Publications by authors named "Jian-Hui Xie"

42 Publications

Therapeutic effect of oxyberberine on obese non-alcoholic fatty liver disease rats.

Phytomedicine 2021 May 17;85:153550. Epub 2021 Mar 17.

The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, PR China; State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510120, PR China; Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, Guangzhou 510120, PR China. Electronic address:

Background: Berberine (BBR) has been widely used to treat non-alcoholic fatty liver disease (NAFLD). The metabolites of BBR were believed to contribute significantly to its pharmacological effects. Oxyberberine (OBB), a gut microbiota-mediated oxidative metabolite of BBR, has been firstly identified in our recent work.

Purpose: Here, we aimed to comparatively investigate the anti-NAFLD properties of OBB and BBR.

Methods: The anti-NAFLD effect was evaluated in high-fat diet-induced obese NAFLD rats with biochemical/ELISA tests and histological staining. The related gene and protein expressions were detected by qRT-PCR and Western blotting respectively. Molecular docking and dynamic simulation were also performed to provide further insight.

Results: Results indicated OBB remarkably and dose-dependently attenuated the clinical manifestations of NAFLD, which (100 mg/kg) achieved similar therapeutic effect to metformin (300 mg/kg) and was superior to BBR of the same dose. OBB significantly inhibited aberrant phosphorylation of IRS-1 and up-regulated the downstream protein expression and phosphorylation (PI3K, p-Akt/Akt and p-GSK-3β/GSK-3β) to improve hepatic insulin signal transduction. Meanwhile, OBB treatment remarkably alleviated inflammation via down-regulating the mRNA expression of MCP-1, Cd68, Nos2, Cd11c, while enhancing Arg1 mRNA expression in white adipose tissue. Moreover, OBB exhibited closer affinity with AMPK in silicon and superior hyperphosphorylation of AMPK in vivo, leading to increased ACC mRNA expression in liver and UCP-1 protein expression in adipose tissue.

Conclusion: Taken together, compared with BBR, OBB was more capable of maintaining lipid homeostasis between liver and WAT via attenuating hepatic insulin pathway and adipocyte inflammation, which was associated with its property of superior AMPK activator.
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http://dx.doi.org/10.1016/j.phymed.2021.153550DOI Listing
May 2021

A comparative investigation of the interaction and pharmacokinetics of hemoglobin with berberine and its oxymetabolite.

J Pharm Biomed Anal 2021 May 20;199:114032. Epub 2021 Mar 20.

The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People's Republic of China. Electronic address:

Berberine (BBR), isolated from Coptis chinensis, is one type of isoquinoline alkaloids. BBR exerts numerous of bioactivities but the plasma concentration is really low. In our previous study, a new oxymetabolite (OBB) has been discovered and showed superior anti-inflammatory effect comparing with BBR. The aim of this study is to investigate the interaction, metabolite and pharmacokinetics of BBR with hemoglobin. Sprague-Dawley rats were used to carry out the interaction, metabolite and pharmacokinetics of BBR and OBB in vivo. Fluorescence spectra were used to analyse the interaction in vitro. Results showed that OBB could be generated after intravenous injection or incubating with BBR in vitro and in vivo; Both BBR and OBB exerted much stronger binding interaction with hemoglobin than plasma and affect the conformation of bovine hemoglobin and change the fluorescence spectral properties; BBR and OBB were mainly presented and transported in the proteins-bound form. These results provide a new insight to understand the dynamic equilibrium of BBR and OBB within body from the perspective of new metabolic pathways.
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http://dx.doi.org/10.1016/j.jpba.2021.114032DOI Listing
May 2021

Apoptosis induced by bruceine D in human non‑small‑cell lung cancer cells involves mitochondrial ROS‑mediated death signaling.

Int J Mol Med 2019 Dec 3;44(6):2015-2026. Epub 2019 Oct 3.

Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510120, P.R. China.

Bruceine D is one of the active components of Brucea javanica (L.) Merr., which is widely used to treat cancer in China. The aim of the present study was to evaluate the potential effect of bruceine D against non‑small‑cell lung cancer (NSCLC) cells and delineate its underlying mechanisms. The results indicated that treatment with bruceine D markedly inhibited the proliferation of wild‑type NSCLC cells and epidermal growth factor receptor‑mutant cells in a dose‑ and time‑dependent manner, and significantly decreased the colony‑forming ability and migration of A549 cells. Hoechst 33342 staining and flow cytometric analysis demonstrated that treatment with bruceine D effectively induced apoptosis of A549 cells. In addition, the proapoptotic effect of bruceine D was found to be associated with G0‑G1 cell cycle arrest, accumulation of intracellular reactive oxygen species (ROS) and malondialdehyde, depletion of glutathione levels and disruption of mitochondrial membrane potential. Additionally, pretreatment with N‑acetylcysteine, a ROS scavenger, significantly attenuated the bruceine D‑induced inhibition in A549 cells. Western blotting demonstrated that treatment with bruceine D significantly suppressed the expression of the anti‑apoptotic proteins Bcl‑2, Bcl‑xL and X‑linked inhibitor of apoptosis, enhanced the expression levels of apoptotic proteins Bax and Bak, and inhibited the expression of pro‑caspase‑3 and pro‑caspase‑8. Based on these results, it may be suggested that inhibition of A549 NSCLC cell proliferation by bruceine D is associated with the modulation of ROS‑mitochondrial‑mediated death signaling. This novel insight may provide further evidence to verify the anticancer efficacy of B. javanica, and support a role for bruceine D in the anti‑NSCLC treatment.
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http://dx.doi.org/10.3892/ijmm.2019.4363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844635PMC
December 2019

Comparison of anti-inflammatory effects of berberine, and its natural oxidative and reduced derivatives from Rhizoma Coptidis in vitro and in vivo.

Phytomedicine 2019 Jan 1;52:272-283. Epub 2018 Oct 1.

Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China. Electronic address:

Background: Berberine (BBR) is the most abundant and major active constituent of Rhizoma Coptidis (RC), which has been widely used to treat inflammatory diseases in traditional oriental medicine. Despite BBR has been found to exhibit pronounced anti-inflammatory effect, the anti-inflammatory activities of its natural derivatives were sparsely dissected out.

Purpose: To comparatively investigate the anti-inflammatory potential of BBR, and its natural oxoderivative (oxyberberine, OBB) and reduced derivative (dihydroberberine, DHBB) in vitro and in vivo, and delineate the possible underlying mechanism.

Methods: LC-MS/MS was used to identify the natural derivatives of BBR in RC. The potential anti-inflammatory properties of BBR and its natural derivatives were comparatively evaluated in vitro by lipopolysaccharide (LPS)-induced RAW264.7 macrophages cells, and in vivo via three typical acute inflammation murine models. Some important inflammation-related molecules were analyzed by ELISA, qRT-PCR and Western blotting.

Results: LC-MS/MS led to the identification of BBR, OBB and DHBB in RC ethyl acetate extract. The in vitro assay indicated that BBR, OBB and DHBB (1.25, 2.5 and 5 μM) pretreatment significantly decreased the levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), prostaglandinE2 (PGE) and nitricoxide (NO), and inhibited the mRNA expressions of cyclooxygenase-2 (COX-2) and inducible nitricoxide synthase (iNOS) in a dose-dependent manner, with relative efficiency of OBB > BBR > DHBB. Furthermore, OBB, BBR and DHBB remarkably inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 and inhibitory kappa Bα (IκBα). In vivo, BBR (20 mg/kg) and OBB (5, 10, and 20 mg/kg) pretreatment significantly ameliorated the xylene-induced ear edema, carrageenan-stimulated paw edema, and acetic acid-elicited vascular permeability in mice in a dose-dependent manner, with OBB exhibiting superior anti-inflammatory effect at the same dose (20 mg/kg). Histopathological analysis indicated that OBB and BBR could markedly attenuate the inflammatory deterioration and decrease the cellular infiltration in paw tissues. Additionally, the carrageenan-induced increases in TNF-α, IL-6, IL-1β, PGE and NO productions, and COX-2 and iNOS mRNA expressions were effectually and concentration-dependently suppressed by OBB and BBR pretreatment.

Conclusion: The anti-inflammatory activity of BBR and its natural derivatives was in the order of OBB > BBR > DHBB. OBB was for the first time found to be endowed with pronounced anti-inflammatory property, which was probably associated with suppressing the activation of NF-κB signaling pathway, and the subsequent gene expressions and productions of pro-inflammatory mediators. The results might contribute to illuminating the pharmacodynamic underpinnings of RC and provide evidence for developing OBB as a safe and promising natural lead compound in inflammation treatment.
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http://dx.doi.org/10.1016/j.phymed.2018.09.228DOI Listing
January 2019

Effects of conservational tillage on water characteristics in dryland farm of central Gansu, Northwest China.

Ying Yong Sheng Tai Xue Bao 2018 Dec;29(12):4022-4028

Gansu Provincial Laboratory of Arid land Crop Sciences/Agronomy college, Gansu Agricultural University, Lanzhou 730070, China.

Productivity is low and unstable in dryland farms of central Gansu, Northwest China. Conservational tillage is an important way for the sustainable development of agriculture. The effects of different tillage measures on soil moisture infiltration, evaporation, crop yield and water use efficiency (WUE) were investigated in this study based on a long-term experiment since 2001 in Longzhong. There were six treatments, i.e. conventional tillage with no straw (T), no-till with straw cover (NTS), no-till with no straw cover (NT), conventional tillage with straw incorporated (TS), conventional tillage with plastic mulch (TP), and no-till with plastic mulch (NTP), with annual rotation of spring wheat and pea. The results showed that compared with T, soil bulk density of NTS decreased and total porosity of soil increased significantly in wheat and pea land. Compared with conventional tillage, conservation tillage reduced soil infiltration rate in 0-5 cm in the pea field by 56.2%. Conservational tillage siginificantly increased soil saturated water conductivity in both wheat and pea lands. Compared with T, the saturated water conductivity in NTS was significantly increased by 52.8%-107.1%. Conservational tillage siginificantly reduced soil evaporation during growing season. Compared with T, the evapotranspiration of NTP, TP and NTS was significantly reduced by 14.4%-50.8%. The soil evaporation after rain was also decreased. Conservational tillage improved crop yield and water use efficiency by 9.5%-62.8% and 0.4%-50.9%, respectively. Therefore, conservational tillage could increase water use efficiency and crop yield in dryland farming area of central Gansu, Northwest China.
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http://dx.doi.org/10.13287/j.1001-9332.201812.007DOI Listing
December 2018

Tetrahydrocurcumin and octahydrocurcumin, the primary and final hydrogenated metabolites of curcumin, possess superior hepatic-protective effect against acetaminophen-induced liver injury: Role of CYP2E1 and Keap1-Nrf2 pathway.

Food Chem Toxicol 2019 Jan 10;123:349-362. Epub 2018 Nov 10.

Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, PR China. Electronic address:

Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity.
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http://dx.doi.org/10.1016/j.fct.2018.11.012DOI Listing
January 2019

Curcumin's Metabolites, Tetrahydrocurcumin and Octahydrocurcumin, Possess Superior Anti-inflammatory Effects Through Suppression of TAK1-NF-κB Pathway.

Front Pharmacol 2018 17;9:1181. Epub 2018 Oct 17.

Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.

Curcumin (CUR), a promising naturally occurring dietary compound, is commonly recognized as the potential anti-inflammatory agent. While the application of CUR was hampered by its low stability and poor systemic bioavailability, it has been suggested that the biological activities of CUR are intimately related to its metabolites. In the current investigation, we aimed to comparatively explore the anti-inflammatory effects of tetrahydrocurcumin (THC), octahydrocurcumin (OHC), and CUR, and to elucidate the underlying action mechanisms on experimental mice models of acute inflammation, i.e., xylene-induced ear edema, acetic acid-induced vascular permeability, and carrageenan-induced paw edema. The results showed that THC and OHC exerted significant and dose-dependent inhibitions on the formation of ear edema induced by xylene and paw edema provoked by carrageenan and inhibited the Evans blue dye leakage in peritoneal cavity elicited by acetic acid. Moreover, THC and OHC treatments were more effective than CUR in selectively inhibiting the expression of cyclooxygenase 2 (COX-2) and suppressing nuclear factor-κB (NF-κB) pathways via transforming growth factor β activated kinase-1 (TAK1) inactivation in the carrageenan-induced mouse paw edema model.
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http://dx.doi.org/10.3389/fphar.2018.01181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199526PMC
October 2018

Angelica sinensis Supercritical Fluid CO Extract Attenuates D-Galactose-Induced Liver and Kidney Impairment in Mice by Suppressing Oxidative Stress and Inflammation.

J Med Food 2018 Sep 15;21(9):887-898. Epub 2018 Aug 15.

4 Shenzhen Key Laboratory of Hospital Chinese Medicine Preparation, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine , Shenzhen, China .

Angelica sinensis (AS, Danggui in Chinese) is an important herbal component of various traditional formulae for the management of asthenia and its tonic effects. Although AS has been shown to ameliorate cognitive damage and nerve toxicity in D-galactose (D-gal)-elicited senescent mice brain, its effects on liver and kidney injury have not yet been explored. In this work, mice were subjected to hypodermic injection with D-gal (200 mg/kg) and orally gavaged with AS (20, 40, or 80 mg/kg) once a day for 8 successive weeks. Results revealed that AS significantly improved liver and kidney function as assessed by organ index and functional parameters. In addition, AS pretreatment effectively ameliorated the histological deterioration. AS attenuated the MDA level and markedly enhanced the activities and gene expressions of antioxidative enzymes, namely Cu, Zn-SOD, CAT, and GPx. Furthermore, AS markedly inhibited the D-gal-mediated increment of expressions of inflammatory cytokines iNOS, COX-2, IκBα, p-IκBα, and p65 and promoted the IκBα expression level in both hepatic and renal tissues. In sum, AS pretreatment could effectively guard the liver and kidney of mice from D-gal-induced injury, and the underlying mechanism was deemed to be intimately related to attenuating oxidative response and inflammatory stress.
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http://dx.doi.org/10.1089/jmf.2017.4061DOI Listing
September 2018

Efficacy and indication optimization of Chinese medicine (Tiao-Chang Ke-Min granules) for diarrhea-predominant irritable bowel syndrome: study protocol for a randomized controlled trial.

Trials 2018 Jul 11;19(1):367. Epub 2018 Jul 11.

Chinese Medicine Syndrome Research Team, Guangdong Provincial Hospital of Chinese Medicine, No. 111, DaDe Road, Guangzhou, 510120, China.

Background: Irritable bowel syndrome (IBS) is a chronic, recurring condition, prevalent in the general population. Current medication treatments usually leave patients undertreated. Nowadays, Chinese medicine (CM) is being considered as a promising treatment approach for IBS. However, due to methodological limitations, there is no strong evidence to support CM. Although IBS relapses are common, the relapse assessment has always been neglected in CM study designs. Meanwhile, in clinical practice and studies, it has been found that certain CM formulas can only benefit certain kinds of patients. Discovering what population and illness characteristics likely respond to outcomes may help improve the effectiveness of CM. The aims of this study are to evaluate the efficacy and safety of Tiao-Chang Ke-Min (TCKM) granules for IBS, especially in reducing IBS symptoms' relapse, by a high-quality randomized controlled trial and then to optimize the indication of the TCKM granules.

Methods/design: This is a parallel-group, randomized, double-blind, placebo-controlled trial embedded with outcome predictive factors. Eligible patients with diarrhea-predominant IBS will be randomized into either a TCKM granule group or a placebo group. Patients from both groups will receive health education. The treatment duration is 4 weeks and the follow-up is 12 weeks. The primary outcome is global improvement measured with adequate relief (AR). The second outcome measures include time until relief, time until first relapse, total relapse times, long-term effectiveness, individual symptoms, IBS-Symptom Severity Score (IBS-SSS), IBS-Quality of Life Questionnaire (IBS-QOL), and Hospital Anxiety and Depression Scale (HADS). Predictive factors associated with patient and illness characteristics have been widely collected. These factors will be embedded in this trial for further identification.

Discussion: This trial may provide high-quality evidence on the efficacy and safety of TCKM granules for IBS and a more accurate indication. Importantly, this trial will provide a new research method for improving the therapeutic effects of CM for clinicians and researchers. To address IBS relapse assessment, a series of special definitions of relapse incidents has been made for this trial.

Trial Registration: Chinese Clinical Trial Registry, ID: ChiCTR-IOR-17010600 . Registered on 9 February 2017.
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http://dx.doi.org/10.1186/s13063-018-2754-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042407PMC
July 2018

Synergistic antitumor effect of brusatol combined with cisplatin on colorectal cancer cells.

Int J Mol Med 2018 Mar 9;41(3):1447-1454. Epub 2018 Jan 9.

College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, P.R. China.

Colorectal cancer (CRC) is a common and life‑threatening type of malignant cancer, which is associated with a high mortality rate. Cisplatin (CDDP) is a commonly used chemotherapy drug with significant side effects. Brusatol (BR) is one of the principal chemical compounds isolated from the Chinese herb Bruceae Fructus, which has been reported to markedly inhibit the proliferation of numerous cancer cell lines. The present study aimed to investigate the possible synergistic anticancer effects of CDDP combined with BR on CT‑26 cells, and to evaluate the underlying mechanisms of action. The growth inhibitory effects of BR, CDDP, and BR and CDDP cotreatment on CT‑26 cells were assessed by MTT assay. Cell apoptosis were determined by flow cytometry and western blot analysis. The results indicated that compared with single‑agent treatment, cotreatment of CT‑26 cells with CDDP and BR synergistically inhibited cell proliferation and increased cellular apoptosis. Furthermore, treatment of CT‑26 cells with CDDP and BR resulted in a marked increase in the release of cytosolic cytochrome c, decreased expression of procaspase‑3 and procaspase‑9, and upregulation of the B‑cell lymphoma 2 (Bcl‑2)‑associated X protein/Bcl‑2 ratio compared with treatment with BR or CDDP alone. These results strongly suggested that the combination of CDDP and BR was able to produce a synergistic antitumor effect in CRC cells, thus providing a solid foundation for further development of this combination regimen into an effective therapeutic method for CRC.
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http://dx.doi.org/10.3892/ijmm.2018.3372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5819912PMC
March 2018

Brucein D, a Naturally Occurring Tetracyclic Triterpene Quassinoid, Induces Apoptosis in Pancreatic Cancer through ROS-Associated PI3K/Akt Signaling Pathway.

Front Pharmacol 2017 22;8:936. Epub 2017 Dec 22.

School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.

Brucein D (BD), a major active quassinoid in , has exhibited pronounced anticancer activities. However, the biologic mechanisms have not been fully explored. In this study, BD exhibited more potent cytotoxic effect on pancreatic cancer (PanCa) cell lines, while exerted weaker cytotoxic effects on GES-1 cells (non-tumorigenic). BD was shown to elicit apoptosis through inducing both the intrinsic and extrinsic mitochondria-mediated caspase activations. Furthermore, the BD-induced apoptotic effects were dependent on the accumulated reactive oxygen species (ROS) and inactivation of PI3K/Akt signaling pathway. Pretreatment with tempol completely prevented the cellular apoptosis induced by BD, and recovered the inactivation of AKT, which suggested ROS essentially involved in BD-elicited apoptosis and down-regulation of PI3K/Akt pathway. In addition, the results obtained from orthotopic xenograft in nude mice were congruent with those of the investigations. These results support the notion that BD held good potential to be further developed into an effective pharmaceutical agent for the treatment of PanCa.
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http://dx.doi.org/10.3389/fphar.2017.00936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744014PMC
December 2017

Protective effects of silymarin on triptolide-induced acute hepatotoxicity in rats.

Mol Med Rep 2018 Jan 3;17(1):789-800. Epub 2017 Nov 3.

Higher Education Institute and Development Research of Chinese Medicine, Guangzhou, Guangdong 510405, P.R. China.

Silymarin has been used in the treatment of a number of liver diseases for a long time, but its efficacy in preventing triptolide induced acute hepatotoxicity has not been reported previously. The present study aimed to assess the protective effect of silymarin against triptolide (TP)-induced hepatotoxicity in rats. Rats were orally administrated with silymarin (50, 100 and 200 mg/kg) for 7 days and received intraperitoneal TP (2 mg/kg) on the day 8. Hepatic injuries were comprehensively evaluated in terms of serum parameters, morphological changes, oxidative damage, inflammation and apoptosis. The results demonstrated that TP-induced increases in serum parameters, including alanine transaminase, aspartate aminotransferase, alkaline phosphatase, total cholesterol and γ-glutamyl transpeptidase, which were determined using a biochemical analyzer, and histopathological alterations and hepatocyte apoptosis as determined by hematoxylin and eosin and TUNEL staining, respectively, were prevented by silymarin pretreatment in a dose-dependent manner. TP-induced depletions in the activity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, glutathione S-transferase and catalase, and glutathione levels, were also significantly reversed by silymarin, as determined using specific kits. Additionally, silymarin dose-dependently exhibited inhibitory effects on malonaldehyde content in the liver. The production of proinflammatory cytokines was investigated using ELISA kits, and the results demonstrated that silymarin dose-dependently inhibited the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and IL-1β in the liver. To determine the mechanism of silymarin, western blot analysis was performed to investigate the protein expression of phosphorylated (p)-p38 and p-c-Jun N-terminal kinase (JNK) of the TNF-α induced inflammatory response and apoptotic pathways. Silymarin significantly blocked p38 and JNK phosphorylation and activation. Additionally, the expression of the proapoptotic proteins cytochrome c, cleaved caspase-3 and Bcl-2-associated X was also reduced following treatment with silymarin, as determined by ELISA, western blotting and immunohistochemistry, respectively. In conclusion, silymarin was demonstrated to dose-dependently protect rat liver from TP-induced acute hepatotoxicity, with the high dose (200 mg/kg) achieving a superior effect. This protective effect may be associated with the improvement of antioxidant and anti-inflammatory status, as well as the prevention of hepatocyte apoptosis. Therefore, silymarin may have the potential to be applied clinically to prevent TP-induced acute hepatotoxicity.
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http://dx.doi.org/10.3892/mmr.2017.7958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780159PMC
January 2018

β-Patchoulene from patchouli oil protects against LPS-induced acute lung injury via suppressing NF-κB and activating Nrf2 pathways.

Int Immunopharmacol 2017 Sep 13;50:270-278. Epub 2017 Jul 13.

Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China; Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine, Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China. Electronic address:

β-Patchoulene (β-PAE), a tricyclic sesquiterpene isolated from the essential oil of the leaves and stems of Pogostemon cablin (Blanco) Benth., has been reported to have potent anti-inflammatory activity. The aim of this study was to evaluate the potential protective effect of β-PAE on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and to illuminate the underlying mechanisms. ALI was induced by intracheal instillation of LPS into lung, and dexamethasone (DEX) was used as a positive control. Results indicated that pretreatment with β-PAE significantly decreased the mortality rate of mice and lung W/D weight ratio, ameliorated lung pathological changes as compared to model group. Meanwhile, β-PAE pretreatment markedly inhibited the increase of TNF-α, IL-6 and IL-1β secretions in the bronchoalveolar lavage fluid, and prevented LPS-induced elevations of MPO activity and MDA level in the lung. Additionally, β-PAE pretreatment significantly elevated miR-146a expression and suppressed the LPS-induced activation of NF-κB and expression of its mediated genes (TNF-α, IL-6 and IL-1β). β-PAE was also observed to markedly upregulate the Nrf2 and HO-1 expression and activate the antioxidant genes (NQO-1, GCLC and HO-1). Taken together, β-PAE possessed protective effect against LPS-induced ALI, which might be associated with its differential regulation of NF-κB and Nrf2 activities and up-regulation of expression of miR-146a. The results rendered β-PAE a promising anti-inflammatory agent worthy of further development into a pharmaceutical drug for the treatment of ALI.
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http://dx.doi.org/10.1016/j.intimp.2017.07.001DOI Listing
September 2017

Anti-inflammatory activity of coptisine free base in mice through inhibition of NF-κB and MAPK signaling pathways.

Eur J Pharmacol 2017 Sep 23;811:222-231. Epub 2017 Jun 23.

The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, People's Republic of China. Electronic address:

Coptisine is one of the main constituents of Coptis chinensis which has been widely used for the remedy of inflammatory disorders. Although the biological activities of coptisine have been well known, the pharmacological properties of its free base have seldomly been elucidated thus far. The aim of this study was to investigate the potential anti-inflammatory properties of coptisine free base (CFB, 8-hydroxy-7,8-dihydrocoptisine) on three animal models, namely xylene-induced ear edema, acetic acid-induced vascular permeability and carrageenan-induced paw edema. The results exhibited that CFB exerted a dose-dependent suppression on ear edema induced by xylene, significantly mitigated the aggravation of vascular permeability caused by acetic acid and paw edema induced by carrageenan. Additionally, CFB significantly suppressed the productions of interleukin-1β (IL-1β), interleukin-6 (IL-6), prostaglandinE2 (PGE) and tumor necrosis factor (TNF-α) in the drug-treated groups as compared with the vehicle group after treatment with carrageenan. Signaling events of nuclear factor-κB (NF-κB) translocation, such as p-IKKα, p-IKKβ, p-IκBα and p65 (nucleus) were significantly inactivated, while inhibitor of nuclear factor κBα (IκBα) and p65 (cytosolic) were markedly up-regulated by CFB. Furthermore, CFB also significantly suppressed the mitogen-activated protein kinase (MAPK) pathway by blocking the phosphorylation of p-p38 (phospho-p38 mitogen-activated protein kinases) and p-JNK (phospho-c-jun N-terminal kinase) but not p-ERK (phospho-extracellular signal-regulated kinase). Hence, CFB efficiently prevented inflammation, at least partially, via inhibition of NF-κB and MAPK pathways. These findings provided a pioneering pharmacological basis for the anti-inflammatory effect of CFB and suggested CFB might be a potential candidate for the therapy of inflammatory disorders.
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http://dx.doi.org/10.1016/j.ejphar.2017.06.027DOI Listing
September 2017

Protective Effects of Li-Fei-Xiao-Yan Prescription on Lipopolysaccharide-Induced Acute Lung Injury via Inhibition of Oxidative Stress and the TLR4/NF-B Pathway.

Evid Based Complement Alternat Med 2017 23;2017:1791789. Epub 2017 Mar 23.

School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, China.

Li-Fei-Xiao-Yan prescription (LFXY) has been clinically used in China to treat inflammatory and infectious diseases including inflammatory lung diseases. The present study was aimed at evaluating the potential therapeutic effects and potential mechanisms of LFXY in a murine model of lipopolysaccharide- (LPS-) induced acute lung injury (ALI). In this study, the mice were orally pretreated with LFXY or dexamethasone (positive drug) before the intratracheal instillation of LPS. Our data indicated that pretreatment with LFXY enhanced the survival rate of ALI mice, reversed pulmonary edema and permeability, improved LPS-induced lung histopathology impairment, suppressed the excessive inflammatory responses decreasing the expression of proinflammatory cytokines (TNF-, IL-1, and IL-6) and chemokine (MIP-2) and inhibiting inflammatory cells migration, and repressed oxidative stress through the inhibition of MPO and MDA contents and the upregulation of antioxidants (SOD and GSH) activities. Mechanistically, treatment with LFXY significantly prevented LPS-induced TLR4 expression and NF-B (p65) phosphorylation. Overall, the present study suggests that LFXY protected mice from acute lung injury induced by LPS inhibition of TLR4/NF-B p65 activation and upregulation of antioxidative enzymes and it may be a potential preventive and therapeutic agent for ALI in the clinical setting.
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http://dx.doi.org/10.1155/2017/1791789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382312PMC
March 2017

The immune-regulating effect of Xiao'er Qixingcha in constipated mice induced by high-heat and high-protein diet.

BMC Complement Altern Med 2017 Mar 31;17(1):185. Epub 2017 Mar 31.

School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People's Republic of China.

Background: Xiao'er Qixingcha (EXQ) has been extensively applied to relieve dyspepsia and constipation in children for hundreds of years in China. However, the therapeutic mechanism underlying its efficacy remained to be defined. The present study aimed to clarify the possible laxative and immune-regulating effects of EXQ on two models of experimental constipation in mice, which mimicked the pediatric constipation caused by high-heat and high-protein diet (HHPD).

Methods: The two models of constipated mice were induced by HHPD or HHPD + atropine respectively. To investigate the laxative and immune-regulating activities of EXQ, animals were treated with three doses of EXQ (0.75, 1.5 and 3 g/kg) for 7 consecutive days. The fecal output parameters (number and weight), weight of intestinal content and, the thymus and spleen indexes were measured. The levels of sIgA, IL-10, TNF-α and LPS in colon and serum were determined by ELISA. Furthermore, the pathological changes of colon tissue were examined after routine H&E staining.

Results: Both HHPD and HHPD + atropine treatments obviously inhibited the fecal output and reduced the colonic sIgA, prominently increased the levels of IL-10 and TNF-α in colonic tissue and elevated the contents of LPS in serum and colonic tissues. In contrast, oral administration of EXQ significantly improved the feces characters and dose-dependently decreased the intestinal changes in both models. In HHPD model test, EXQ efficaciously boosted the sIgA level in a dose-dependent manner, significantly elicited decreases in TNF-α and IL-10 levels, and evidently decreased the spleen and thymus indexes. In HHPD + atropine model test, EXQ treatment reversed the pathological changes by not only dramatically decreasing the spleen index and the levels of LPS and IL-10, but also markedly elevating the thymus index. Furthermore, microscopic observation revealed that EXQ treatment maintained the integrity of colonic mucosa, and protected the colonic tissues from inflammation in the both models.

Conclusions: EXQ exhibited prominent laxative activity and effectively protected the colonic mucosal barrier in two models of constipated mice, of which the mechanism might be closely associated with its propulsive and immune-regulating properties. The current results not only validated the rationale for the clinical application of EXQ in pediatric constipation related symptoms, but also threw new light on the immune-inflammatory responses accompanied with chronic constipation pathology.
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http://dx.doi.org/10.1186/s12906-017-1700-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374715PMC
March 2017

Effect-enhancing and toxicity-reducing activity of usnic acid in ascitic tumor-bearing mice treated with bleomycin.

Int Immunopharmacol 2017 May 8;46:146-155. Epub 2017 Mar 8.

Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510120, China; Postdoctoral Programme, Guangzhou University of Chinese Medicine, Guangzhou 510120, China. Electronic address:

Usnic acid (UA) can be found in certain lichen species. Growing evidence suggests that UA possesses antitumoral, antioxidative and anti-inflammatory activities. Bleomycin (BLM) is widely used in the treatment of malignant ascites, however, it unexpectedly causes pulmonary fibrosis (PF). Researches show that excessive inflammatory response and oxidative stress in lung tissue is conspicuous causes of BLM-induced PF. Here we investigated mechanism underlying the effect-enhancing and toxicity-reducing activity of UA on H22-bearing mice treated with BLM. UA combined with BLM was significantly more effective than BLM alone in inhibiting the tumor growth, arresting the cell cycle at G0/G1 phase, and promoting the cleaved caspase-3 and cleaved caspase-8 activities to induce cancer cellular apoptosis. The mechanism may be associated with the transcriptional regulation of p53/p21/Cyclin pathway. Furthermore, UA effectively moderated the histopathological changes, reduced the content of MDA, HYP, TNF-α, IL-1β, IL-6 and TGF-β1, and increased the level of SOD when combined with BLM in lung tissues of H22-bearing mice, which was believed to be related to the inhibition on the protein level of p-Smad2/3 and enhancement of Smad7 expression. These findings suggested that UA might be a potential effect-enhancing and toxicity-reducing candidate for BLM in the treatment of malignant ascites.
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http://dx.doi.org/10.1016/j.intimp.2017.03.004DOI Listing
May 2017

Anti-inflammatory effects of Brucea javanica oil emulsion by suppressing NF-κB activation on dextran sulfate sodium-induced ulcerative colitis in mice.

J Ethnopharmacol 2017 Feb 22;198:389-398. Epub 2017 Jan 22.

Guangdong Provincial Key Laboratory of New Chinese Medicinal Development and Research, College of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, People's Republic of China; Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Songshan Hu Industrial Park, Dongguan 523808, Guangdong, People's Republic of China. Electronic address:

Ethnopharmacological Relevance: Brucea javanica is an important traditional medicinal herb used for the treatment of dysentery, malaria, inflammation and cancer in southeast Asia for many years. However, the anti-inflammatory mechanism of Brucea javanica in the treatment of dysentery (also known as ulcerative colitis, UC) has not been fully illuminated. Brucea javanica oil emulsion (BJOE) is the major active and most common application form of Brucea javanica oil (BJO), which has a variety of pharmacological activities. The aim of this study was to investigate the potential anti-inflammatory effect of BJOE and possible mechanism of action on dextran sulfate sodium (DSS)-induced UC in mice.

Materials And Methods: The components of BJOE were determined by gas chromatography-mass spectrometry (GC-MS). Balb/C mice with dextran sulfate sodium (DSS, 30mg/mL) induced colitis were treated with BJOE (0.5, 1 and 2g/kg) and two positive drugs (sulfasalazine, SASP, 200mg/kg; and azathioprine, AZA, 13mg/kg) once daily by gavage for 7 days. Mice in normal control group and DSS group were orally given the same volume of distilled water and soybean lecithin suspension (0.15g/kg) respectively. The effects of BJOE on DSS-induced UC were assessed by determination of body weight loss, disease activity index (DAI), colon length, histological analysis, as well as levels of pro-inflammatory cytokines. The mRNA expression of MPO, iNOS and COX-2 in colon tissues was detected by qRT-PCR. In addition, NF-κB p65, p-p65 and IκB-α, p-IκBα protein expression levels in colon tissues were investigated using Western blotting.

Results: The major components of BJOE were found to be oleic acid (62.68%) and linoleic acid (19.53%) as detected by GC-MS. Our results indicated that BJOE, SASP and AZA showed beneficial effect on DSS-induced colitis in mice, and significantly reduced the body weight loss and DAI, restored the colon length, repaired colonic pathological variations, decreased histological scores, and decreased the levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-17 and IFN-γ) as compared with the DSS group. In addition, the mRNA expression of MPO, iNOS and COX-2 induced by DSS treatment was remarkably inhibited by BJOE, SASP or AZA treatments. Furthermore, when compared with DSS-treated mice, the activation of NF-κB was significantly inhibited by AZA and BJOE treatment.

Conclusions: Our study shows that BJOE possessed appreciable anti-inflammatory effect against murine experimental UC induced by DSS. The protective mechanism of BJOE may involve inhibition of NF-κB signal transduction pathways and subsequent down-regulation of inflammatory mediators. These findings suggest that BJOE might be an efficacious and promising therapeutic approach for the treatment of UC. Our investigation might also provide experimental evidence for the traditional application of Brucea javanica in the treatment of dysentery and might add new dimension to the clinical indications for BJOE.
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http://dx.doi.org/10.1016/j.jep.2017.01.042DOI Listing
February 2017

Inhibition of Helicobacter pylori and Its Associated Urease by Palmatine: Investigation on the Potential Mechanism.

PLoS One 2017 3;12(1):e0168944. Epub 2017 Jan 3.

Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, PR China.

In this paper, we evaluated the anti-Helicobacter pylori activity and the possible inhibitory effect on its associated urease by Palmatine (Pal) from Coptis chinensis, and explored the potential underlying mechanism. Results indicated that Pal exerted inhibitory effect on four tested H. pylori strains (ATCC 43504, NCTC 26695, SS1 and ICDC 111001) by the agar dilution test with minimum inhibitory concentration (MIC) values ranging from 100 to 200 μg/mL under neutral environment (pH 7.4), and from 75 to 100 μg/mL under acidic conditions (pH 5.3), respectively. Pal was observed to significantly inhibit both H. pylori urease (HPU) and jack bean urease (JBU) in a dose-dependent manner, with IC50 values of 0.53 ± 0.01 mM and 0.03 ± 0.00 mM, respectively, as compared with acetohydroxamic acid, a well-known urease inhibitor (0.07 ± 0.01 mM for HPU and 0.02 ± 0.00 mM for JBU, respectively). Kinetic analyses showed that the type of urease inhibition by Pal was noncompetitive for both HPU and JBU. Higher effectiveness of thiol protectors against urease inhibition than the competitive Ni2+ binding inhibitors was observed, indicating the essential role of the active-site sulfhydryl group in the urease inhibition by Pal. DTT reactivation assay indicated that the inhibition on the two ureases was reversible, further supporting that sulfhydryl group should be obligatory for urease inhibition by Pal. Furthermore, molecular docking study indicated that Pal interacted with the important sulfhydryl groups and inhibited the active enzymatic conformation through N-H ∙ π interaction, but did not interact with the active site Ni2+. Taken together, Pal was an effective inhibitor of H. pylori and its urease targeting the sulfhydryl groups, representing a promising candidate as novel urease inhibitor. This investigation also gave additional scientific support to the use of C. chinensis to treat H. pylori-related gastrointestinal diseases in traditional Chinese medicine. Pal might be a potentially beneficial therapy for gastritis and peptic ulcers induced by H. pylori infection and other urease-related diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168944PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207512PMC
September 2017

Erratum to: JMJD2A contributes to breast cancer progression through transcriptional repression of the tumor suppressor ARHI.

Breast Cancer Res 2016 11 21;18(1):114. Epub 2016 Nov 21.

Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui district, Shanghai, 200032, People's Republic of China.

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http://dx.doi.org/10.1186/s13058-016-0776-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116818PMC
November 2016

Polydatin attenuates d-galactose-induced liver and brain damage through its anti-oxidative, anti-inflammatory and anti-apoptotic effects in mice.

Food Funct 2016 Nov;7(11):4545-4555

Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510120, P.R. China.

Accumulating evidence has shown that chronic injection of d-galactose (d-gal) can mimic natural aging, with accompanying liver and brain injury. Oxidative stress and apoptosis play a vital role in the aging process. In this study, the antioxidant ability of polydatin (PD) was investigated using four established in vitro systems. An in vivo study was also conducted to investigate the possible protective effect of PD on d-gal-induced liver and brain damage. The results showed that PD had remarkable in vitro free radical scavenging activity on 2,2-diphenyl-1-picryl-hydrazyl (DPPH˙), 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) (ABTS˙) radical ions, and hydroxyl and superoxide anions. Results in vivo indicated that, in a group treated with d-gal plus PD, PD remarkably decreased the depression of body weight and organ indexes, reduced the levels of the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and alleviated alterations in liver and brain histopathology. PD also significantly decreased the level of MDA and elevated SOD, GSH-Px, CAT activity and T-AOC levels in the liver and brain. In addition, the levels of inflammatory mediators, such as TNF-α, IL-1β and IL-6 in serum were markedly reduced after PD treatment. Western blotting results revealed that PD treatment noticeably attenuated the d-gal-induced elevation of Bcl-2/Bax ratio and caspase-3 protein expression in liver and brain. Overall, our findings indicate that PD treatment could effectively attenuate d-gal-induced liver and brain damage, and the mechanism might be associated with decreasing the oxidative stress, inflammation and apoptosis caused by d-gal. PD holds good potential for further development into a promising pharmaceutical candidate for the treatment of age-associated diseases.
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http://dx.doi.org/10.1039/c6fo01057aDOI Listing
November 2016

[Research Progress of circRNA and Its Significance in Forensic Science].

Fa Yi Xue Za Zhi 2016 Apr;32(2):131-3

RNA has received more attention in the field of forensic medicine and the development of the new biological markers based on RNA shows great significance in the analysis of complex cases. circular RNA (circRNA) is a kind of non-coding RNA which is widely reported recently. Although the regulatory mechanisms of generation and expression are not fully clear, the existing research indicates that circRNA has important biological functions. CircRNA has a cell-type-specific expression with great stability and a high expression level, which makes it meaningful in forensic applications potentially. In this paper, the research progress, the generation and regulation of circRNA as well as its biological characteristics and functions are summarized, which will provide references for related studies and forensic applications.
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April 2016

[Application of the Peak Area Ratio of STR Loci to Amelogenin Locus in the Estimation of DNA Degradation].

Fa Yi Xue Za Zhi 2016 Apr;32(2):105-8

Objective: To explore the change rules of peak area ratio of STR loci to Amelogenin (AMEL) locus (STR/AMEL), a sex-determining gene in DNA degradation, and to evaluate the application of STR/AMEL value in the estimation of DNA degradation degree.

Methods: DNA was extracted from iliopsoas, and the variations of STR/AMEL value (Penta E/AMEL, Penta D/AMEL, FGA/AMEL) were analyzed after the artificial degradation was made by DNase I, and the changes of these three ratios of the iliopsoas naturally degraded in an outdoor environment were also analyzed. The regression curves were analyzed using the periods of DNA degradation and outside the body as the independent variable (x) and the STR/AMEL value as the dependent variable (y) and three curve equations under two conditions were established.

Results: Both under the conditions of artificial and natural degradation, STR/AMEL value had a negative relationship with the degradation time. The relationship between STR/AMEL and degradation time can be well simulated by the cubic function. R2 was over 0.99 under controlled degradation condition and over 0.86 under natural degradation condition.

Conclusion: The STR/AMEL value (Penta E/AMEL, Penta D/AMEL, FGA/AMEL) is negatively related with the DNA degradation degree, which follows mathematical regression models strictly, and it might be applied to evaluate the DNA degradation degree.
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April 2016

Gartanin Protects Neurons against Glutamate-Induced Cell Death in HT22 Cells: Independence of Nrf-2 but Involvement of HO-1 and AMPK.

Neurochem Res 2016 Sep 9;41(9):2267-77. Epub 2016 May 9.

Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China.

Oxidative stress mediates the pathogenesis of neurodegenerative disorders. Gartanin, a natural xanthone of mangosteen, possesses multipharmacological activities. Herein, the neuroprotection capacity of gartanin against glutamate-induced damage in HT22 cells and its possible mechanism(s) were investigated for the first time. Glutamate resulted in cell death in a dose-dependent manner and supplementation of 1-10 µM gartanin prevented the detrimental effects of glutamate on cell survival. Additional investigations on the underlying mechanisms suggested that gartanin could effectively reduce glutamate-induced intracellular ROS generation and mitochondrial depolarization. We further found that gartanin induced HO-1 expression independent of nuclear factor erythroid-derived 2-like 2 (Nrf2). Subsequent studies revealed that the inhibitory effects of gartanin on glutamate-induced apoptosis were partially blocked by small interfering RNA-mediated knockdown of HO-1. Finally, the protein expression of phosphorylation of AMP-activated protein kinase (AMPK) and its downstream signal molecules, Sirtuin activator (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), increased after gartanin treatment. Taken together, these findings suggest gartanin is a potential neuroprotective agent against glutamate-induced oxidative injury partially through increasing Nrf-2-independed HO-1 and AMPK/SIRT1/PGC-1α signaling pathways.
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http://dx.doi.org/10.1007/s11064-016-1941-xDOI Listing
September 2016

Evaluation of safety of modified-Danggui Buxue Tang in rodents:immunological, toxicity and hormonal aspects.

J Ethnopharmacol 2016 May 28;183:59-70. Epub 2015 Dec 28.

Department of Orthopaedics, Dongguan Kanghua Hospital, Dongguan 523080, PR China. Electronic address:

Ethnopharmacological Relevance: Radix Astragali (RA), Radix Angelicae Sinensis (RAS) and Folium Epimedii (FE) are three of the extensively applied herbs among traditional Chinese medicines for gynecological disorders and osteoporosis. A derivative herbal formula-RRF, consisting of the three medicines with a weight ratio of 5:1:5, is derived from a famous Chinese herbal formula-Danggui Buxue Tang (DBT). RRF has shown noteworthy perimenopause ameliorating effect in both ovariectomized rats and natural aging female rats, which might represent a promising candidate for the treatment of perimenopausal disorders. The aim of this study was to evaluate its immunological potential, chronic toxicity and reproductive effects by 26-week repeated daily administration in female rats, in order to optimize its safe use.

Materials And Methods: The effect of RRF on immunological function was studied by macrophage phagocytosis, immune organ index, serum immunoglobulin level as well as delayed type hypersensitivity (DTH) in mice. For toxicity assessment, acute toxicity study was performed according to fixed dose procedure with a single oral administration of RRF to mice. In the oral chronic toxicity, 120 female rats were administrated RRF orally in 0, 1100, 4400, or 8800mg/kg/day doses for 26 weeks. Clinical signs, mortality, body weights, feed consumption, haemato-biochemical parameters, organ weights, histopathology and reproductive hormone profiles were examined at the end of the 13- and 26-week dosing period, as well as after the 4-week recovery period.

Results: Oral administration of RRF at three doses (282, 564 and 1128mg/kg) significantly increased the indices of phagocytosis K, as compared with prednisone acetate (PR) group (p<0.05 or 0.01). Exposure of RRF dose-dependently boosted circulating serum IgM level (all p<0.01) in response to CRBC in PR-induced mice. Furthermore, RRF treatment elicited a significant increment (all p<0.01) in DNFB-induced DTH response and the immune organ indices in a dose-dependent manner in mice, in parellel to DNFB-induced group. In the single dose acute toxicity and repeated dose 90-day chronic toxicity investigations, no toxic signs/mortality were observed. RRF treatment did not cause any toxicologically significant changes in clinical signs, food consumption, body weight, relative organ weight, hematological parameters, clinical chemistry, gross pathology and histopathology between treatment and control groups. No treatment related gross/histopathological lesions were observed and no target organ was identified. Long-term repeated administration of RRF exerted a significant promotion on serum level of steroid hormone estradiol, progesterone and testosterone release, along with decrease of circulating pituitary follicle stimulating hormone, luteinizing hormone, and prolactin levels in female rats. The No Observed Adverse Effect Level (NOAEL) of RRF was determined to be over 8800mg/kg/day for elderly female rats, a dose that was equivalent to 50 times of human dose.

Conclusion: The present investigation demonstrated that RRF possessed appreciable immunopotentiating activity and had a relatively wide margin of safety. Long-term treatment of RRF exhibited estrogenic properties, and retarded certain age-associated degenerations. RRF might have the potential for further development as a safe and effective alternative/complementary to conventional medication in relieving perimenopausal symptoms.
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http://dx.doi.org/10.1016/j.jep.2015.12.049DOI Listing
May 2016

The gastroprotective effect of pogostone from Pogostemonis Herba against indomethacin-induced gastric ulcer in rats.

Exp Biol Med (Maywood) 2016 Jan 19;241(2):193-204. Epub 2015 Aug 19.

The First Affiliated Hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510405, People's Republic of China.

Pogostemonis Herba, known as "Guang-Huo-Xiang" in Chinese, has been widely used in the treatment of gastrointestinal dysfunction. Pogostone is one of the major constituents of Pogostemonis Herba. The aim was to scientifically evaluate the possible gastroprotective effect and the underlying mechanisms of pogostone against indomethacin-induced gastric ulcer in rats. Rats were orally treated with vehicle, lansoprazole (30 mg/kg) or pogostone (10, 20 and 40 mg/kg) and subsequently exposed to acute gastric lesions induced by indomethacin. Gross evaluation, histological observation, gastric mucosal superoxide dismutase activity, glutathione content, catalase activity, malonaldehyde level and prostaglandin E2 production were performed. Immunohistochemistry and reverse transcription polymerase chain reaction for cyclooxygenase-1 and cyclooxygenase-2, as well as terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, immunohistochemistry for heat-shock protein 70, B-cell lymphoma-2 and Bax were conducted. Results indicated that rats pretreated with pogostone showed remarkable protection from the gastric mucosa damage compared to vehicle-treated rats based on the ulcer index and inhibition percentage. Histologically, oral administration of pogostone resulted in observable improvement of gastric injury, characterized by reduction of necrotic lesion, flattening of gastric mucosa and alleviation of submucosal edema with hemorrhage. Pogostone pretreatment significantly raised the depressed activities of superoxide dismutase, glutathione and catalase, while reduced the elevated malonaldehyde level compared with indomethacin-induced group. Pogostone-pretreated group induced a significant increase in gastric mucosal prostaglandin E2 level and obvious up-regulation of protein levels and mRNA expressions of cyclooxygenase-1 and cyclooxygenase-2. Furthermore, antiapoptotic effect of pogostone was verified by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, and the apoptotic process triggered by pogostone involved the up-expression of heat-shock protein70 and B-cell lymphoma-2 protein, and suppression of Bax protein expressions in the ulcerated tissues. It is speculated that the gastroprotective effect of pogostone against indomethacin-induced gastric ulceration might be associated with its stimulation of cyclooxygenase-mediated prostaglandin E2, antioxidant and antiapoptotic effect.
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http://dx.doi.org/10.1177/1535370215600099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935386PMC
January 2016

Andrographolide sodium bisulphite-induced inactivation of urease: inhibitory potency, kinetics and mechanism.

BMC Complement Altern Med 2015 Jul 16;15:238. Epub 2015 Jul 16.

Guangdong Provincial Key Laboratory of of New Chinese Medicinals Development and Research, Guangzhou University of Chinese Medicine, Guangzhou, 510006, P. R. China.

Background: The inhibitory effect of andrographolide sodium bisulphite (ASB) on jack bean urease (JBU) and Helicobacter pylori urease (HPU) was performed to elucidate the inhibitory potency, kinetics and mechanism of inhibition in 20 mM phosphate buffer, pH 7.0, 2 mM EDTA, 25 °C.

Methods: The ammonia formations, indicator of urease activity, were examined using modified spectrophotometric Berthelot (phenol-hypochlorite) method. The inhibitory effect of ASB was characterized with IC50 values. Lineweaver-Burk and Dixon plots for JBU inhibition of ASB was constructed from the kinetic data. SH-blocking reagents and competitive active site Ni2+ binding inhibitors were employed for mechanism study. Molecular docking technique was used to provide some information on binding conformations as well as confirm the inhibition mode.

Results: The IC50 of ASB against JBU and HPU was 3.28±0.13 mM and 3.17±0.34 mM, respectively. The inhibition proved to be competitive and concentration- dependent in a slow-binding progress. The rapid formation of initial ASB-JBU complex with an inhibition constant of Ki=2.86×10(-3) mM was followed by a slow isomerization into the final complex with an overall inhibition constant of Ki*=1.33×10(-4) mM. The protective experiment proved that the urease active site is involved in the binding of ASB. Thiol reagents (L-cysteine and dithiothreithol) strongly protect the enzyme from the loss of enzymatic activity, while boric acid and fluoride show weaker protection, indicating that the active-site sulfhydryl group of JBU was potentially involved in the blocking process. Moreover, inhibition of ASB proved to be reversible since ASB-inactivated JBU could be reactivated by dithiothreitol application. Molecular docking assay suggested that ASB made contacts with the important sulfhydryl group Cys-592 residue and restricted the mobility of the active-site flap.

Conclusions: ASB was a competitive inhibitor targeting thiol groups of urease in a slow-binding manner both reversibly and concentration-dependently, serving as a promising urease inhibitor for the treatment of urease-related diseases.
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http://dx.doi.org/10.1186/s12906-015-0775-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504079PMC
July 2015

Gastroprotective effect of andrographolide sodium bisulfite against indomethacin-induced gastric ulceration in rats.

Int Immunopharmacol 2015 Jun 24;26(2):384-91. Epub 2015 Apr 24.

School of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China; Dongguan Mathematical Engineering Academy of Chinese Medicine, Guangzhou University of Chinese Medicine, Dongguan 523808, PR China. Electronic address:

Andrographolide sodium bisulfite (ASB), a water-soluble sulfonate of andrographolide has been shown to possess anti-inflammatory, antipyretic and analgesic activities. However, there is no report on the gastroprotective effect of ASB against indomethacin-induced gastric ulcer. Here we investigated the possible anti-ulcerogenic potential of ASB and the underlying mechanism against indomethacin-induced gastric ulcer in rats. The ulcer area, histopathological assessment, contents of gastric mucosal glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), malonaldehyde (MDA) and prostaglandin E2 (PGE2) were examined. In addition, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) mRNA expression and immunohistochemical evaluation of HSP70, Bcl-2 and Bax proteins were also investigated. Results indicated that ASB pre-treatment significantly reduced the ulcer areas induced by indomethacin compared with the vehicle group. The gastric levels of GSH, CAT and SOD were markedly increased by ASB while the level of MDA was decreased. In addition, ASB pretreatment significantly promoted the gastric PGE2 levels and up-regulated the COX-1 and COX-2 mRNA expression in comparison with the vehicle group. Immunohistochemistry analysis showed obvious up-regulation of HSP70 and Bcl-2 protein expression while suppression of Bax protein in the gastric tissue of ASB-pretreated group. Taken together, these findings indicated that the gastroprotective effect of ASB might be associated with the improvement of antioxidative status, activation of COX-mediated PGE2 synthesis, down-regulation of Bax proteins and up-regulation of Bcl-2 and HSP70 proteins. ASB might have the potential for further development as a promising alternative for antiulcer treatment.
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http://dx.doi.org/10.1016/j.intimp.2015.04.025DOI Listing
June 2015

Novel patchouli alcohol ternary solid dispersion pellets prepared by poloxamers.

Iran J Pharm Res 2015 ;14(1):15-26

School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.

The present study investigates the possibility of using poloxamers as solubility and dissolution rate enhancing agents of poorly water soluble bioactive constituent patchouli alcohol (PA) that can be used for the preparation of immediate release pellets formulation. Two commercially available grades poloxamer 188 (P 188) and poloxamer 407 (P 407) were selected, and solid dispersions (SDs) containing different weight ratio of PA and poloxamers, and the combination of P 188 and P 407 as dispersing carriers of ternary solid dispersions (tSDs) were prepared by a low temperature melting method and solidified rapidly by dropping into the 10-15 °C condensing agent atoleine. Both PA/P 188 and PA/P 407 binary solid dispersions (bSDs) could remarkably promote the dissolution rate of PA, increasing approximately 16 times in bSDs with poloxamers in comparison with pure PA within 180 min. P188 contributed to a faster dissolution rate than P 407, however, P 407 had a better solubility. It is interesting to note that the incorporation of P 188 in PA/P 407 bSD pellets could strongly enhance the dissolution rate of PA. DSC and FTIR were used to explore the characteristics of PA-SD pellets. The enhancement of dissolution from the SDs may be attributed partly to the reduction in particle size in PA crystalline due to the formation of eutectic system with poloxamers. Moreover, a simple, accurate in-vitro dissolution test method for volatility drug was established, and the process of PA-SD pellets preparation was simple, rapid, cost effective, uncomplicated and potentially scalable.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277615PMC
January 2015

Biological evaluation and molecular docking of baicalin and scutellarin as Helicobacter pylori urease inhibitors.

J Ethnopharmacol 2015 Mar 31;162:69-78. Epub 2014 Dec 31.

College of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, P.R. China. Electronic address:

Ethnopharmacological Relevance: Baicalin and scutellarin are the principal bioactive components of Scutellaria baicalensis Georgi which has extensively been incorporated into heat-clearing and detoxification formulas for the treatment of Helicobacter pylori-related gastrointestinal disorders in traditional Chinese medicine. However, the mechanism of action remained to be defined.

Aim Of The Study: To explore the inhibitory effect, kinetics and mechanism of Helicobacter pylori urease (the vital pathogenetic factor for Helicobacter pylori infection) inhibition by baicalin and scutellarin, for their therapeutic potential.

Materials And Methods: The ammonia formations, indicator of urease activity, were examined using modified spectrophotometric Berthelot (phenol-hypochlorite) method. The inhibitory effect of baicalin and scutellarin was characterized with IC50 values, compared to acetohydroxamic acid (AHA), a well known Helicobacter pylori urease inhibitor. Lineweaver-Burk and Dixon plots for the Helicobacter pylori urease inhibition of baicalin and scutellarin was constructed from the kinetic data. SH-blocking reagents and competitive active site Ni(2+) binding inhibitors were employed for mechanism study. Molecular docking technique was used to provide some information on binding conformations as well as confirm the inhibition mode. Moreover, cytotoxicity experiment using Gastric Epithelial Cells (GES-1) was evaluated.

Results: Baicalin and scutellarin effectively suppressed Helicobacter pylori urease in dose-dependent and time-independent manner with IC50 of 0.82±0.07 mM and 0.47±0.04 mM, respectively, compared to AHA (IC50=0.14±0.05 mM). Structure-activity relationship disclosed 4'-hydroxyl gave flavones an advantage to binding with Helicobacter pylori urease. Kinetic analysis revealed that the types of inhibition were non-competitive and reversible with inhibition constant Ki of 0.14±0.01 mM and 0.18±0.02 mM for baicalin and scutellarin, respectively. The mechanism of urease inhibition was considered to be blockage of the SH groups of Helicobacter pylori urease, since thiol reagents (L,D-dithiothreitol, L-cysteine and glutathione) abolished the inhibitory action and competitive active site Ni(2+) binding inhibitors (boric acid and sodium fluoride) carried invalid effect. Molecular docking study further supported the structure-activity analysis and indicated that baicalin and scutellarin interacted with the key residues Cys321 located on the mobile flap through S-H·π interaction, but did not interact with active site Ni(2+). Moreover, Baicalin (at 0.59-1.05 mM concentrations) and scutellarin (at 0.23-0.71 mM concentrations) did not exhibit significant cytotoxicity to GES-1.

Conclusions: Baicalin and scutellarin were non-competitive inhibitors targeting sulfhydryl groups especially Cys321 around the active site of Helicobacter pylori urease, representing potential to be good candidate for future research as urease inhibitor for treatment of Helicobacter pylori infection. Furthermore, our work gave additional scientific support to the use of Scutellaria baicalensis in traditional Chinese medicine (TCM) to treat gastrointestinal disorders.
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http://dx.doi.org/10.1016/j.jep.2014.12.041DOI Listing
March 2015
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