Hepatic Infiltration Research Articles

Etanercept attenuates immune-mediated hepatitis induced by concanavalin A via differential regulation of the key effector cytokines of CD4+ T cells

AimsThe current study aims to investigate the role of the key effector cytokines produced by CD4+T cells in the pathogenesis of Con A-induced liver injury in mice and testing whether etanercept can be repurposed to differentially regulate these cytokines. Main methodsFour groups of mice were used: group I: control group, group II: mice received 15 mg/kg Con A i.v, group III: mice received 15 mg/kg etanercept i.p, group IV: mice received both Con A and etanercept as described. Hepatic injury and necroinflammation were assessed. Infiltration of CD4+ T cells and neutrophils were evaluated. Hepatic levels of TNF-α, IL-4, IL-10, and MDA were assigned and expression of NF-κB as well. Key findingsA significant decrease in ALT, AST, and LDH levels occurred when etanercept was injected before Con A. Hepatic necrosis and infiltration of CD4+ T cells and neutrophils were reduced by etanercept. Levels of TNF-α, IL-4, and MDA were significantly decreased in group IV compared to group II while that of IL-10 was increased. Also, number of NF-κB positive cells was significantly low in group IV. SignificanceThe study elucidates an interplay between the two effector cytokines of CD4+ T cells, TNF-α and IL-4, and their key role in Con A-induced liver injury. Additionally, our results showed that etanercept could be repurposed to differentially regulate effector cytokines produced by CD4+ T cells. Not only TNF-α, but also IL-4 signaling pathways, through which it exerts immunomodulatory, anti-inflammatory, and anti-oxidant effects leading to attenuation of Con A-induced liver injury.

Aqueous Mulberry Leaf Extract Ameliorates Alcoholic Liver Injury Associating with Upregulation of Ethanol Metabolism and Suppression of Hepatic Lipogenesis

Excessive alcohol intake is a major cause of chronic liver damage and is highly associated with the development of a spectrum of hepatic disorders, including steatohepatitis, liver cirrhosis, and liver cancer. Thus, we aimed to explore the hepatoprotective effects of an aqueous mulberry leaf extract (AME) on alcoholic fatty liver disorder (AFLD) by using a mouse model fed with excessive ethanol. Compared with the normal diet, the ethanol diet significantly increased the body weight of the mice, while the AME supplement reduced the weight gain caused by the ethanol diet. The ethanol diet also attenuated the activity of alcohol dehydrogenase and antioxidant enzymes but increased lipid peroxidation in the liver, which were reversed by AME supplementation. Additionally, AME supplementation diminished the ethanol diet-induced hepatic leukocyte infiltration and expressions of IL-6 and TNFα. Moreover, AME supplementation also reduced the ethanol-diet-induced lipid accumulation and expression of 1-acylglycerol-3-phosphate acyltransferase, acetyl-CoA carboxylase, low-density lipoprotein receptor, and sterol regulatory element-binding protein-1/2 in the liver. Collectively, AME supplementation improved liver lipid accumulation and proinflammatory response in mice induced by the ethanol diet, which was associated with the upregulation of ethanol-metabolizing enzymes and the downregulation of lipogenesis components.

Vitamin B12 Induces Hepatic Fatty Infiltration through Altered Fatty Acid Metabolism.

Rise in global incidence of obesity impacts metabolic health. Evidence from human and animal models show association of vitamin B12 (B12) deficiency with elevated BMI and lipids. Human adipocytes demonstrated dysregulation of lipogenesis by low B12 via hypomethylation and altered microRNAs. It is known de novo hepatic lipogenesis plays a key role towards dyslipidaemia, however, whether low B12 affects hepatic metabolism of lipids is not explored. HepG2 was cultured in B12-deficient EMEM medium and seeded in different B12 media: 500nM(control), 1000pM(1nM), 100pM and 25pM(low) B12. Lipid droplets were examined by Oil Red O (ORO) staining using microscopy and then quantified by elution assay. Gene expression were assessed with real-time quantitative polymerase chain reaction (qRT-PCR) and intracellular triglycerides were quantified using commercial kit (Abcam, UK) and radiochemical assay. Fatty acid composition was measured by gas chromatography and mitochondrial function by seahorse XF24 flux assay. HepG2 cells in low B12 had more lipid droplets that were intensely stained with ORO compared with control. The total intracellular triglyceride and incorporation of radio-labelled-fatty acid in triglyceride synthesis were increased. Expression of genes regulating fatty acid, triglyceride and cholesterol biosynthesis were upregulated. Absolute concentrations of total fatty acids, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), trans-fatty acids and individual even-chain and odd-chain fatty acids were significantly increased. Also, low B12 impaired fatty acid oxidation and mitochondrial functional integrity in HepG2 compared with control. Our data provide novel evidence that low B12 increases fatty acid synthesis and levels of individual fatty acids, and decreases fatty acid oxidation and mitochondrial respiration, thus resulting in dysregulation of lipid metabolism in HepG2. This highlights the potential significance of de novo lipogenesis and warrants possible epigenetic mechanisms of low B12.

Hepatotoxicity Caused by Repeated and Subchronic Pulmonary Exposure to Low-Level Vinyl Chloride in Mice

Vinyl chloride (VC) is classified as a group 1 carcinogen to humans by the International Agency for Research on Cancer, and inhalation is considered to be an important route of occupational exposure. In addition, increasing numbers of studies have observed adverse health effects in people living in the vicinity of petrochemical complexes. The objective of this study was to investigate the adverse in vivo health effects on the lungs and liver caused by pulmonary exposure to low-level VC. BALB/c mice were repeatedly intranasally administrated 50 µL/mouse VC at 0, 1, and 200 ng/mL (5 days/week) for 1, 2, and 3 weeks. We observed that exposure to 1 and 200 ng/mL VC significantly increased the tidal volume (μL). Dynamic compliance (mL/cmH2O) significantly decreased after exposure to 200 ng/mL VC for 3 weeks. Total protein, lactate dehydrogenase (LDH), and interleukin (IL)-6 levels in bronchoalveolar lavage fluid (BALF) significantly increased after exposure to 200 ng/mL VC for 2 and/or 3 weeks. Significant decreases in 8-isoprostane and caspase-3 and an increase in IL-6 in the lungs were found after VC exposure for 2 and/or 3 weeks. We observed that aspartate aminotransferase (AST), alkaline phosphatase (ALKP), albumin (ALB), and globulin (GLOB) had significantly increased after three weeks of VC exposure, whereas the ALB/GLOB ratio had significantly decreased after 3 weeks of exposure to VC. IL-6 in the liver increased after exposure to 1 ng/mL VC, but decreased after exposure to 200 ng/mL. IL-1β in the liver significantly decreased following exposure to 200 ng/mL VC, whereas tumor necrosis factor (TNF)-α and caspase-3 significantly increased. Hepatic inflammatory infiltration was confirmed by histological observations. In conclusion, sub-chronic and repeated exposure to low levels of VC can cause lung and liver toxicity in vivo. Attention should be paid to all situations where humans are frequently exposed to elevated VC levels such as workplaces or residents living in the vicinity of petrochemical complexes.

Acute Inflammatory Demyelinating Polyneuropathy (AIDP) Masked by Autoimmune Thyroiditis

Hashimoto’s thyroiditis and Guillain-Barre syndrome (GBS) are autoimmune disorders that are both well-known in their own right. Hashimoto’s is one of the most common causes of primary hypothyroidism, and GBS involves immune mediated damage to the peripheral nervous system. The association between the two is a rare clinical entity. This case demonstrates that these entities can occur together and could be related in similar pathophysiology.A 37 year old male presented with complaints of bilateral hand and feet numbness for one month. The numbness started in the hands, then involved the feet, and was mostly felt in tips of extremities. He also complained of weakness in arms and legs. Neurology exam showed bilateral patellar, ankle, and biceps hyporeflexia. Muscle strength was 5/5 in all extremities, but decreased grip strength was noted in the hands. Initial lab work including complete blood count, comprehensive metabolic profile and urinalysis were all in normal range. Computerized tomographic scan (CT) head was normal while CT abdomen/pelvis showed hepatic fatty infiltration. Other lab tests including HIV, syphilis, Hepatitis B, Hepatitis C, glycosylated hemoglobin A1c, lipid panel, anti-nuclear antibody, anti-neutrophil cytoplasmic antibodies, serum/urine protein electrophoresis, alcohol level, vitamin B1, B6, folate, copper, and creatine kinase were all negative or within normal range. Lab abnormalities included elevated thyroid stimulating hormone (TSH) of 20.2 mIU/l and low normal B12 level of 289 pg/ml. His triiodothyronine (T3) and thyroxine (T4) hormone levels were in normal range. A thyroid peroxidase antibody level came back as high as 966 IU/ml. A diagnosis of Hashimoto’s thyroiditis leading to subclinical hypothyroidism was made. Patient was discharged on vitamin B12 and 112mcg of Synthroid. Instead of getting better, he returned 1 week later with worsening numbness and tingling which was now ascending upward to bilateral knees and elbows. Meanwhile TSH improved to 10 mIU/l and vitamin B12 increased to 1162 pg/ml. A magnetic resonance imaging (MRI) of the cervical/thoracic spine was unremarkable. A lumbar puncture showed negative xanthochromia, 0 WBC, 0 RBC, 0 neutrophils, 0 lymphocytes, 0 monocytes, glucose 63 mg/dl, elevated protein of 57 mg/dl, and culture was negative. Guillain-Barre syndrome was then the working diagnosis, more specifically its most common subtype, acute inflammatory demyelinating polyneuropathy (AIDP). Patient received five days of intravenous immunoglobulins and his symptoms improved. He was then discharged to follow up with endocrinologist.This subtle presentation of GBS/AIDP masked by Hashimoto’s thyroiditis and vitamin B12 deficiency suggests a close association of autoimmune etiology between these disorders. Although rare, endocrinologists should consider this rare association in cases of paresthesias with unexplained symptoms.

Gulf War Illness‐related Chemicals Increase Hepatic Steatosis and Enhance Chronic Ethanol‐induced Liver Damage in Mice

Gulf War illness (GWI) affected military veterans of the 1990-1991 Persian Gulf War. GWI symptoms include systemic inflammation, chronic fatigue, fibromyalgia, and memory deficits. Studies on animal models revealed that insecticides (permethrin, DEET) and nerve gas prophylactics (pyridostigmine-bromide, PB) induce symptoms similar to GWI. Previously we showed that rats’ exposure to GWI chemicals enhanced biliary hyperplasia and hepatic fibrosis after BDL-induced cholestasis which was associated with increased Kupffer cells/monocyte-derived macrophages (KC/MoMF). We further investigate the influence of GWI chemicals on liver function in a mouse model of chronic alcohol consumption and assess the role of hepatic inflammation in this process. Male C57BL/6 mice were injected with PB and permethrin (GWI mice) or vehicle (naïve mice) daily for 10 days and allowed to recover for 4 months. Then, GWI and naïve mice were treated with either vehicle or Pexidartinib (PLX3397) to reduce hepatic macrophage infiltration, followed by a chronic-plus-single-binge ethanol (EtOH) feeding challenge. Serum biochemistry and liver histopathology were assessed using ELISA, H&E, and IHC. Oil Red O was used for lipid droplet (LD) detection. Reactive oxygen species (ROS) were assayed using a commercial kit. Gene markers for mitochondrial fatty acid oxidation (FAO) and steatosis were assessed by RT-qPCR array. Genes of fibrosis (TGFb, CTGF, aSMA, Col1A1) and inflammation (IL-1b, IL-6, CCL2, TNFa) were assayed by RT-qPCR. GWI chemicals induced hepatic microvesicular steatosis and increased KC (CD68+/Clec4f+) and MoMF (CD68+/CD11b+) in the liver. GWI exposure resulted in increased ROS and impaired FAO coupled with LD formation. Mitochondrial FAO genes including PPARa, CPT1A, CPT2 were downregulated while genes of LD formation, e.g. PLIN1-3, were upregulated by GWI chemicals. Upon treatment with chronic-EtOH-plus-binge feeding, mice exposed to GWI chemicals had increased levels of serum AST, ALT, and increased fibrosis markers compared to EtOH-mice without GWI treatment. Macrophage markers CD68, Clec4f, and CD11b/c that were slightly augmented by the GWI chemicals, were significantly enhanced in GWI+EtOH compared to EtOH mice. PLX3397 treatment reduced KC/MoMF infiltration induced by GWI chemicals and attenuated the GWI-induced increase of hepatic serum markers and steatosis observed after EtOH exposure. These data suggest that exposure to GWI chemicals causes long- term changes in liver pathology, resulting in low level inflammation, oxidative stress and microvesicular steatosis. These GWI-induced changes contribute to increased susceptibility to alcohol-induced liver damage that is driven, at least in part, by an increased macrophage infiltration.

NLRP3 deficiency did not attenuate NASH development under high fat calorie diet plus high fructose and glucose in drinking water

NOD-like receptor protein 3 (NLRP3) promotes the inflammatory response during progression of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). This study aimed to further delineate the role of NLRP3 in NASH development by abolishing its expression in mice. A high-fat and calorie diet plus high fructose and glucose in drinking water (HFCD-HF/G) was used to establish NASH in both wild-type (WT) and NLRP3 knock-out (KO) mice. Hepatocellular injury, hepatic steatosis and fibrosis, as well as inflammatory response and insulin resistance in the liver and epidydimal white adipose tissue (eWAT) were determined. Elevated body weight, liver weight and serum alanine transaminase level, increased hepatic triglyceride accumulation and collagen deposition, and worsened systemic insulin resistance were observed in Nlrp3−/− mice compared to WT mice under HFCD-HF/G feeding. Upregulated hepatic transcription of tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1), and enhanced infiltration of inducible nitric oxide synthase-positive (iNOS+) M1 macrophages were also documented in HFCD-HF/G-fed Nlrp3−/− mice in comparison to HFCD-HF/G-fed WT mice. Moreover, transcription of TNF-α and MCP-1 and infiltration of iNOS+ M1 macrophages were increased in the liver of Nlrp3−/− mice under control diet. NLRP3 deficiency did not attenuate, but instead aggravated NASH development under HFCD-HF/G feeding. The worsened extent of NASH might be attributed to enhanced hepatic MCP-1 expression and M1 macrophage infiltration in Nlrp3−/− mice. Our study points to additional caution when NLRP3 blockade is considered as a therapeutic strategy in the treatment of human NASH.

Disease Status-Dependent Drug-Herb Interactions: NASH Lowered the Risk of Hepatotoxicity in Rats Coadministered With Simvastatin and Gardenia jasminoides J. Ellis.

Concurrent use of simvastatin (SV) and Gardenia jasminoides J. Ellis (GJ) was adopted in patients with multi-morbidity, such as stroke rehabilitation patients with NASH. Although hepatotoxicity has been reported in both of them and NASH could alter the pharmacokinetics of drugs/herbs, the interaction between SV and GJ and the related hepatotoxicity remained uninvestigated under neither healthy nor NASH condition. The current study aimed to evaluate the potential hepatotoxicity resulted from the interactions between SV and GJ in both healthy and NASH rats. Both healthy and NASH rats received two-week SV (p. o., 8.66 mg/kg, once daily) and/or GJ (p.o., 325 mg/kg, twice daily). Pharmacokinetic profiles of SV, simvastatin acid (SVA, active metabolite of SV), and geniposide (major component in GJ); hepatic Cyp2c11/Oatp1b2/P-gp expression; and biomarker levels of liver function, lipid levels, and liver histology were compared to demonstrate the interactions in rats. To explore the mechanism of the interaction-mediated hepatotoxicity, hepatic genipin-protein adduct content and iNOS/COX-1/COX-2 expressions from related groups were compared. Moreover, liver histology of healthy/NASH rats at 90 days after discontinuation of two-week GJ in the absence and presence of SV was evaluated to estimate the long-term impact of the interactions. GJ reduced the systemic exposures of SV and SVA by up-regulating the hepatic P-gp expression in healthy but not NASH rats. Meanwhile, SV increased the systemic exposure of geniposide via inhibiting the activity of P-gp in both healthy and NASH rats. Although neither SV nor GJ induced hepatotoxicity in healthy rats, their co-treatment elevated serum ALT and AST levels, which may attribute to the aggravated genipin-protein adduct formation, inflammation infiltration, and iNOS/COX-1 expressions in the liver. In NASH rats, SV and/or GJ reduced serum ALT, AST, LDL/vLDL, and TC levels via alleviating hepatic inflammation infiltration and iNOS/COX-1 expressions. Moreover, in comparison to NASH rats, more severe fibrosis was observed in the livers of healthy rats at 90 days after discontinuation of two-week SV and GJ coadministration. Although interactions between SV and GJ induced short-term and long-term liver injuries in healthy rats, NASH condition in rats could lower such risk.

Fenofibrate Regulates Visceral Obesity and Nonalcoholic Steatohepatitis in Obese Female Ovariectomized C57BL/6J Mice.

Fibrates, including fenofibrate, are a class of hypolipidemic drugs that activate peroxisome proliferator-activated receptor α (PPARα), which in-turn regulates the expression of lipid and lipoprotein metabolism genes. We investigated whether fenofibrate can reduce visceral obesity and nonalcoholic fatty liver disease via adipose tissue PPARα activation in female ovariectomized (OVX) C57BL/6J mice fed a high-fat diet (HFD), a mouse model of obese postmenopausal women. Fenofibrate reduced body weight gain (−38%, p < 0.05), visceral adipose tissue mass (−46%, p < 0.05), and visceral adipocyte size (−20%, p < 0.05) in HFD-fed obese OVX mice. In addition, plasma levels of alanine aminotransferase and aspartate aminotransferase, as well as free fatty acids, triglycerides, and total cholesterol, were decreased. Fenofibrate also inhibited hepatic lipid accumulation (−69%, p < 0.05) and infiltration of macrophages (−72%, p < 0.05), while concomitantly upregulating the expression of fatty acid β-oxidation genes targeted by PPARα and decreasing macrophage infiltration and mRNA expression of inflammatory factors in visceral adipose tissue. These results suggest that fenofibrate inhibits visceral obesity, as well as hepatic steatosis and inflammation, in part through visceral adipose tissue PPARα activation in obese female OVX mice.

Inhibitory effect of Xinhui citrus fermentation liquor on liver fibrosis in mice

To investigate the inhibitory effect of Xinhui citrus fermentation liquor on liver fibrosis in mice. Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4 in 105 male C57BL/6 mice, followed by gavage of 0.1 mL 40% CCl4 olive oil 3 times a week (model group, n=49) or daily gavage of citrus liquor at the dose of 0.26 mL (citrus liquor group, n=56) for 8 weeks. Seven mice receiving only olive oil treatment (0.1 mL, 3 times a week) and another 7 treated with citrus liquor served as the control group. Liver tissues and serum samples were collected from 7 mice in the citrus liquor group and model group each week and from the mice in the two control groups at the 8th week for pathological examination of the liver tissues using HE staining and Sirius red staining and for determination of the biochemical indexes of liver function. The mice in the model group showed progressively worsened liver fibrosis with obvious hepatic steatosis, necrosis and inflammatory cell infiltration. These liver pathologies were much ameliorated in citrus liquor group, which showed significantly reduced vacuolation, inflammatory cell infiltration, collagen deposition and the Ishak score of the liver tissue (P < 0.05). Serum levels of cholyglycine, alanine aminotransferase, transglutaminase and alanine aminotransferase were all significantly lower in citrus liquor group than in the model group (P < 0.05). Xinhui citrus fermentation liquor has protective effect on the liver and can significantly ameliorate liver fibrosis in mice.

Dietary Oxysterol, 7-Ketocholesterol Accelerates Hepatic Lipid Accumulation and Macrophage Infiltration in Obese Mice.

Non-alcoholic fatty liver disease is strongly associated with obese and type 2 diabetes. It has been reported that an oxidized cholesterol, 7-ketocholesterol (7KC), might cause inflammatory response in macrophages and plasma 7KC concentration were higher in patients with cardiovascular diseases or diabetes. Therefore, we have decided to test whether small amount of 7KC in diet might induce hepatic steatosis and inflammation in two types of obese models. We found that addition of 0.01% 7KC either in chow diet (CD, regular chow diet with 1% cholesterol) or western type diet (WD, high fat diet with 1% cholesterol) accelerated hepatic neutral lipid accumulation by Oil Red O staining. Importantly, by lipid extraction analysis, it has been recognized that triglyceride rather than cholesterol species was significantly accumulated in CD+7KC compared to CD as well as in WD+7KC compared to WD. Immunostaining revealed that macrophages infiltration was increased in CD+7KC compared to CD, and also in WD+7KC compared to WD. These phenotypes were accompanied by inducing inflammatory response and downregulating fatty acid oxidation. Furthermore, RNA sequence analysis demonstrated that 7KC reduced expression of genes which related to autophagy process. Levels of LC3-II protein were decreased in WD+7KC compared to WD. Similarly, we have confirmed the effect of 7KC on acceleration of steatohepatitis in db/db mice model. Collectively, our study has demonstrated that small amount of dietary 7KC contributed to accelerate hepatic steatosis and inflammation in obese mice models.

Lipopolysaccharide induced unfolded protein response and related anti‐lipopolysaccharide factor expression in Pacific white shrimp, Litopenaeus vannamei

Lipopolysaccharide (LPS), known as endotoxin, is the cell wall component of Gram-negative bacteria. In this study, the haemolymph enzyme activities, the morphology of hepatopancreas, the immunological responses of hepatopancreas and haemocytes in Litopenaeus vannamei (L. vannamei) were studied to investigate the physiological responses after LPS injection. Histological results indicated that necrotic hepatic tubules occurred after injection of LPS for 12 hours (h), and then, the increasing number of the necrotic hepatic tubules and inflammatory cell infiltration was observed. Furthermore, the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) decreased before 12 h and then increased to the peak at 48 h. However, ALP activity increased significantly. Anti-lipopolysaccharide factors (ALFs) of crustacean play an important role against bacterial infection. Specifically, it was worth mentioning that the expression of ALFC in the hepatopancreas and haemocytes increased significantly at 6 h and the expression of ALFB increased significantly at 24 h in haemocytes. Moreover, the expression of unfolded protein response (UPR) related genes decreased at 3 h and then increased in the hepatopancreas and haemocytes and the expression of glucose-regulated protein 78 kDa (GRP78), inositol-requiring enzyme-1 (IRE1) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) in haemocytes increased significantly at 48 h. These results revealed that LPS injection damaged hepatopancreas structure of L. vannamei, increased haemolymph enzyme activities and activated the UPR pathway and ALF-related genes.

Targeted peripheral focused ultrasound stimulation attenuates obesity-induced metabolic and inflammatory dysfunctions

Obesity, a growing health concern, is associated with an increased risk of morbidity and mortality. Chronic low-grade inflammation is implicated in obesity-driven metabolic complications. Peripheral focused ultrasound stimulation (pFUS) is an emerging non-invasive technology that modulates inflammation. Here, we reasoned that focused ultrasound stimulation of the liver may alleviate obesity-related inflammation and other comorbidities. After 8 weeks on a high-fat high-carbohydrate “Western” diet, C57BL/6J mice were subjected to either sham stimulation or focused ultrasound stimulation at the porta hepatis. Daily liver-focused ultrasound stimulation for 8 weeks significantly decreased body weight, circulating lipids and mitigated dysregulation of adipokines. In addition, liver-focused ultrasound stimulation significantly reduced hepatic cytokine levels and leukocyte infiltration. Our findings demonstrate the efficacy of hepatic focused ultrasound for alleviating obesity and obesity-associated complications in mice. These findings suggest a previously unrecognized potential of hepatic focused ultrasound as a possible novel noninvasive approach in the context of obesity.

Acute liver failure caused by metastatic malignant melanoma of liver

Abstract Introduction: Malignant melanoma of liver is an exceedingly rare cause of acute liver failure (ALF), whether primary or metastatic. Only few cases have been reported in the worldwide literature, and all the patients with ALF secondary to diffuse hepatic infiltration by melanoma subsequently died within days. Patient concerns: The patient was a 70-year-old man admitted to our hospital for abdominal distention and progressive jaundice for 15 days. Diagnoses: Ultrasonography and computed tomography findings indicated the presence of hepatomegaly with homogeneous normal echogenicity without focal lesions. Due to the history of alcohol consumption, acute liver failure (ALF) caused by alcoholic live disease was suspected. Interventions: After 4 time artificial liver treatment, the patient continued to deteriorate and deceased donor liver transplantation was performed after discussion with the next-of-kin. Outcomes: Postoperative pathology revealed clusters of malignant melanoma cells that had diffusely infiltrated the liver parenchyma. The patient was discharged on the eleventh day post-operation. Three months post-transplantation, he was readmitted because of elevated liver enzymes, and died of acute liver failure 9 days later. Conclusions: To our knowledge, this is the first report of liver transplantation for ALF due to diffuse hepatic melanoma. When the etiology of liver failure is unclear, diffuse metastatic tumor infiltration should be considered and early liver biopsy would be helpful in establishing the diagnosis and guiding treatment, particularly when liver transplantation is a treatment option as a metastatic malignancy is a contraindication for liver transplantation.

Morphometric characteristics of effects induced by &lt;i&gt;Ensifer meliloti&lt;/i&gt; lipopolysaccharide fractions on parenchymatous organs in laboratory rats with secondary immunodeficiency

Introduction. Gram-negative bacteria-derived lipopolysaccharides (LPS) are better known as bacterial endotoxins. However, an increasing body of evidence has been accumulated regarding a whole range of LPS-bound physiological effects also observed in normal settings. In particular, LPS derived from some bacterial species was shown to exhibit an immunomodulating activity.Study objective — to characterize physiological effects of Ensifer meliloti lipopolysaccharides in modelled rat induced immunodeficiency.Materials and methods. Biological activity of intraperitoneally administered E. meliloti LPS fractions was studied for 21 days in 60 outbred male rats after induction of a minimal immunodeficiency state 24 hours later after inoculating cytostatic agent cyclophosphamide (CF). Animals were euthanized on day 22 followed by conducting an autopsy and morphometric study of internal organs. Later, paraffin-embedded sections of parenchymal organs were stained with hematoxylin-eosin and examined histologically by light microscopy.Results. It was found that at the end of the experiment cyclophosphamide applied to laboratory animals insignificantly decreased weight of liver and kidney, but not that of heart and spleen (compared to intact animals). In contrast, lung weight was solely significantly increased in immunodeficient rats compared to control. Intraperitoneally administered LPS fractions during secondary immunodeficiency affected weight parameters in the liver and kidney as the most intensively blood supplied organs suggesting its systemic effects. Quantity of follicles with large germinal centers as well as secondary follicles and lymphatic sheath formation in splenic stroma was increased that features activated immune response. Moreover, hepatic lymphoid infiltration in the portal tracts and reversal to normal vascular pattern were found as well. In contrast, LPS and Licopid administered to rats resulted in marked lung hyperplasia of lymphoid tissue containing large germinal centers.Conclusion. The data obtained indicate that E. meliloti-derived LPS fractions administered to rats with secondary immunodeficiency positively affected immunoreactivity.

Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+ROR\u03b3t+IL-17+ Tregs and improve metabolism

Interactions between host and gut microbial communities are modulated by diets and play pivotal roles in immunological homeostasis and health. We show that exchanging the protein source in a high fat, high sugar, westernized diet from casein to whole-cell lysates of the non-commensal bacterium Methylococcus capsulatus Bath is sufficient to reverse western diet-induced changes in the gut microbiota to a state resembling that of lean, low fat diet-fed mice, both under mild thermal stress (T22 °C) and at thermoneutrality (T30 °C). Concomitant with microbiota changes, mice fed the Methylococcus-based western diet exhibit improved glucose regulation, reduced body and liver fat, and diminished hepatic immune infiltration. Intake of the Methylococcu-based diet markedly boosts Parabacteroides abundances in a manner depending on adaptive immunity, and upregulates triple positive (Foxp3+RORγt+IL-17+) regulatory T cells in the small and large intestine. Collectively, these data point to the potential for leveraging the use of McB lysates to improve immunometabolic homeostasis.

Epigallocatechin-3-Gallate Dampens Non-Alcoholic Fatty Liver by Modulating Liver Function, Lipid Profile and Macrophage Polarization.

Epigallocatechin-3-gallate (EGCG) has been shown to attenuate obesity, fatty liver disease, hepatic inflammation and lipid profiles. Here, we validate the efficacy of EGCG in a murine model of non-alcoholic fatty liver disease (NAFLD) and extend the mechanistic insights. NAFLD was induced in mice by a high-fat diet (HFD) with 30% fructose. EGCG was administered at a low dose (25 mg/kg/day, EGCG-25) or high dose (50 mg/kg/day, EGCG-50) for 8 weeks. In HFD-fed mice, EGCG attenuated body and liver weight by ~22% and 47%, respectively, accompanied by ~47% reduction in hepatic triglyceride (TG) accumulation and ~38% reduction in serum cholesterol, resonating well with previous reports in the literature. In EGCG-treated mice, the hepatic steatosis score and the non-alcoholic steatohepatitis activity score were both reduced by ~50% and ~57%, respectively, accompanied by improvements in hepatic inflammation grade. Liver enzymes were improved ~2–3-fold following EGCG treatment, recapitulating previous reports. Hepatic flow cytometry demonstrated that EGCG-fed mice had lower Ly6C+, MHCII+ and higher CD206+, CD23+ hepatic macrophage infiltration, indicating that EGCG impactedM1/M2 macrophage polarization. Our study further validates the salubrious effects of EGCG on NAFLD and sheds light on a novel mechanistic contribution of EGCG, namely hepatic M1-to-M2 macrophage polarization. These findings offer further support for the use of EGCG in human NAFLD.

Alpha-1 antitrypsin governs alcohol-related liver disease in mice and humans

ObjectiveAlcohol-related liver disease (ALD) is a global healthcare problem with limited treatment options. Alpha-1 antitrypsin (AAT, encoded by SERPINA1) shows potent anti-inflammatory activities in many preclinical and clinical trials. In...

Renohepatic crosstalk: a review of the effects of acute kidney injury on the liver.

Several theories regarding acute kidney injury (AKI)-related mortality have been entertained, although mounting evidence supports the paradigm that impaired kidney function directly and adversely affects the function of several remote organs. The kidneys and liver are fundamental to human metabolism and detoxification, and it is therefore hardly surprising that critical illness complicated by hepatorenal dysfunction portends a poor prognosis. Several diseases can simultaneously impact the proper functioning of the liver and kidneys, although this review will address the impact of AKI on liver function. While evidence for this relationship in humans remains sparse, we present supportive studies and then discuss the most likely mechanisms by which AKI can cause liver dysfunction. These include 'traditional' complications of AKI (uremia, volume overload and acute metabolic acidosis, among others) as well as systemic inflammation, hepatic leukocyte infiltration, cytokine-mediated liver injury and hepatic oxidative stress. We conclude by addressing the therapeutic implications of these findings to clinical medicine.

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