirmed by their 1H and 13C nuclear magnetic resonance spectra in addition to their mass spectra. Extraction-HPPC device and solvent recovery process were designed and developed, which can potentially be applied to industrial production because the process is easy-to-operate and ecofriendliness. In addition, the solvents used can be easily recovered and reused, and neither waste water nor other pollutions are emitted.


Assuntos
Alcatrão/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Temperatura Alta , Hidrocarbonetos Policíclicos Aromáticos/isolamento & purificação , Pressão , Antracenos/isolamento & purificação , Fluorenos/isolamento & purificação , Naftalenos/isolamento & purificação , Fenantrenos/isolamento & purificação , Pirenos/isolamento & purificação
19.
Molecules ; 24(13)2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31284554

RESUMO

Nardochinoid B (NAB) is a new compound isolated from Nardostachys chinensis. Although our previous study reported that the NAB suppressed the production of nitric oxide (NO) in lipopolysaccharide (LPS)-activated RAW264.7 cells, the specific mechanisms of anti-inflammatory action of NAB remains unknown. Thus, we examined the effects of NAB against LPS-induced inflammation. In this study, we found that NAB suppressed the LPS-induced inflammatory responses by restraining the expression of inducible nitric oxide synthase (iNOS) proteins and mRNA instead of cyclooxygenase-2 (COX-2) protein and mRNA in RAW264.7 cells, implying that NAB may have lower side effects compared with nonsteroidal anti-inflammatory drugs (NSAIDs). Besides, NAB upregulated the protein and mRNA expressions of heme oxygenase (HO)-1 when it exerted its anti-inflammatory effects. Also, NAB restrained the production of NO by increasing HO-1 expression in LPS-stimulated RAW264.7 cells. Thus, it is considered that the anti-inflammatory effect of NAB is associated with an induction of antioxidant protein HO-1, and thus NAB may be a potential HO-1 inducer for treating inflammatory diseases. Moreover, our study found that the inhibitory effect of NAB on NO is similar to that of the positive drug dexamethasone, suggesting that NAB has great potential for developing new drugs in treating inflammatory diseases.


Assuntos
Heme Oxigenase-1/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/biossíntese , Mediadores da Inflamação , Magnoliopsida/química , Camundongos , Modelos Biológicos , Estrutura Molecular , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Extratos Vegetais/química , Células RAW 264.7
20.
Planta Med ; 85(9-10): 729-737, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31167298

RESUMO

Rotundic acid and pedunculoside are the most abundant constituents in Ilicis Rotundae Cortex, and possess lipid-lowering activity. In this study, we evaluated the pharmacokinetic interactions of rotundic acid with pedunculoside and other ingredients from Ilicis Rotundae Cortex with rotundic acid and pedunculoside, and preliminarily investigated the effects of gut microbiota on their pharmacokinetics using a pseudo-germ-free rat model. After a single oral administration of each monomer, a monomer mixture, and Ilicis Rotundae Cortex extract to the conventional and pseudo-germ-free rats, rotundic acid and pedunculoside were quantified in plasma by an UPLC/Q-TOF-MS/MS method. The systemic exposure (maximum plasma concentration and area under concentration-time curve) of two analytes in conventional rats were increased in an approximately dose-dependent manner. Oral administration of rotundic acid and pedunculoside in the forms of a monomer mixture and Ilicis Rotundae Cortex extract to the conventional rats significantly decreased the systemic exposure compared with the monomer groups, which demonstrated the existence of significant pharmacokinetic interactions. The pseudo-germ-free rats were prepared by nonabsorbable antibiotic treatment, and the systemic exposure of two analytes were significantly decreased and most of the "time to reach the maximum" values were delayed in comparison to conventional rats, therefore gut microbiota might serve as an efficient absorption promoter. These results provide a scientific basis for the clinical application of the two bioactive constituents and Ilicis Rotundae Cortex.


Assuntos
Microbioma Gastrointestinal/fisiologia , Glucose/análogos & derivados , Triterpenos/farmacocinética , Administração Oral , Animais , Calibragem , Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Microbioma Gastrointestinal/efeitos dos fármacos , Glucose/administração & dosagem , Glucose/farmacocinética , Interações Ervas-Drogas , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos , Triterpenos/administração & dosagem
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