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Herbal medicines harbor essential therapeutic agents for the treatment of cholestasis. In this study, we have assessed the anticholestatic potential of Stachys pilifera Benth 's (SPB's) hydroalcoholic extract encapsulated into liposomes using bile duct ligation- (BDL-) induced hepatic cholestasis in rats. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), malondialdehyde (MDA), total thiol (T-SH) content, protein carbonyl (PCO), total bilirubin (TBIL), albumin (ALB), and nitric oxide (NO) metabolite levels were measured in either liver tissue or plasma to assess liver damage. Moreover, expression of proinflammatory cytokines (IL-1 β and TNF- α ) and liver fibrosis markers (TGF- β and SM- α ) which are driving forces of many liver disorders was also determined. The activity of AST, ALT, and ALP was significantly enhanced in the BDL group in comparison to the control group; however, treatment with liposomal (SPB) hydroalcoholic extract significantly reduced AST and ALT's activity. Increases in MDA, TBIL, and NO levels and T-SH content due to BDL were restored to control levels by liposomal (SPB) hydroalcoholic extract treatment. Similarly, hepatic and plasma oxidative marker MDA levels, significantly enhanced by BDL, were significantly decreased by liposomal (SPB) hydroalcoholic extract treatment. Moreover, histopathological findings further demonstrated a significant decrease in hepatic damage in the liposomal (SPB) hydroalcoholic extract-treated BDL group. In addition, liposomal (SPB) hydroalcoholic extract treatment decreased the liver expression of inflammatory cytokines (IL-1 β , TNF- α ) and liver fibrosis markers (TGF- β and SM- α ). Since liposomal (SPB) hydroalcoholic extract treatment alleviated the BDL-induced injury of the liver and improved the hepatic structure and function more efficiently in comparison to free SPB hydroalcoholic extract, probable liposomal (SPB) hydroalcoholic extract exhibits required potential therapeutic value in protecting the liver against BDL-caused oxidative injury., Competing Interests: There is no conflict of interest among authors., (Copyright © 2021 Zahra Moslemi et al.)

Objective: TMEM55B (transmembrane protein 55B) is a phosphatidylinositol-(4,5)-bisphosphate (PI[4,5]P 2 ) phosphatase that regulates cellular cholesterol, modulates LDLR (low-density lipoprotein receptor) decay, and lysosome function. We tested the effects of Tmem55b knockdown on plasma lipids in mice and assessed the roles of LDLR lysosomal degradation and change in (PI[4,5]P 2 ) in mediating these effects. Approach and Results: Western diet-fed C57BL/6J mice were treated with antisense oligonucleotides against Tmem55b or a nontargeting control for 3 to 4 weeks. Hepatic Tmem55b transcript and protein levels were reduced by ≈70%, and plasma non-HDL (high-density lipoprotein) cholesterol was increased ≈1.8-fold ( P <0.0001). Immunoblot analysis of fast protein liquid chromatography (FPLC) fractions revealed enrichment of ApoE-containing particles in the LDL size range. In contrast, Tmem55b knockdown had no effect on plasma cholesterol in Ldlr mice. In primary hepatocytes and liver tissues from -/- mice. In primary hepatocytes and liver tissues from Tmem55b knockdown mice, there was decreased LDLR protein. In the hepatocytes, there was increased lysosome staining and increased LDLR-lysosome colocalization. Impairment of lysosome function (incubation with NH 4 Cl or knockdown of the lysosomal proteins LAMP1 or RAB7 ) abolished the effect of TMEM55B knockdown on LDLR in HepG2 (human hepatoma) cells. Colocalization of the recycling endosome marker RAB11 (Ras-related protein 11) with LDLR in HepG2 cells was reduced by 50% upon TMEM55B knockdown. Finally, knockdown increased hepatic PI(4,5)P 2 levels in vivo and in HepG2 cells, while TMEM55B overexpression in vitro decreased PI(4,5)P 2 . TMEM55B knockdown decreased, whereas overexpression increased, LDL uptake in HepG2 cells. Notably, the TMEM55B overexpression effect was reversed by incubation with PI(4,5)P 2. Conclusions: These findings indicate a role for TMEM55B in regulating plasma cholesterol levels by affecting PI(4,5)P 2 -mediated LDLR lysosomal degradation.

Objective: AUP1 (ancient ubiquitous protein 1) is an endoplasmic reticulum-associated protein that also localizes to the surface of lipid droplets (LDs), with dual role in protein quality control and LD regulation. Here, we investigated the role of AUP1 in hepatic lipid mobilization and demonstrate critical roles in intracellular biogenesis of apoB100 (apolipoprotein B-100), LD mobilization, and very-low-density lipoprotein (VLDL) assembly and secretion. APPROACH AND RESULTS: siRNA (short/small interfering RNA) knockdown of AUP1 significantly increased secretion of VLDL-sized apoB100-containing particles from HepG2 cells, correcting a key metabolic defect in these cells that normally do not secrete much VLDL. Secreted particles contained higher levels of metabolically labeled triglyceride, and AUP1-deficient cells displayed a larger average size of LDs, suggesting a role for AUP1 in lipid mobilization. Importantly, AUP1 was also found to directly interact with apoB100, and this interaction was enhanced with proteasomal inhibition. Knockdown of AUP1 reduced apoB100 ubiquitination, decreased intracellular degradation of newly synthesized apoB100, and enhanced extracellular apoB100 secretion. Interestingly, the stimulatory effect of AUP1 knockdown on VLDL assembly was reminiscent of the effect previously observed after MEK-ERK (mitogen-activated protein kinase kinase-extracellular signal-regulated kinase) inhibition; however, further studies indicated that the AUP1 effect was independent of MEK-ERK signaling., Conclusions: In summary, our findings reveal an important role for AUP1 as a regulator of apoB100 stability, hepatic LD metabolism, and intracellular lipidation of VLDL particles. AUP1 may be a crucial factor in apoB100 quality control, determining the rate at which apoB100 is degraded or lipidated to enable VLDL particle assembly and secretion., (© 2017 American Heart Association, Inc.)

In recent years, iron oxide nanorods find a lot of applications including drug delivery, cell separation, hyperthermia and magnetic resonance imaging. In this study the cytotoxicity of iron oxide nanorods was evaluated based on mouse fibroblast cell behavior and wistar rat's liver and kidney function. At first for modification, nanorods were added to Dulbecco's modified Eagle's medium (DMEM) which contained a lot of sources of vitamins, amino acids, proteins in Fetal Bovine Serum (FBS). The MTT assay was employed for evaluating the toxic effects of 200 and 400 μg/mL modified and non-modified iron oxide nanorods on L929 mouse fibroblast cells in a 24h period. Changes in cell granularity and size as well as cell cycle were investigated using flow cytometry. Moreover liver and kidney function test and serum iron level measurement were performed 24h after the injection of modified iron oxide nanorods via the tail peripheral vein of wistar rats. Results indicated that greater concentration of modified iron oxide nanorods had no significant effect on cell viability while greater concentration of non-modified iron oxide nanorods significantly decreased cell viability. Modified iron oxide nanorods did not have significant effects on cell cycle. The results of liver and kidney function tests did not differ significantly while a significant increase in serum iron level was observed. After H&E staining of slices, there were no changes on morphology of rat's kidney and liver cells. This study suggests that short-time use of 200 and 400 μg/mL iron oxide nanorods are probably safe. Further studies are needed for investigation of toxic effects of different concentrations, coatings, and exposure time periods of iron oxide nanorods., (Copyright © 2015 Elsevier GmbH. All rights reserved.)

Introduction: Iron plays an important role in physiological processes as a trace element. Today, iron oxide nanoparticles have attracted extensive attention due to their super paramagnetic properties and a variety of potential applications in many fields. The main objective of this study was to evaluate in vitro and in vivo toxic effects of the iron oxide nanoparticles on L929 cell line, kidney and liver function, in order to achieve a safe application of the mentioned nanoparticles. Methods: The toxicity effects of 200 and 800 μg/ml iron oxide nanorods on L929 were determined using (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide )MTT( test. One and 24 h after the injection of iron oxide via tail vein, serum iron, blood urea nitrogen (BUN) and liver enzymes (ALT, AST, and ALP) were measured as indicators of the kidney and liver function, respectively. Histopathological studies on liver and kidney was carried out using light microscopy following tissue processing steps and standard H&E staining. Results: The viability of the cells exposed to iron oxide nanorods, was decreased with increasing dose. No significant differences were observed between biochemical factors, 1 and 24 h after the injection of nanoparticles. Serum iron level showed no difference with control 1 h after the injection. However, it exhibited a significant increase 24 h after the injection as compared to the control. Meanwhile, pathological studies did not show any acute toxic damage. Conclusion: Use of the iron oxide in short-time and in doses less than 800μg/ml may be safe. More studies are needed for accurate assessment of the toxicity of these particles in terms of dose time and the type of covering. [ABSTRACT FROM AUTHOR]