Activation of AhR-NQO1 Signaling Pathway Protects Against Alcohol-Induced Liver Injury by Improving Redox Balance.

BACKGROUND & AIMS: Aryl hydrocarbon receptor (AhR) is a liver-enriched xenobiotic receptor that plays important role in detoxification response in liver. This study aimed to investigate how AhR signaling may impact the pathogenesis of alcohol-related liver disease (ALD). METHODS: Chronic alcohol feeding animal studies were conducted with mouse models of hepatocyte-specific AhR knockout (AhRΔhep) and NAD(P)H quinone dehydrogenase 1 (NQO1) overexpression, and dietary supplementation of the AhR ligand indole-3-carbinol. Cell studies were conducted to define the causal role of AhR and NQO1 in regulation of redox balance and apoptosis. RESULTS: Chronic alcohol consumption induced AhR activation and nuclear enrichment of NQO1 in hepatocytes of both alcoholic hepatitis patients and ALD mice. AhR deficiency exacerbated alcohol-induced liver injury, along with reduction of NQO1. Consistently, in vitro studies demonstrated that NQO1 expression was dependent on AhR. However, alcohol-induced NQO1 nuclear translocation was triggered by decreased cellular oxidized nicotinamide adenine dinucleotide (NAD+)-to-NADH ratio, rather than by AhR activation. Furthermore, both in vitro and in vivo overexpression NQO1 prevented alcohol-induced hepatic NAD+ depletion, thereby enhancing activities of NAD+-dependent enzymes and reversing alcohol-induced liver injury. In addition, therapeutic targeting of AhR in the liver with dietary indole-3-carbinol supplementation efficiently reversed alcoholic liver injury by AhR-NQO1 signaling activation. CONCLUSIONS: This study demonstrated that AhR activation is a protective response to counteract alcohol-induced hepatic NAD+ depletion through induction of NQO1, and targeting the hepatic AhR-NQO1 pathway may serve as a novel therapeutic approach for ALD.

The Treatment of Rhodiola Mimics Exercise to Resist High-Fat Diet-Induced Muscle Dysfunction via Sirtuin1-Dependent Mechanisms.

Muscle dysfunction is a complication of high-fat diet (HFD)-induced obesity that could be prevented by exercise, but patients did not get enough therapeutic efficacy from exercise due to multiple reasons. To explore alternative or supplementary approaches to prevent or treat muscle dysfunction in individuals with obesity, we investigated the effects of Rhodiola on muscle dysfunction as exercise pills. SIRT1 might suppress atrogenes expression and improve mitochondrial quality control, which could be a therapeutic target stimulated by exercise and Rhodiola, but further mechanisms remain unclear. We verified the lipid metabolism disorders and skeletal muscle dysfunction in HFD feeding mice. Moreover, exercise and Rhodiola were used to intervene mice with a HFD. Our results showed that exercise and Rhodiola prevented muscle atrophy and dysfunction in obese mice and activating the SIRT1 pathway, while atrogenes were suppressed and mitochondrial quality control was improved. EX-527, SIRT1 inhibitor, was used to validate the essential role of SIRT1 in salidroside benefit. Results of cell culture experiment showed that salidroside alleviated high palmitate-induced atrophy and mitochondrial quality control impairments, but these improvements of salidroside were inhibited by EX-527 in C2C12 myotubes. Overall, Rhodiola mimics exercise that activates SIRT1 signaling leading to improvement of HFD-induced muscle dysfunction.

Unconventional Antiferromagnetic Quantum Critical Point in Ba(Fe_{0.97}Cr_{0.03})_{2}(As_{1-x}P_{x})_{2}.

We have systematically studied physical properties of Ba(Fe_{0.97}Cr_{0.03})_{2}(As_{1-x}P_{x})_{2}, where superconductivity in BaFe_{2}(As_{1-x}P_{x})_{2} is fully suppressed by just 3% of Cr substitution of Fe. A quantum critical point is revealed at x∼0.42, where non-Fermi-liquid behaviors similar to those in BaFe_{2}(As_{1-x}P_{x})_{2} are observed. Neutron diffraction and inelastic neutron scattering measurements suggest that the quantum critical point is associated with the antiferromagnetic order, which is not of conventional spin-density-wave type as evidenced by the ω/T scaling of spin excitations. On the other hand, no divergence of low-temperature nematic susceptibility is observed when x is decreased to 0.42 from higher doping level, demonstrating that there are no nematic quantum critical fluctuations. Our results suggest that non-Fermi-liquid behaviors in iron-based superconductors can be solely resulted from the antiferromagnetic quantum critical fluctuations, which cast doubts on the role of nematic fluctuations played in the normal-state properties in iron-based superconductors.

Mitochondria-targeted ubiquinone (MitoQ) enhances acetaldehyde clearance by reversing alcohol-induced posttranslational modification of aldehyde dehydrogenase 2: A molecular mechanism of protection against alcoholic liver disease.

Alcohol metabolism in the liver generates highly toxic acetaldehyde. Breakdown of acetaldehyde by aldehyde dehydrogenase 2 (ALDH2) in the mitochondria consumes NAD+ and generates reactive oxygen/nitrogen species, which represents a fundamental mechanism in the pathogenesis of alcoholic liver disease (ALD). A mitochondria-targeted lipophilic ubiquinone (MitoQ) has been shown to confer greater protection against oxidative damage in the mitochondria compared to untargeted antioxidants. The present study aimed to investigate if MitoQ could preserve mitochondrial ALDH2 activity and speed up acetaldehyde clearance, thereby protects against ALD. Male C57BL/6J mice were exposed to alcohol for 8 weeks with MitoQ supplementation (5mg/kg/d) for the last 4 weeks. MitoQ ameliorated alcohol-induced oxidative/nitrosative stress and glutathione deficiency. It also reversed alcohol-reduced hepatic ALDH activity and accelerated acetaldehyde clearance through modulating ALDH2 cysteine S-nitrosylation, tyrosine nitration and 4-hydroxynonenol adducts formation. MitoQ ameliorated nitric oxide (NO) donor-mediated ADLH2 S-nitrosylation and nitration in Hepa-1c1c7 cells under glutathion depletion condition. In addition, alcohol-increased circulating acetaldehyde levels were accompanied by reduced intestinal ALDH activity and impaired intestinal barrier. In accordance, MitoQ reversed alcohol-increased plasma endotoxin levels and hepatic toll-like receptor 4 (TLR4)-NF-κB signaling along with subsequent inhibition of inflammatory cell infiltration. MitoQ also reversed alcohol-induced hepatic lipid accumulation through enhancing fatty acid ß-oxidation. Alcohol-induced ER stress and apoptotic cell death signaling were reversed by MitoQ. This study demonstrated that speeding up acetaldehyde clearance by preserving ALDH2 activity critically mediates the beneficial effect of MitoQ on alcohol-induced pathogenesis at the gut-liver axis.

Exercise Combined with Rhodiola sacra Supplementation Improves Exercise Capacity and Ameliorates Exhaustive Exercise-Induced Muscle Damage through Enhancement of Mitochondrial Quality Control.

Mounting evidence has firmly established that increased exercise capacity (EC) is associated with considerable improvements in the survival of patients with cardiovascular disease (CVD) and that antistress capacity is a prognostic predictor of adverse cardiovascular events in patients with CVD. Previous studies have indicated that aerobic exercise (AE) and supplementation with Rhodiola sacra (RS), a natural plant pharmaceutical, improve EC and enable resistance to stress; however, the underlying mechanism remains unclear. This study explored the ability of AE and RS, alone or combined, to improve EC and ameliorate exhaustive exercise- (EE-) induced stress and elucidate the mechanism involved. We found that AE and RS significantly increased EC in mice and ameliorated EE-induced stress damage in skeletal and cardiac muscles (SCM); furthermore, a synergistic effect was detected for the first time. To our knowledge, the present work is the first to report that AE and RS activate mitophagy, mitochondrial dynamics, and biogenesis in SCM, both in the resting state and after EE. These data indicate that AE and RS synergistically improve EC in mice and protect SCM from EE-induced stress by enhancing mitochondrial quality control, including the activation of mitophagy, mitochondrial dynamics, and biogenesis, both at rest and after EE.

Dietary Fisetin Supplementation Protects Against Alcohol-Induced Liver Injury in Mice.

BACKGROUND: Overproduction of reactive oxygen species is associated with the development of alcoholic liver disease (ALD). Plant polyphenols have been used as dietary interventions for multiple diseases including ALD. The objective of this study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury. METHODS: C57BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol (EtOH) diet for 4 weeks with or without fisetin supplementation at 10 mg/kg/d. RESULTS: Alcohol feeding induced lipid accumulation in the liver and increased plasma alanine aminotransferase and aspartate aminotransferase activities, which were attenuated by fisetin supplementation. The EtOH concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin supplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal levels after alcohol exposure. Alcohol-induced apoptosis and up-regulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin supplementation attenuated alcohol-induced hepatic steatosis through increasing plasma adiponectin levels and hepatic protein levels of p-AMPK, ACOX1, CYP4A, and MTTP. CONCLUSIONS: This study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating EtOH clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD.

Modulation of Intestinal Barrier and Bacterial Endotoxin Production Contributes to the Beneficial Effect of Nicotinic Acid on Alcohol-Induced Endotoxemia and Hepatic Inflammation in Rats.

Alcohol consumption causes nicotinic acid deficiency. The present study was undertaken to determine whether dietary nicotinic acid supplementation provides beneficial effects on alcohol-induced endotoxin signaling and the possible mechanisms at the gut-liver axis. Male Sprague-Dawley rats were pair-fed the Lieber-DeCarli liquid diets containing ethanol or isocaloric maltose dextrin for eight weeks, with or without dietary supplementation with 750 mg/liter nicotinic acid. Chronic alcohol feeding elevated the plasma endotoxin level and activated hepatic endotoxin signaling cascade, which were attenuated by nicotinic acid supplementation. Alcohol consumption remarkably decreased the mRNA levels of claudin-1, claudin-5, and ZO-1 in the distal intestine, whereas nicotinic acid significantly up-regulated these genes. The concentrations of endotoxin, ethanol, and acetaldehyde in the intestinal contents were increased by alcohol exposure, and niacin supplementation reduced the intestinal endotoxin and acetaldehyde levels. Nicotinic acid supplementation upregulated the intestinal genes involved in aldehyde detoxification via transcriptional regulation. These results demonstrate that modulation of the intestinal barrier function and bacterial endotoxin production accounts for the inhibitory effects of nicotinic acid on alcohol-induced endotoxemia and hepatic inflammation.

Preventing Gut Leakiness and Endotoxemia Contributes to the Protective Effect of Zinc on Alcohol-Induced Steatohepatitis in Rats.

BACKGROUND: Zinc deficiency has been well documented in alcoholic liver disease. OBJECTIVE: This study was undertaken to determine whether dietary zinc supplementation provides beneficial effects in treating alcohol-induced gut leakiness and endotoxemia. METHODS: Male Sprague Dawley rats were divided into 3 groups and pair-fed (PF) Lieber-DeCarli liquid diet for 8 wk: 1) control (PF); 2) alcohol-fed (AF; 5.00-5.42% wt:vol ethanol); and 3) AF with zinc supplementation (AF/Zn) at 220 ppm zinc sulfate heptahydrate. The PF and AF/Zn groups were pair-fed with the AF group. Hepatic inflammation and endotoxin signaling were determined by immunofluorescence and quantitative polymerase chain reaction (qPCR). Alterations in intestinal tight junctions and aldehyde dehydrogenases were assessed by qPCR and Western blot analysis. RESULTS: The AF rats had greater macrophage activation and cytokine production (P < 0.05) in the liver compared with the PF rats, whereas the AF/Zn rats showed no significant differences (P > 0.05). Plasma endotoxin concentrations of the AF rats were 136% greater than those of the PF rats, whereas the AF/Zn rats did not differ from the PF rats. Ileal permeability was 255% greater in the AF rats and 19% greater in the AF/Zn rats than in the PF rats. The AF group had reduced intestinal claudin-1, occludin, and zona occludens-1 (ZO-1) expression, and the AF/Zn group had upregulated claudin-1 and ZO-1 expression (P < 0.05) compared with the PF group. The intestinal epithelial expression and activity of aldehyde dehydrogenases were elevated (P < 0.05) in the AF/Zn rats compared with those of the AF rats. Furthermore, the ileal expression and function of hepatocyte nuclear factor 4α, which was impaired in the AF group, was significantly elevated in the AF/Zn group compared with the PF group. CONCLUSIONS: The results demonstrate that attenuating hepatic endotoxin signaling by preserving the intestinal barrier contributes to the protective effect of zinc on alcohol-induced steatohepatitis in rats.

Zinc deficiency mediates alcohol-induced apoptotic cell death in the liver of rats through activating ER and mitochondrial cell death pathways.

Hepatic zinc deficiency has been well documented in alcoholic patients, but the mechanisms by which zinc deficiency mediates cell death have not been well defined. The objectives of this study were to determine whether alcohol perturbs subcellular zinc homeostasis and how organelle zinc depletion may link with cell death pathways. Wistar rats were pair-fed with the Lieber-DeCarli control or ethanol diet for 5 mo. Chronic alcohol exposure significantly reduced zinc level in isolated hepatic endoplasmic reticulum (ER) and mitochondria. Among the detected zinc transporters, ER Zrt/Irt-like protein (ZIP)13 and mitochondrial ZIP8, which transport zinc from ER and mitochondria to cytosol, were significantly increased. Mitochondrial zinc transporter (ZnT) 4, which transports zinc from cytosol to mitochondria, was also increased. ER phosphorylated eukaryotic initiation factor 2α, activating transcription factor 4, and C/EBP homologous protein were significantly upregulated, and mitochondrial cytochrome c release and Bax insertion were detected in association with caspase-3 activation and apoptotic cell death. To define the role of zinc deficiency in ER and mitochondrial stress, H4IIEC3 cells were treated with 3 µM N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine for 6 h with or without supplementation with zinc or N-acetylcysteine (NAC). The results demonstrated that zinc deprivation induced caspase-3 activation and apoptosis in association with ER and mitochondria dysfunction, which were inhibited by zinc as low as 10 µM but not by 2 mM NAC. These results suggest that chronic ethanol exposure induced in ER and mitochondrial zinc deficiency might activate intrinsic cell death signaling pathway, which could not be effectively rescued by antioxidant treatment.

Astragaloside IV inhibits platelet-derived growth factor-BB-stimulated proliferation and migration of vascular smooth muscle cells via the inhibition of p38 MAPK signaling.

Astragaloside IV (AS-IV), the major active component extracted from Astragalus membranaceus, has been demonstrated to exhibit protective effects on the cardiovascular, immune, digestive and nervous systems; thus, has been widely used in traditional Chinese medicine. Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) is closely associated with the initiation and progression of cardiovascular diseases, including atherosclerosis and restenosis. However, the effects of AS-IV on VSMCs remain unknown. For the first time, the present study demonstrated that AS-IV markedly suppressed platelet-derived growth factor (PDGF)-BB-stimulated cellular proliferation and migration of HDMEC-a human dermal VSMCs (HDVSMCs). Further investigation into the underlying molecular mechanisms demonstrated that the administration of AS-IV attenuated the PDGF-BB-stimulated switch of HDVSMCs into a proliferative phenotype. Furthermore, AS-IV inhibited the PDGF-BB-induced expression of cell cycle-associated proteins, as well as the upregulation of matrix metalloproteinase (MMP)2, but not MMP9. In addition, AS-IV was shown to downregulate the activation of p38 mitogen-activated protein kinase (MAPK) signaling induced by PDGF-BB in HDVSMCs. Therefore, the observations of the present study indicate that AS-IV inhibits PDGF-BB-stimulated VSMC proliferation and migration, possibly by inhibiting the activation of the p38 MAPK signaling pathway. Thus, AS-IV may be useful for the treatment of vascular diseases.

Dietary nicotinic acid supplementation ameliorates chronic alcohol-induced fatty liver in rats.

BACKGROUND: Alcohol abuse frequently causes niacin deficiency in association with the development of alcoholic liver disease. The objective of the present study was to determine whether dietary nicotinic acid (NA) deficiency exaggerates and whether dietary NA supplementation alleviates alcohol-induced fatty liver. METHODS: Male Sprague-Dawley rats were pair-fed with 4 isocaloric liquid diets: control, ethanol (EtOH), EtOH with dietary NA deficiency, and EtOH with dietary NA supplementation, respectively, for 8 weeks. The control and EtOH diets contained normal levels of NA (7.5 mg/l). Dietary NA deficiency (0 mg NA/l) was achieved by removing NA from the vitamin mix, while NA was added to the liquid diet at 750 mg/l for dietary NA supplementation. RESULTS: Chronic EtOH feeding induced significant lipid accumulation in the liver, which was not worsened by dietary NA deficiency, but was ameliorated by dietary NA supplementation. Liver total NAD, NAD(+) , and NADH levels were remarkably higher in the NA supplemented group than the NA deficient or EtOH alone groups. Dietary NA supplementation to EtOH-fed rats increased the protein levels of hepatic cytochrome P450 4A1 (CYP4A1) and acyl-coenzyme A oxidase 1 without affecting their mRNA levels. Interestingly, we found dietary NA supplementation reduced the ubiquitination level of CYP4A1. In addition, hepatic fatty acid synthase expression was reduced, while the serum ß-hydroxybutyrate and adiponectin concentrations were significantly elevated by dietary NA supplementation. Moreover, dietary NA supplementation modulated EtOH-perturbed liver and serum metabolite profiles. CONCLUSIONS: These results demonstrate that alcoholic fatty liver was not exaggerated by dietary NA deficiency, but was ameliorated by dietary NA supplementation. Increased hepatic fatty acid oxidation and decreased hepatic de novo lipogenesis contribute to the effects of dietary NA supplementation.

Effect of Chinese traditional herb Epimedium grandiflorum C. Morren and its extract Icariin on osteoarthritis via suppressing NF-kappaB pathway.

Osteoarthritis (OA), which is also called degenerative arthritis, is the leading cause of disabilities in the old people. The Chinese traditional herb Epimedium grandiflorum had long been found to attenuate osteoarthritis process, but the detailed mechanism was not clear. To study the mechanisms of E. grandiflorum in the treatment of osteoarthritis, rabbit osteoarthritis model combined with D-galactose was used. After different treatments for 10 weeks, cartilage sections were analyzed by immunohistochemistry for uPA, uPAR and PAI expression level. E. grandiflorum could significantly attenuate OA condition and decrease uPA, uPAR and PAI expression. The extract of E. grandiflorum, icariin also had a similar effect when compared with E. grandiflorum treatment alone. Rabbit chondrocytes were further isolated to be stimulated by TNFalpha combined with different reagents treatment. Here, icariin treatment significantly reduced nuclear factor kappa B NF-kappaB (P65) activity, decreased uPA expression level and increased Ikappabetaalpha protein level. The results indicated that E. grandiflorum and its extract icariin could attenuate OA condition, reduce the expression of uPA and uPAR and increase PAI in experimental rabbit model and this effect may be conducted by suppressing NF-kappaB activity by increasing IkappaBalpha level.

[Study of molecular mechanisms of fuyuan capsule, icariin and arasaponin R1 in treatment of osteoarthritis].

OBJECTIVE: To study the molecular mechanisms of Fuyuan capsule serum containing, icariin and arasaponin R1 in the treatment of osteoarthritis from the urokinase-type plasminogen activator (uPA) system. METHOD: Chondrocytes were isolated, cultured and identified using type II collagens immunostaining. After stimulating with TNF-alpha 10 microg x L(-1), 1 h, then the chondrocytes were treatment with glucosamine hydrochloride 25 g x L(-1), 20% Fuyuan capsule serum containing, icariin 12.5 mg x L(-1), arasaponin R1 125 mg x L(-1), icariin 12.5 mg x L(-1) + arasaponin R1 125 mg x L(-1). After 2 h, expression of uPA and nuclear factor kappa B (NF-kappaB P65) mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR), the activities of NF-kappaB(P65) combine DNA were determined by electrophoretic mobility shift assays (EMSA), 1kappaBalpha were detected by Western blotting. RESULT: Fuyuan capsule, icariin and arasaponin R1 could significantly reduce NF-kappaB (P65) activities and uPA mRNA expression, and increase expression of IkappaBalpha (P < 0.01), but no significant difference between all treatment groups. CONCLUSION: Fuyuan capsule and its two main active ingredients, icariin and arasaponin R1, could protect chondrocytes from damage through reducing the NF-kappaB (P65) activities, increasing the express of IkappaBalpha and then reducing uPA of chondrocytes.

[Effects of Erbie San on Walker-256 liver cancer and adjustment to unbalance of VEGF/endostatin in rats].

OBJECTIVE: To investigate the anticancer effects of Erbie San on the rats bearing Walker-256 liver cancer and the potential mechanism of its angiogenesis effects. METHOD: Wistar rats bearing Walker-256 liver cancer were used in this study. The experimental groups were treated with Erbie San 1.25, 2.5, 5 g x kg(-1) x d(-1), and 5-Fluorouracil injection 75 mg x kg(-1), respectively. The tumor's weight, the expression of VEGF, Endostatin and the ratio of VEGF/endostatin in serum of each groups were observed. RESULT: Compared to the model group, Erbie San 2.5, 5 g x kg(-1) x d (-1) and 5-Fluorouracil injection groups can reduce the tumor's weight significantly (P<0.05 or P<0.01). The expression of VEGF was reduced, while endostatin was increased, and the ratio of VEGF/endostatin was reduced (P<0.05 or P<0.01). CONCLUSION: Erbie San can effectively inhibit the growth of Walker-256 liver cancer of rats and can inhibit the expression of VEGF but increase the expression of endostatin, which suggest that Erbie San has the inhibition of angiogenesis which is responsible for its anticancer effects.

[Effects of electroacupuncture on tumor growth and immune function in the Walker-256 model rat].

OBJECTIVE: To study the effect of acupuncture on tumor and its mechanism. METHODS: Liver cancer, gastric cancer and hypodermic tumor rat models were made by implantation of replicated Walker-256 cell strain. The 3 model rats were respectively divided into two groups at random, a model control group and an electroacupuncture group. The electroacupuncture groups were treated with electroacupuncture (EA) at "Zusanli" (ST 36), "Hegu" (LI 4) and "San-yinjiao" (SP 6), once each day, 15 min one session, for 15 days. The gross tumor volume and the tumor inhibitory rate, and the levels of humoral immunity index, including serum 1gG, IgM, IgA and C3, C4, and the levels of cellular immunity index, including CD4+, CD8+ and CD4+/CD8+ in the peripheral blood in each group were detected. RESULTS: The gross tumor volumes in the EA groups were significantly smaller than those in the model control group (P<0.01). The contents of IgG, IgM and C3 in the EA groups increased significantly compared with those in the model control group (P<0.05 or P<0.01). The contents of IgA and C4 in the EA groups did not significantly change (P>0.05). The content of CD4+ and CD4+/CD8+ in the EA groups are significantly higher than those in the model control group (P<0.05 or P<0.01). CONCLUSION: Acupuncture at "Zusanli" (ST 36), "Hegu" (LI 4) and "Sanyinjiao" (SP 6) can increase immune function and inhibit tumor growth in Walker-256 liver cancer, gastric cancer and hypodermic tumor rats.

[Preliminary analysis on the significance of the new edition of pharmacology of Chinese Materia Medica in guiding theoretical research and clinical practice of integrated Chinese and Western medicine].

The new edition of Pharmacology of Chinese Materia Medica has broken through the previous mode of the teaching materials, it classified traditional Chinese drugs distinctly into three categories--the drugs for radical cure depending on syndrome differentiation, the drugs for etiological treatment aimed at pathogenesis, and the drugs for symptomatic treatment, and introduced some new concepts about integrated Chinese and Western medicine, showing active significance in guiding the theoretical research and clinical practice of integrated traditional Chinese and Western medicine.