Exploring the pharmacological and adverse reaction mechanism of a drug by network pharmacology strategy: Using colchicine to treat Behcet syndrome as an example.

Colchicine (COLC) is a natural alkaloid used to treat Behcet syndrome (BS), but its adverse reactions limit its clinical application in treating BS. However, the adverse reaction mechanism of COLC in the treatment of BS remains unclear. Herein, a network pharmacology-based strategy was designed to analyze the pharmacological and adverse reaction mechanism of COLC in treating BS. The biological functions of COLC and BS pathogenesis were analyzed through a series of network construction and analysis. The data above predicted the pharmacological and adverse reaction mechanism of COLC in BS treatment. The pharmacological mechanism of COLC against BS was predicted to control inflammatory responses. Interleukin-8, interleukin-18, integrin alpha-4, integrin beta-2, and tubulin targets are crucial in treating BS. The adverse reactions of COLC in BS treatment were predicted as neurotoxicity and hepatotoxicity. The mechanism of hepatotoxicity may be related to the decrease of cytochrome P450 family 3 subfamily A activity caused by various factors, such as poor hepatic function, the dosage of COLC, and combination with inhibitors. The mechanism of neurotoxicity may be related to the disruption of microtubules in the nervous system by COLC transport across the blood-brain barrier. This study provided basic evidence for the medication safety management of COLC used in treating BS. Moreover, this study demonstrated that it is feasible to analyze the adverse reaction mechanisms of drugs using a network pharmacology strategy, which facilitates systematic drug safety management and evaluation.

Extract of Jasminum grandiflorum L. alleviates CCl4-induced liver injury by decreasing inflammation, oxidative stress and hepatic CYP2E1 expression in mice.

Jasminum grandiflorum L. (JG) is a medicinal plant containing many bioactive ingredients. Herein, we analyzed the effects of four different extracts and two compounds of JG on acute liver injury caused by carbon tetrachloride (CCl4) and underlying molecular mechanisms. 7 weeks old C57BL/6 male mice were used to establish a liver injury model by injecting with 1% CCl4, 10 mL/kg ip. Four different extracts and two compounds of JG were given to mice by gavage for 3 days. Clinical and histological chemistry assays were performed to assess liver injury. Moreover, hepatic oxidative stress and inflammation related markers were determined by immunohistochemistry and western blotting. As a result, JG extracts and two functional components showed different degree of protect effects against CCl4-induced liver injury by the decrease of elevated serum transaminases and liver index, and the attenuation of histopathological changes in mice, among which JG extracted with petroleum ether (PET) had the most significant effect. In addition, PET remarkably alleviated hepatic oxidative stress and inflammation. Further studies revealed that PET significantly inhibited the TNF-α expression, signal pathway expression, NF-κB p65 and inflammatory factors IL-1ß and IL-6 expression in CCl4-induced liver injury mice. Nevertheless, hydroxytyrosol (HT) alleviated liver injury by reducing oxidative stress. Apart from PET extract, other extracts of JG can inhibit cytochrome CYP2E1 expression to protect liver tissue. These findings suggest that the extracts and its components of JG possesses the potential protective effects against CCl4-induced liver injury in mice by exerting antioxidative stress and anti-inflammation.

Toxic hepatitis-associated aplastic anaemia after dual homeopathic remedies and Gymnema sylvestre use.

Hepatitis-associated aplastic anaemia (HAAA) is a rare condition characterised by onset of acute hepatitis which is followed by development of severe pancytopenia due to bone marrow failure within 6 months. This syndrome can be precipitated by acute viral infections, but the aetiology remains unknown in the majority. Drug-induced HAAA is extremely rare and has been reported with nutritional and dietary supplements in current literature. We report the first cases of ayurvedic herbal and homeopathic remedies-associated HAAA in two patients which proved fatal in both. Evaluation of patients with acute hepatitis and severe pancytopenia must include a detailed evaluation for complementary and alternative medicine use.

Hepatoprotective effect of Spirulina platensis against carbon tetrachloride-induced liver injury in male rats.

OBJECTIVES: Spirulina platensis (SP) is an edible Cyanobacterium with ethnomedicinal significance. This study aims at evaluating the beneficial effect of SP against carbon tetrachloride (CCl4)-induced liver toxicity in male rats. METHODS: Rats received intraperitoneal injections of CCl4 (2 ml/kg body weight [b.w.] per every other day) for 40 days, alone or in combination with oral treatments of SP (400 mg/kg b.w. per day). KEY FINDINGS: SP attenuated haematological disturbances, serum liver markers, hepatic necrosis and inflammation, and dyslipidemia in CCl4-intoxicated rats. SP also reduced CCl4-induced oxidative stress by increasing the activities of antioxidant enzymes, such as glutathione peroxidase, superoxide dismutase and catalase and glutathione content, and inhibiting lipid peroxidation products and nitric oxide levels in the rat liver. Further investigations revealed that SP counteracted CCl4-induced increased hepatic levels of Ki-67 (a parameter of cell proliferation), interleukin-6, and tumour necrosis factor-alpha and cyclooxygenase-2 messenger RNA expression. Noticeably, the supplementation of SP restored the decrease of proapoptotic p53 protein levels in the liver of rats treated with CCl4. CONCLUSIONS: SP prevented liver damage in CCl4-treated rats via augmentation of antioxidant defense mechanisms and inhibition of inflammatory cytokines/mediators and antiproliferative effects.

Drug-induced liver injury in Australia, 2009-2020: the increasing proportion of non-paracetamol cases linked with herbal and dietary supplements.

OBJECTIVE: To compare the characteristics and outcomes of drug-induced liver injury (DILI) caused by paracetamol and non-paracetamol medications, particularly herbal and dietary supplements. DESIGN: Retrospective electronic medical record data analysis. SETTING, PARTICIPANTS: Adults admitted with DILI to the Gastroenterology and Liver Centre at the Royal Prince Alfred Hospital, Sydney (a quaternary referral liver transplantation centre), 2009-2020. MAIN OUTCOME MEASURES: 90-day transplant-free survival; drugs implicated as causal agents in DILI. RESULTS: A total of 115 patients with paracetamol-related DILI and 69 with non-paracetamol DILI were admitted to our centre. The most frequently implicated non-paracetamol medications were antibiotics (19, 28%), herbal and dietary supplements (15, 22%), anti-tuberculosis medications (six, 9%), and anti-cancer medications (five, 7%). The number of non-paracetamol DILI admissions was similar across the study period, but the proportion linked with herbal and dietary supplements increased from 2 of 13 (15%) during 2009-11 to 9 of 19 (47%) during 2018-20 (linear trend: P = 0.011). Despite higher median baseline model for end-stage liver disease (MELD) scores, 90-day transplant-free survival for patients with paracetamol-related DILI was higher than for patients with non-paracetamol DILI (86%; 95% CI, 79-93% v 71%; 95% CI, 60-82%) and herbal and dietary supplement-related cases (59%; 95% CI, 34-85%). MELD score was an independent predictor of poorer 90-day transplant-free survival in both paracetamol-related (per point increase: adjusted hazard ratio [aHR], 1.19; 95% CI, 1.09-3.74) and non-paracetamol DILI (aHR, 1.24; 95% CI, 1.14-1.36). CONCLUSION: In our single centre study, the proportion of cases of people hospitalised with DILI linked with herbal and dietary supplements has increased since 2009. Ninety-day transplant-free survival for patients with non-paracetamol DILI, especially those with supplement-related DILI, is poorer than for those with paracetamol-related DILI.

Evaluation of drug-induced liver injury as etiology for acute liver failure in Brazil.

INTRODUCTION AND OBJECTIVES: Little is known about the etiology of acute liver failure (ALF) in Latin America. The objective of this paper is to investigate the main etiologies of ALF in Brazil, including Drug Induced Liver Injury (DILI) using stringent causality criteria. PATIENTS OR MATERIAL AND METHODS: All the cases of individuals who underwent liver transplantation (LT) in 12 centers in Brazil for ALF were reviewed. When DILI was stated as the cause of ALF, causality criteria were applied on site by the main investigator in order to rule out other etiologies. RESULTS: 325 individuals had ALF mainly for unknown reasons (34%), DILI (27%) and AIH (18%). Reassessment of the 89 cases of DILI, using stringent causality criteria, revealed that in only 42 subjects could DILI be confirmed as the cause of ALF. Acetaminophen (APAP) toxicity (n = 3) or DILI due to herbal and dietary supplements (HDS) (n = 2) were not commonly observed. CONCLUSIONS: Undetermined etiology and DILI are the main causes of ALF in Brazil. However, APAP toxicity and DILI due to HDS are mostly uncommon.

Iron loading exerts synergistic action via a different mechanistic pathway from that of acetaminophen-induced hepatic injury in mice.

Acetaminophen (APAP) overdose is a major cause of drug-induced acute liver failure. In such cases, free iron is released from lysosomes and is transported to mitochondria where it plays a pivotal role in APAP-induced liver injury. We previously reported that ascorbic acid (Asc) markedly mitigates APAP-induced hepatic damage in aldehyde reductase (Akr1a)-knockout (KO) mice that produce about 10% Asc as wild-type (WT) mice. However, the issue of the protective mechanism of Asc in association with the status of iron remains ambiguous. To gain additional insights into this issue, we examined effects of APAP (500 mg/kg) on female KO mice under conditions of iron loading. While the KO mice without AsA supplementation were more sensitive to APAP toxicity than the WT mice, FeSO4 loading (25 mg/kg) to WT mice aggravated the hepatic injury, which was a similar extent to that of the KO mice. Supplementation of Asc (1.5 mg/ml in the drinking water) ameliorated KO mice irrespective of iron status but did not change the iron-mediated increase in the lethality in the WT mice. Hepatic cysteine and glutathione levels declined to similar extents in all mouse groups at 3 h irrespective of the iron status and largely recovered at 18 h after the APAP treatment when liver damage was evident. Asc prominently mitigated APAP toxicity in KO mice irrespective of the iron status but had no effect on the synergistic action of iron and APAP in the WT mice, suggesting that the mechanism for the deteriorating action of loaded iron is different from that of APAP toxicity.

The landscape of hepatobiliary adverse reactions across 53 herbal and dietary supplements reveals immune-mediated injury as a common cause of hepatitis.

Recent evidence suggests herbal-induced liver injury (HILI) to account for 20% of cases among the U.S. Drug-Induced-Liver-Injury-Network. To define injury patterns of HILI, we reviewed the clinical data of 413 patients exposed to 53 HDS products by considering the evidence for HILI and its grades of severity. Outstandingly, females developed HILI more rapidly (p = 0.018) and the time to recovery was significantly increased (p = 0.0153). > 90% of reported cases were severe and half of HDS products caused acute liver failure (ALF) requiring liver transplantation or resulted in fatal outcomes. Liver biopsies of 243 patients defined 13 histological features; two-thirds of products elicited immune-mediated hepatitis and included 154 Hy's law positive cases. The histological injury patterns were confirmed among unrelated patients, while accidental re-challenges evidenced culprits as causative. Furthermore, one-fifth of patients presented elevated autoantibody titres indicative of autoimmune-like HILI, and one-third of the products were linked to chronic hepatitis and cholestatic injuries not resolving within 6 months. Lastly, INR and TBL are critical laboratory parameters to predict progression of severe HILI to ALF. Our study highlights the need for a regulatory framework to minimize the risk for HILI. Better education of the public and a physician-supervised self-medication plan will be important measures to abate risk of HILI.

Hepatoprotective Actions of Ascorbic Acid, Alpha Lipoic Acid and Silymarin or Their Combination Against Acetaminophen-Induced Hepatotoxicity in Rats.

Background and objectives: Ascorbic acid, alpha lipoic acid (ALA) and silymarin are well-known antioxidants that have hepatoprotective effects. This study aims to investigate the effects of these three compounds combined with attenuating drug-induced oxidative stress and cellular damage, taking acetaminophen (APAP)-induced toxicity in rats as a model both in vivo and in vitro. Materials and Methods: Freshly cultured primary rat hepatocytes were treated with ascorbic acid, ALA, silymarin and their combination, both with and without the addition of APAP to evaluate their in vitro impact on cell proliferation and mitochondrial activity. In vivo study was performed on rats supplemented with the test compounds or their combination for one week followed by two toxic doses of APAP. Results: Selected liver function tests and oxidative stress markers including superoxide dismutase (SOD), malondialdehyde (MDA) and oxidized glutathione (GSSG) were detected. The in vivo results showed that all three pretreatment compounds and their combination prevented elevation of SOD and GSSG serum levels indicating a diminished burden of oxidative stress. Moreover, ascorbic acid, ALA and silymarin in combination reduced serum levels of liver enzymes; however, silymarin markedly maintained levels of all parameters to normal ranges. Silymarin either alone or combined with ascorbic acid and ALA protected cultured rat hepatocytes and increased cellular metabolic activity. The subjected agents were capable of significantly inhibiting the presence of oxidative stress induced by APAP toxicity and the best result for protection was seen with the use of silymarin. Conclusions: The measured liver function tests may suggest an augmented hepatoprotection of the combination preparation than when compared individually.

Primary biliary cholangitis associated with drug-induced liver injury and alcoholic liver fibrosis: A case report.

RATIONALE: Primary biliary cholangitis (PBC) is a liver autoimmune disease. If this disease is associated with other liver injury factors, both misdiagnosis and missed diagnosis will easily occur. Therefore, detailed disease history collection and related laboratory examination should be performed on patients with liver injury for unidentified causes. When necessary, liver biopsy should be performed to confirm the histopathological diagnosis. PATIENT CONCERNS: The subject patient was a 63-year-old Chinese male with chronic liver injury who had a drinking history of about 30 years and drank 500 g daily on average and began to take health products and dietary supplements (multivitamins) since June 2014. DIAGNOSES: Drug-induced liver injury (DILI) and alcoholic fatty liver disease (AFLD) were initially considered because the patient had a history of using health products (HP) and dietary supplements (DS) and drinking alcohol. However, he was subsequently considered with PBC based on the findings of anti-mitochondrial antibody positivity and elevated immunoglobulin level. Obstructive jaundice and space-occupying lesion in the liver were excluded by imaging examinations. Liver biopsy was performed to confirm the reasons for liver injury. Histopathological examination was conducted, and the patient was diagnosed with PBC associated with DILI and alcoholic liver fibrosis. INTERVENTIONS: Ursodeoxycholic acid, glycyrrhizic acid, and methylprednisolone (small dose) were used to treat the patient. OUTCOMES: After 2 months, the serum levels of ALT, AST, AKP, GGT, and globulin returned to normal. After 4 months, the patient showed liver injury once again (an increase in ALT, AST, AKP, GGT and GLB) caused by repaglinide administration due to hyperglycemia. Ursodeoxycholic acid and methylprednisolone replaced the repaglinide administration. After 3 weeks, the levels of ALT, AST, AKP, GGT, and GLB returned to normal again. LESSONS: The correct knowledge on PBC and early-stage recognition and diagnosis should be emphasized. When other causes of the liver injury cannot be excluded, liver biopsy is suggested. Histopathological change can be used to further clarify the reasons for liver injury and the principal contradiction as well as to guide the theraputic regimen.

Anti-Inflammatory Effect of a Polyphenol-Enriched Fraction from Acalypha wilkesiana on Lipopolysaccharide-Stimulated RAW 264.7 Macrophages and Acetaminophen-Induced Liver Injury in Mice.

A polyphenol-enriched fraction (PEF) from Acalypha wilkesiana, whose leaves have been traditionally utilized for the treatment of diverse medical ailments, was investigated for the anti-inflammatory effect and molecular mechanisms by using lipopolysaccharide- (LPS-) stimulated RAW 264.7 macrophages and acetaminophen- (APAP-) induced liver injury mouse model. Results showed that PEF significantly attenuated LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production and suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in RAW 264.7 macrophages. PEF also reduced the secretion of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin- (IL-) 1ß, and IL-6 in LPS-stimulated RAW 264.7 macrophages. Moreover, PEF potently inhibited LPS-induced phosphorylation of mitogen-activated protein kinases (MAPKs) as well as the activation of nuclear factor-κB (NF-κB) by preventing the degradation of inhibitor κB-α (IκB-α). In vivo, PEF pretreatment ameliorated APAP-induced liver injury and hepatic inflammation, as presented by decreased hepatic damage indicators and proinflammatory factors at both plasma and gene levels. Additionally, PEF pretreatment remarkably diminished Toll-like receptor 3 (TLR3) and TLR4 expression and the subsequent MAPKs and NF-κB activation. HPLC analysis revealed that two predominantly polyphenolic compounds present in PEF were geraniin and corilagin. These results indicated that PEF has an anti-inflammatory effect, and its molecular mechanisms may be involved in the inactivation of the TLR/MAPK/NF-κB signaling pathway, suggesting the therapeutic potential of PEF for inflammatory diseases.

Acute liver injury following Garcinia cambogia weight-loss supplementation: case series and literature review.

Herbal weight-loss supplements are sold as self-medication products, and are often used under the misconception that their natural origin guarantees their safety. Food supplements are not required to provide any benefit/risk profile evaluation before marketing; however, possible risks associated with use of herbal extracts in food supplements are becoming more and more documented in the literature. Some herbs are listed as the leading cause of herb-induced liver injury, with a severe or potentially lethal clinical course, and unpredictable herb-drug interactions. Garcinia cambogia (GC) extract and GC-containing products are some of the most popular dietary supplements currently marketed for weight loss. Here, we present four cases of acute liver failure in women taking GC extract for weight loss, and a literature review of clinical evidences about hepatic toxicity in patients taking dietary supplements containing GC extract.

Flupirtine drug-induced liver injury in a patient developing acute liver failure.

A patient is admitted with complaints of recent onset nausea, discomfort, jaundice and blood tests that reveal severe hepatitis. At the time, she had been taking medication with Hypericum perforatum (St John's wort) for 6 months, and 6 weeks before this event, she took flupirtine maleate. A few days after being admitted, she developed encephalopathy progressing to acute liver failure (ALF) requiring unsuccessful liver transplantation. The patient was ultimately diagnosed with drug-induced liver injury (DILI). In this context, while H. perforatum could interfere with other medication or trigger DILI itself, flupirtine appears to have triggered the DILI, given its liver toxicity capacity. DILI is one of the major ALF causes and can jeopardise patient's life. Accordingly, all efforts to reduce medication potentially hazardous to the liver are recommended.

Case Report: Severe Hematological, Muscle and Liver Toxicity Caused by Drugs and Artichoke Infusion Interaction in an Elderly Polymedicated Patient.

BACKGROUND: Case report, in a patient with a history of diabetes and hypertension, treated with metformin, gliclazide, enalapril + hydrochlorothiazide, amlodipine, aspirin and diazepam, recently medicated for a gouty crisis with colchicine and clonixin without improvement. Believing it could help in the treatment of gouty crisis symptoms he took about 1.5 L of artichoke infusion (Cynara cardunculus). He felt better and did agriculture work but developed a distal muscle pain, severe anemia, standard biochemical liver cholestasis, increase of alkaline phosphatase and marked increase of inflammatory parameters (hyperleucocytosis) and enters in the emergency department at the hospital. OBJECTIVE: Evaluation of the cause of complaints and laboratory abnormalities and the involvement of artichoke infusion. RESULTS: The prominence of the inflammatory parameters was ruled out because of exhaustive autoimmune, infectious or para-neoplastic syndrome (blood cultures, serology, diagnostic imaging, bone marrow and bone biopsy, muscle biopsy and nerve, abdominal angiography) were carried out showing normal results. The evaluation pointed out that the concomitant intake of artichoke infusion may have been involved in the framework developed, since the drugs which were being administered to/by the patient have a metabolism mainly mediated by CYP450 3A4 and 2C9 that could be compromised when these isoenzymes are inhibited by phenolic and flavonoid compounds from plants. Colchicine was one of the last drugs took that have as side effects most of the symptoms felt by patient including diarrhea and anemia. CONCLUSION: The spontaneous and complete recovery of the patient and the negativity of research looking for other causes, conduce to a strong possibility of the interaction between artichoke and the drugs in the clinical presentation of this case.

Enfermedad venooclusiva hepática inducida por hierbas medicinales chinas / Hepatic veno-occlusive disease induced by Chinese medicinal herbs

No disponible

Antrodia Cinnamomea Reduces Carbon Tetrachloride-induced Hepatotoxicity In Male Wister Rats.

BACKGROUND/AIM: Antrodia cinnamomea is found with polysaccharides, lipids, vitamins, fibers and ash (minerals) and is well known in Taiwan as a traditional Chinese medicine. Its biological activities have been reported to have anti-inflammatory, anti-fatigue, anti-tumor and immunomodulatory effects, but its protective effects on liver function are still unclear. MATERIALS AND METHODS: We determined if Antrodia cinnamomea was hepatoprotective against carbon tetrachloride (CCl4) toxicity in Wistar rats. Six groups were used in the study: 1) control (no induction by CCl4); 2) negative control (CCl4-induction and no treatment); 3) positive control (silymarin treatment); 4) groups 4-6 were treated with CC14 and different concentrations (350 mg/kg, 1,400 mg/kg, 3,150 mg/kg) of Antrodia cinnamomea. Blood and liver samples of rats were harvested and then detected by biochemical and tissue histochemical analysis. Activity of the antioxidative enzymes glutathione peroxidase, superoxide dismutase and catalase in the liver were also monitored. RESULTS: Only the high-dose treatment was able to decrease serum glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels and improve liver function. High and medium doses increased total liver protein and reduced hydroxyproline. It was also observed that the high dose treatment reduced lipid peroxidation. Liver sections of CC14 treated animals receiving Antrodia cinnamomea showed less fibrosis compared to the CCl4 control group. CONCLUSION: This finding suggested that Antrodia cinnamomea can either enhance liver recovering from CCl4 damage or attenuate CCl4 toxicity in rats.

Curcumin and Curcuma longa L. extract ameliorate lipid accumulation through the regulation of the endoplasmic reticulum redox and ER stress.

For this study, we examined the effects of curcumin against acute and chronic stress, paying specific attention to ROS. We also aimed to clarify the differences between acute and chronic stress conditions. We investigated the effects of curcumin against acute stress (once/1 day CCl4 treatment) and chronic-stress (every other day/4week CCl4 treatment). Compared with acute stress, in which the antioxidant system functioned properly and aspartate transaminase (AST) and ROS production increased, chronic stress increased AST, alanine aminotransferase (ALT), hepatic enzymes, and ROS more significantly, and the antioxidant system became impaired. We also found that ER-originated ROS accumulated in the chronic model, another difference between the two conditions. ER stress was induced consistently, and oxidative intra-ER protein folding status, representatively PDI, was impaired, especially in chronic stress. The PDI-associated client protein hepatic apoB accumulated with the PDI-binding status in chronic stress, and curcumin recovered the altered ER folding status, regulating ER stress and the resultant hepatic dyslipidemia. Throughout this study, curcumin and curcumin-rich Curcuma longa L. extract promoted recovery from CCl4-induced hepatic toxicity in both stress conditions. For both stress-associated hepatic dyslipidemia, curcumin and Curcuma longa L. extract might be recommendable to recover liver activity.

An aqueous extract from Moringa oleifera leaves ameliorates hepatotoxicity in alloxan-induced diabetic rats.

This study was carried out to evaluate the possible mechanisms through which an aqueous extract from MO leaves demonstrates hepatoprotective effects in alloxan-induced diabetic rats. Eighty albino rats were assigned to 4 groups. The control group was orally administered sterile saline. The second group was injected with alloxan (150 mg/kg body mass (b.m.)) by intraperitoneal injection (i.p.). The third group was given MO (250 mg/kg b.m.) orally, daily. The fourth group was injected with alloxan, as for the second group, and administrated an aqueous extract of MO leaves, as for the third group. Alloxan induced degenerative changes in hepatic and pancreatic tissues, increased hepatic lipid peroxidation, and increased gene expression of PC and caspase 3. However, it decreased the activities of hepatic SOD and CAT, and gene expression of GS. In contrast, the MO extract prevented changes to the histoarchitecture of hepatic and pancreatic tissues and normalized the reduced hepatic levels of glutathione, as well as the activities of SOD and CAT, and the gene expression of GS, while reducing blood glucose levels, hepatic lipid peroxidation, and the gene expression of PC and caspase 3. This study indicated that an aqueous extract of MO leaves can be a potent antioxidant and used as an hepatoprotective agent.

Curcumin Protects Against Intestinal Origin Endotoxemia in Rat Liver Cirrhosis by Targeting PCSK9.

Intestinal origin endotoxemia always occurs in severe liver injury. The aim of the current study was to test antiendotoxemia effect of curcumin on tetrachloride (CCl4 )-induced liver cirrhosis rats, and to elucidate the underlying molecular mechanism. Rat cirrhosis models were constructed with CCl4 subcutaneous injections with curcumin (200 mg/kg/d) administered via gavages for 12 wk until the rats were sacrificed. We found that the administration of curcumin improved the physiological condition pertaining to activity index and temperature, and ameliorated the liver injury in CCl4 -induced cirrhosis rats. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qRT-PCR) showed that curcumin could reduce c-reaction protein levels and inflammatory cytokine (TNF-α, IL-1ß, IL-6, and CINC-1/IL-8) concentrations in peripheral serum and liver tissue. Furthermore, curcumin treatment decreased lipopolysaccharide (LPS) levels in peripheral vein, but not in portal vein. As low-density lipoprotein receptor (LDLR) is the important receptor on the surface of hepatocyte during LPS detoxification process, we used qRT-PCR, western blot, and immunohistochemistry (IHC), finding that curcumin significantly increased LDLR protein levels, but not gene levels in the liver tissues. We also tested proprotein convertase subtilisin/kexin type 9 (PCSK9), one negative regulator of LDLR, by qRT-PCR, western blot, and IHC. The results showed that PCSK9 significantly decreased both gene and protein levels in the rat liver tissues of curcumin treatment. Thus, we concluded that curcumin could function to protect against intestinal origin endotoxemia by inhibiting PCSK9 to promote LDLR expression, thereby enhancing LPS detoxification as one pathogen lipid through LDLR in the liver.