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      Xiaochaihu Decoction attenuates the vicious circle between the oxidative stress and the ALP inactivation through LPS-catecholamines interactions in gut, liver and brain during CCI 4+ethanol-induced mouse HCC

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          Abstract

          Background

          Xiaochaihu Decoction (XCHD) prevents hepatocarcinogenesis in association with inhibition of oxidative stress. However, alkaline phosphatase (ALP) activity, lipopolysaccharides (LPS)-catecholamines (CA) interactions in gut, liver and brain may play an important role in the status of oxidative stress. This study was to assess whether XCHD attenuates the vicious circle between oxidative stress and ALP inactivation through LPS-CA interactions.

          Methods

          Hepatocellular carcinoma group (HCC) were induced by CCI 4 + ethanol; HCC with Liver Depression and Spleen Deficiency (HCC + LDSD) were induced by squeezing tails (30 min/day), solitary breeding and intermittent fasting on the basis of HCC; XCHD was administered after 4 weeks of the HCC + LDSD. The degree of tissue injury were studied using a scoring system, and brain weights were measured. Peroxynitrite (ONOO ), malondialdehyde (MDA), 4-hydroxy-3-methoxymandelic acid (VMA, CA metabolites), lipopolysaccharide-phosphate (LPS-P), ALP activity (ALP-A) and Concanavalin A (ConA)-binding rate of ALP (ALP-C) were determined by colorimetric method and lectin (ConA) affinity precipitation method.

          Results

          More injuries and ONOO , MDA, VMA, LPS-P, ALP-C were increased, ALP-A were decreased in the gut, liver and brain of HCC group, the most in HCC + LDSD group, after treatment with XCHD, all of which were improved. A positive association found between gut-liver-brain injury and ONOO , MDA, VMA, LPS-P, ALP-C, between ONOO , MDA, VMA, LPS-P and ALP-C in the gut, liver and brain, and a negative association found between gut-liver-brain injury and ALP-A, between ALP-A and ONOO , MDA, VMA, LPS-P, ALP-C in the gut, liver and brain.

          Conclusions

          XCHD can attenuates the vicious circle between the oxidative stress, nitrosative stress, N-glycan deficiency and inactivation of ALP through LPS-CA interactions in gut, liver and brain.

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          Most cited references31

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          Endotoxin accumulation prevents carcinogen-induced apoptosis and promotes liver tumorigenesis in rodents.

          Increasing evidence suggests that the presence of endotoxemia is of substantial clinical relevance to patients with cirrhosis, but it is unclear whether and how gut-derived LPS amplifies the tumorigenic response of the liver. We found that the circulating levels of LPS were elevated in animal models of carcinogen-induced hepatocarcinogenesis. Reduction of LPS using antibiotics regimen in rats or genetic ablation of its receptor Toll-like receptor 4 (TLR4) in mice prevented excessive tumor growth and multiplicity. Additional investigation revealed that TLR4 ablation sensitizes the liver to carcinogen-induced toxicity via blocking NF-κB activation and sensitizing the liver to reactive oxygen species (ROS)-induced toxicity, but lessens inflammation-mediated compensatory proliferation. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored diethylnitrosamine (DEN)-induced hepatic inflammation and proliferation, indicating a paracrine mechanism of LPS in tumor promotion. Meanwhile, deletion of gut-derived endotoxin suppressed DEN-induced cytokine production and compensatory proliferation, whereas in vivo LPS pre-challenge promotes hepatocyte proliferation. Our data indicate that sustained LPS accumulation represents a pathological mediator of inflammation-associated hepatocellular carcinoma (HCC) and manipulation of the gut flora to prevent pathogenic bacterial translocation and endotoxin absorption may favorably influence liver function in patients with cirrhosis who are at risk of developing HCC.
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            Removal of phosphate from lipid A as a strategy to detoxify lipopolysaccharide.

            Lipopolysaccharide (LPS) may cause sepsis when it enters the blood circulation. The toxic moiety of LPS is the well-preserved lipid A part. Lipid A contains two phosphate groups attached to diglucosamine, which are crucial for the many biological activities of LPS. In previous studies we found that alkaline phosphatase (AP) was able to dephosphorylate LPS. To test whether LPS-dephosphorylation can be used for intervention during sepsis, we investigated the effects of Salmonella minnesota Re 595 LPS and its dephosphorylated counterpart monophosphoryl lipid A (MPLA) on macrophage activation in vivo and in vitro. Exposure of RAW264.7 cells to LPS induced high levels of tumor necrosis factor (TNFalpha) and nitric oxide (NO), whereas MPLA elicited no response. LPS in vivo induced a significant rise in TNFalpha levels in mice and an enhanced inflammatory cell influx in the lung, whereas MPLA did not. Having shown the relevance of this particular phosphate group of LPS, we subsequently explored the LPS-dephosphorylating ability of AP in different tissues, and the effect of AP administration in mice challenged with LPS. Histochemical data show that AP dephosphorylated native LPS in all tissues examined, whereas MPLA was not dephosphorylated. When mice received AP immediately after the LPS challenge, the survival rate was 100%, over 57% in the control group. We conclude that the enzymatic removal of phosphate groups from LPS by AP represents a crucial detoxification reaction, which may provide a new strategy to treat LPS-induced diseases like sepsis.
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              Prospective study of chemoprevention of hepatocellular carcinoma with Sho-saiko-to (TJ-9).

              Most hepatocellular carcinomas (HCC) arise in patients with cirrhosis, in whom its incidence is high. The prevention of HCC in patients with cirrhosis is important. A prospective, randomized, nonblind controlled study was performed to evaluate the preventive effect of Sho-saiko-to (TJ-9) on HCC development. TJ-9 is a Chinese herbal medicine that contains crude extracts of seven herbs; it has antitumor effects in experimental animals. Two hundred sixty patients with cirrhosis were randomly assigned to two groups, matched for age, sex, presence of hepatitis B surface antigen, and the severity of liver damage. The patients in the trial group were given TJ-9 at a daily oral dose of 7.5 g in addition to the conventional drugs given to the control patients. The patients were prospectively monitored for 60 months and the cumulative incidence of HCC and the survival rate in the two groups were calculated. The cumulative incidence curve for 5 years of the trial group was lower than that of the control group (P = 0.071). For the patients without HBs antigen, the difference was significant (P = 0.024). The survival curve for 5 years of the trial group was higher than that of the control group (P = 0.053). For the patients without HBs antigen, the difference was significant (P = 0.043). TJ-9 helped to prevent the development of HCC in patients with cirrhosis, particularly in patients without HBs antigen.
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                Author and article information

                Journal
                BMC Complement Altern Med
                BMC Complement Altern Med
                BMC Complementary and Alternative Medicine
                BioMed Central
                1472-6882
                2013
                28 December 2013
                : 13
                : 375
                Affiliations
                [1 ]Piwei Research Institutes, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong, China
                [2 ]The Fourth People’s Hospital, Zhanjiang 524008, Guangdong, China
                Article
                1472-6882-13-375
                10.1186/1472-6882-13-375
                3884004
                24373196
                897cc036-fca4-4b13-bf9a-87640e523d61
                Copyright © 2013 liu et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 April 2013
                : 13 November 2013
                Categories
                Research Article

                Complementary & Alternative medicine
                liver depression and spleen deficiency (ldsd),oxidative stress,lipopolysaccharid,catecholamines,xiaochaihu decoction (xchd),ethanol,cci4,hepatocellular carcinoma (hcc),nitrosative stress,alkaline phosphatase (alp)

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