Interrupting tumor necrosis factor–alpha signaling prevents parenteral nutrition–associated cholestasis in mice

Kasmi, Karim C. El; Anderson, Aimee L.; Devereaux, Michael W.; Balasubramaniyan, Natarajan; Suchy, Frederick J.; Orlicky, David J.; Shearn, Colin T.; Sokol, Ronald J.

doi:10.1002/jpen.2279

Cited by 8 publications

(19 citation statements)

References 43 publications

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“…SM supplementation enhanced the downregulation of the Nr1h family members, key regulators of macrophage function responsible for controlling genes involved in lipid homeostasis and inflammation. Nr1h nuclear receptors affect the expression of Srebp1 and Pparγ and the cholesterol transporters G5 and G8 [73] (Figures 4B and 5). chemical-induced health benefits of SM than the direct scavenging of free radicals [75].…”

Section: Discussionmentioning

confidence: 99%

The Beneficial Additive Effect of Silymarin in Metformin Therapy of Liver Steatosis in a Pre-Diabetic Model

et al. 2021

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The combination of plant-derived compounds with anti-diabetic agents to manage hepatic steatosis closely associated with diabetes mellitus may be a new therapeutic approach. Silymarin, a complex of bioactive substances extracted from Silybum marianum, evinces an antioxidative, anti-inflammatory, and hepatoprotective activity. In this study, we investigated whether metformin (300 mg/kg/day for four weeks) supplemented with micronized silymarin (600 mg/kg/day) would be effective in mitigating fatty liver disturbances in a pre-diabetic model with dyslipidemia. Compared with metformin monotherapy, the metformin–silymarin combination reduced the content of neutral lipids (TAGs) and lipotoxic intermediates (DAGs). Hepatic gene expression of enzymes and transcription factors involved in lipogenesis (Scd-1, Srebp1, Pparγ, and Nr1h) and fatty acid oxidation (Pparα) were positively affected, with hepatic lipid accumulation reducing as a result. Combination therapy also positively influenced arachidonic acid metabolism, including its metabolites (14,15-EET and 20-HETE), mitigating inflammation and oxidative stress. Changes in the gene expression of cytochrome P450 enzymes, particularly Cyp4A, can improve hepatic lipid metabolism and moderate inflammation. All these effects play a significant role in ameliorating insulin resistance, a principal background of liver steatosis closely linked to T2DM. The additive effect of silymarin in metformin therapy can mitigate fatty liver development in the pre-diabetic state and before the onset of diabetes.

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Section: Discussionmentioning

confidence: 99%

The Beneficial Additive Effect of Silymarin in Metformin Therapy of Liver Steatosis in a Pre-Diabetic Model

et al. 2021

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“…Transporter inhibitors are compounds that competitively bind or inhibit transporter activity [ 23 , 24 ]. Therefore, in the case of multi-disease combination, there will be interactions between drugs, such as P-gp [ 25 , 26 ], which has a variety of inducers in vivo, including antibacterial drug rifampicin, anti-tumor drug vincristine, doxorubicin, cardiovascular drug verapamil [ 27 ], hyperlipidemia drug atorvastatin [ 28 ], etc., which can induce the overexpression of P-gp in vivo. As a result, the pharmacokinetics parameters of drugs such as digoxin in vivo are significantly changed, while digoxin has a narrow treatment window, and the blood concentration of digoxin will be greatly reduced in a multi-drug combination, so that digoxin cannot play a therapeutic role.…”

Section: Discussionmentioning

confidence: 99%

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics

et al. 2022

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With the widespread clinical use of drug combinations, the incidence of drug–drug interactions (DDI) has significantly increased, accompanied by a variety of adverse reactions. Drug transporters play an important role in the development of DDI by affecting the elimination process of drugs in vivo, especially in the pathological state. Tubulointerstitial fibrosis (TIF) is an inevitable pathway in the progression of chronic kidney disease (CKD) to end-stage renal disease. Here, the dynamic expression changes of eleven drug transporters in TIF kidney have been systematically investigated. Among them, the mRNA expressions of Oat1, Oat2, Oct1, Oct2, Oatp4C1 and Mate1 were down-regulated, while Oat3, Mrp2, Mrp4, Mdr1-α, Bcrp were up-regulated. Pearson correlation analysis was used to analyze the correlation between transporters and Creatinine (Cr), OCT2 and MATE1 showed a strong negative correlation with Cr. In contrast, Mdr1-α exhibited a strong positive correlation with Cr. In addition, the pharmacokinetics of cimetidine, ganciclovir, and digoxin, which were the classical substrates for OCT2, MATE1 and P-glycoprotein (P-gp), respectively, have been studied. These results reveal that changes in serum creatinine can indicate changes in drug transporters in the kidney, and thus affect the pharmacokinetics of its substrates, providing useful information for clinical use.

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“…For murine studies, male C57BL6/J (WT) mice (8-10wks old; N = 5/group) were subjected to sham or BDL surgery as previously described [ 27 ]. After 3 days of BDL or sham surgery, mice were anesthetized and blood and liver removed [ 28 , 29 ], plasma was separated by centrifugation at 5000 rpm for 5 min at 4°C and was assayed for alanine aminotransferase (ALT), aspartate amino transferase (AST), alkaline phosphatase activity and total bilirubin [ 30 ]. Whole livers were excised and weighed.…”

Section: Methodsmentioning

confidence: 99%

“…qPCR was performed using TaqMan probes from Applied Biosystems (Foster City, CA) as previously described [ 30 ].…”

Section: Methodsmentioning

confidence: 99%

The autophagic protein p62 is a target of reactive aldehydes in human and murine cholestatic liver disease

et al. 2022

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Inflammatory cholestatic liver diseases, including Primary Sclerosing Cholangitis (PSC), are characterized by periportal inflammation with progression to cirrhosis. The objective of this study was to examine interactions between oxidative stress and autophagy in cholestasis. Using hepatic tissue from male acute cholestatic (bile duct ligated) as well as chronic cholestatic (Mdr2KO) mice, localization of oxidative stress, the antioxidant response and induction of autophagy were analyzed and compared to human PSC liver. Concurrently, the ability of reactive aldehydes to post-translationally modify the autophagosome marker p62 was assessed in PSC liver tissue and in cell culture. Expression of autophagy markers was upregulated in human and mouse cholestatic liver. Whereas mRNA expression of Atg12, Lamp1, Sqstm1 and Map1lc3 was increased in acute cholestasis in mice, it was either suppressed or not significantly changed in chronic cholestasis. In human and murine cholestasis, periportal hepatocytes showed increased IHC staining of ubiquitin, 4-HNE, p62, and selected antioxidant proteins. Increased p62 staining colocalized with accumulation of 4-HNE-modified proteins in periportal parenchymal cells as well as with periportal macrophages in both human and mouse liver. Mechanistically, p62 was identified as a direct target of lipid aldehyde adduction in PSC hepatic tissue and in vitro cell culture. In vitro LS-MS/MS analysis of 4-HNE treated recombinant p62 identified carbonylation of His123, Cys128, His174, His181, Lys238, Cys290, His340, Lys341 and His385. These data indicate that dysregulation of autophagy and oxidative stress/protein damage are present in the same periportal hepatocyte compartment of both human and murine cholestasis. Thus, our results suggest that both increased expression as well as ineffective autophagic degradation of oxidatively-modified proteins contributes to injury in periportal parenchymal cells and that direct modification of p62 by reactive aldehydes may contribute to autophagic dysfunction.

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Interrupting tumor necrosis factor–alpha signaling prevents parenteral nutrition–associated cholestasis in mice

Cited by 8 publications

References 43 publications

The Beneficial Additive Effect of Silymarin in Metformin Therapy of Liver Steatosis in a Pre-Diabetic Model

The Beneficial Additive Effect of Silymarin in Metformin Therapy of Liver Steatosis in a Pre-Diabetic Model

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics

The autophagic protein p62 is a target of reactive aldehydes in human and murine cholestatic liver disease

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