Subsequent Liver Research Articles

SAT-223 Metastatic Pheochromocytoma in MEN2A: Clinical Features, Laboratory Data and Radiological Findings of a Rare Association - Case Report

Background: Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant syndrome caused by inactivating mutations in the RET proto-oncogene. It is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and hyperparathyroidism (HPTH). MTC is one of the initial manifestations in 90% of patients. PHEO affects approximately 50% of patients, is almost always benign (98% of cases), usually bilateral and confined to the adrenal glands. HPTH occurs in 20-30% of patients. The clinical presentation, evolution and prognosis of metastatic PHEO associated with RET mutations are not yet well known. Clinical Case: A previously healthy man was initially diagnosed with hypertension at 24 years of age. Two years later, after recurrent paroxysms of headache, tremors and tachycardia, the patient was suspected of having bilateral PHEO based on laboratory and radiological findings. Bilateral adrenalectomy was performed and the anatomopathological analysis confirmed the suspected diagnosis.Soon afterward, although the patient was asymptomatic, with urinary metanephrines in the normal range, two possibly metastatic lesions were identified – one in the liver (9 x 8 mm) and one in the left adrenal bed. Some of the patient’s family members were also found to have PHEO and/or MTC, leading to the diagnosis of MEN2A. A RET germline mutation in codon 634 (p.Cys634Phe) of exon 11 was then found in the patient’s family pedigree. At the time, the patient (index case) had no evidence of MTC or HPTH.Diagnostic 131I-MIBG scintigraphy showed increased uptake in the patient’s liver. The subsequent percutaneous liver biopsy confirmed the presence of metastatic PHEO. Interestingly, no significant 18F-FDG uptake was found on the 18F-FDG-PET/CT scan in the metastatic PHEO sites. For more than 10 years of follow-up with no specific treatment, the metastatic lesions demonstrated slow growth rates; metanephrine levels, although increased (total = 1422 mcg/24h, NR <1000; normetanephrine = 676 mcg/24h, NR <320; and metanephrine = 574 mcg/24h, NR <390), were relatively stable; blood pressure and adrenergic symptoms were under control with a few antihypertensive medications.At 36 years of age, the calcitonin level was slightly increased (8.6 pg/mL, NR <8.4) and a minuscule thyroid nodule (3 x 3 x 2 mm) was identified on the ultrasound scan. Prophylactic thyroidectomy was performed, with a diagnosis of a 2.5-mm MTC. More recently, an increase in the metanephrine levels was found and treatment with iobenguane 131I may be an option. Conclusion: Patients with metastatic PHEO caused by mutations in the RET proto-oncogene (MEN2A) may have a long survival time. In such patients, an 18F-FDG-PET/CT scan may exhibit low sensitivity for the diagnosis of metastasis and the onset of PHEO may precede that of MTC by many years.

Association between NR1I2 polymorphisms and susceptibility to anti-tuberculosis drug-induced hepatotoxicity in an Eastern Chinese Han population: A case-control study

ObjectiveAnti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction, and its pathogenic mechanism is still largely unknown. Pregnane X receptor (PXR, encoded by the NR1I2 gene) is a ligand-dependent transcription factor, and rifampicin is a human PXR-specific activator. Rifampicin and isoniazid co-therapy targets porphyrin biosynthesis via PXR and results in hepatic protoporphyrin IX accumulation and subsequent liver injury. The present study aimed to investigate the associations between genetic polymorphisms in NR1I2 and ATDH in an Eastern Chinese Han population. MethodsA 1:4 matched case-control study was conducted using 146 ATDH cases and 584 controls. Seven single nucleotide polymorphisms (SNPs) were detected and analysed. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATDH by the odds ratios (ORs) with 95% confidence intervals (CIs), with liver disease history, hepatoprotectant use, smoking history and drinking history as covariates. ResultsPatients carrying the GG genotype of rs7643645 were at a higher risk of ATDH than those carrying the AA genotype (OR = 1.864, 95% CI: 1.106–3.141, P = .020), and significant differences were also found under the recessive model (P = .029) and additive model (P = .021). Patients with a polymorphism at rs2276707 were at a reduced risk of ATDH under the recessive model (OR = 0.600, 95% CI: 0.364–0.988, P = .045). Subgroup analysis confirmed the relationship in mild hepatotoxicity cases under the additive model (rs7643645, OR = 1.429, 95% CI: 1.027–1.988, P = .034) and recessive model (rs2276707, OR = 0.478, 95% CI: 0.253–0.902, P = .023). Functional annotation using ENCODE data also indicated that rs2276707 and rs7643645 were located in the histone modification regions targeting enhancers or promoter (H3K4Me1, H3K4Me3 and H3K27Ac). ConclusionsBased on this case-control study, SNPs rs7643645 and rs2276707 in NR1I2 may contribute to susceptibility to ATDH in Eastern Chinese Han anti-TB treatment patients. Further studies in larger varied populations are needed to validate our findings.

Activation of TREM1 Signaling in Kupffer Cells Following HIV and HCV Stimulation Augments Hepatic Inflammatory Responses

Abstract In this study, we sought to examine inflammatory responses following HIV or HCV stimulation of macrophages or Kupffer cells (KCs), that may contribute to virus mediated inflammation and subsequent liver disease. KCs are liver-resident macrophages and reports have provided evidence that HIV can stimulate and infect them. In order to characterize HIV-intrinsic innate immune responses that may occur in the liver, we performed microarray analyses on KCs following HIV stimulation. Our data demonstrate that KCs upregulate several innate immune signaling pathways involved in inflammation, myeloid cell maturation, stellate cell activation, and Triggering Receptor Expressed on Myeloid cells 1 (TREM1) signaling. TREM1 is a member of the immunoglobulin superfamily of receptors and it is reported to be involved in systemic inflammatory responses due to its ability to amplify activation of host defense signaling pathways. Our data demonstrate that stimulation of KCs with HIV or HCV induces the upregulation of TREM1. Additionally, HIV viral proteins can upregulate expression of TREM1 mRNA through NF-κB signaling. Furthermore, activation of the TREM1 signaling pathway, with a targeted agonist, increased HIV or HCV-mediated inflammatory responses in macrophages due to enhanced activation of the ERK1/2 signaling cascade. Silencing TREM1 dampened inflammatory immune responses elicited by HIV or HCV stimulation. Finally, HIV and HCV infected patients exhibit higher expression and frequency of TREM1 and CD68 positive cells. Taken together, TREM1 induction by HIV contributes to chronic inflammation in the liver and targeting TREM1 signaling may be a therapeutic option to minimize HIV induced chronic inflammation.

Design and Simulation Study of Drug-Eluting Stents for Treating Hepatic Artery Stenosis Post Liver Transplantation

Hepatocellular carcinoma is amongst the most common cancers worldwide, accounting for nearly 1 million deaths annually. Early diagnosis would help in treating with chemotherapy and ablative techniques but with most of the liver being affected; only transplantation would be a treatment of choice. Apparently, after orthotopic liver transplantation (OLT), an issue of hepatic artery stenosis (HAS) can occur which would later lead to hepatic artery thrombosis (HAT), with subsequent liver failure in 30% of patients. Operative intervention or retransplantation has been the traditional solution but endovascular therapy has emerged as a less invasive treatment strategy which would include placing of the stents. In the present paper we would discuss about designing a MEMS-based drug-eluting stent and its simulation study using Comsol Multiphysics to understand how HAS could be treated. Keywords: hepatocellular carcinoma, hepatic artery thrombosis (HAT), hepatic artery stenosis (HAS), drug-eluting stent, simulation Cite this Article Shilpa Nagod, Sharanappa V. Halse. Design and Simulation Study of Drug-Eluting Stents for Treating Hepatic Artery Stenosis Post Liver Transplantation. Research & Reviews: A Journal of Bioinformatics . 2020; 7(1): 7–13p.

Intravenous Arginine Administration Benefits CD4+ T-Cell Homeostasis and Attenuates Liver Inflammation in Mice with Polymicrobial Sepsis.

This study investigated the effects of a single dose of arginine (Arg) administration at the beginning of sepsis on CD4+ T-cell regulation and liver inflammation in C57BL/6J mice. Mice were divided into normal control (NC), sham (SH), sepsis saline (SS), and sepsis Arg (SA) groups. An inducible nitric oxide (NO) synthase (iNOS) inhibitor was administered to additional sepsis groups to evaluate the role of NO during sepsis. Sepsis was induced using cecal ligation and puncture (CLP). The SS and SA groups received saline or Arg (300 mg/kg body weight) via tail vein 1 h after CLP. Mice were euthanized at 12 and 24 h post-CLP. Blood, para-aortic lymph nodes, and liver tissues were collected for further measurement. The findings showed that sepsis resulted in decreases in blood and para-aortic lymph node CD4+ T-cell percentages, whereas percentages of interleukin (IL)-4- and IL-17-expressing CD4+ T cells were upregulated. Compared to the SS group, Arg administration resulted in maintained circulating and para-aortic lymph node CD4+ T cells, an increased Th1/Th2 ratio, and a reduced Th17/Treg ratio post-CLP. In addition, levels of plasma liver injury markers and expression of inflammatory genes in liver decreased. These results suggest that a single dose of Arg administered after CLP increased Arg availability, sustained CD4+ T-cell populations, elicited more-balanced Th1/Th2/Th17/Treg polarization in the circulation and the para-aortic lymph nodes, and attenuated liver inflammation in sepsis. The favorable effects of Arg were abrogated when an iNOS inhibitor was administered, which indicated that NO may be participated in regulating the homeostasis of Th/Treg cells and subsequent liver inflammation during sepsis.

Long-term Outcomes and Survival in Moderate-severe Portopulmonary Hypertension After Liver Transplant

Portopulmonary hypertension is present in an estimated 5.3% to 8.5% of liver transplant candidates. Untreated, 5-year survival is estimated between 14% and 28%. Moderate-severe disease is a contraindication to liver transplant due to the high perioperative mortality, but patients optimized with pulmonary vasodilator therapy can become eligible for transplant. There is minimal data regarding posttransplant outcomes and ability to discontinue pulmonary vasodilator therapy posttransplant. We performed a single-center retrospective analysis to evaluate long-term outcomes of patients with moderate-severe portopulmonary hypertension who were optimized with pulmonary vasodilator therapy, became eligible for liver transplant, and subsequently underwent transplant. We identified 24 patients optimized with pulmonary vasodilator therapy who underwent subsequent liver transplantation and 25 patients who were treated with pulmonary vasodilator therapy alone. In the transplanted cohort, 1-year survival from portopulmonary hypertension diagnosis date: 95.8%, 3-year survival: 90.9%, and 5-year survival: 90.9%. Posttransplant; 1-, 3-, and 5-year survival was 86.9%. Among transplanted patients, 41.6% (10/24) were optimized with nonparenteral therapy. Following transplantation, 100% (14/14) of the surviving patients were able to discontinue parenteral therapy; median time: 7.2 months (interquartile range: 5.1-8.9 mo), while 61.9% (13/21) were able to discontinue pulmonary vasodilator therapy altogether; median time: 13.9 months (interquartile range: 5.1-17.6 mo). Patients who are optimized with pulmonary vasodilator therapy before liver transplant can have excellent long-term outcomes posttransplant. Oral pulmonary vasodilator therapy can be effective treatment to qualify a patient for transplant, and the majority are able to wean from pulmonary vasodilator therapy entirely posttransplant.

Natural Toxins of Ageratum conyzoides from Hepatic Vein Occlusive Disease Affected Community in Ethiopia

Pyrrolizidine alkaloids (PAs) are phytotoxins produced by plants as a secondary metabolite against herbivores. PAs account for acute hepatotoxic, mutagenic, carcinogenic and teratogenic effects in humans and animals. In vivo PA intoxications of humans and animals are well documented all over the globe. The current study investigated the toxicological chemical make-up of Ageratum conyzoides L, collected from North Western Zones of Tigray region of Ethiopia, where episodic outbreak of hepatic veno-occlusive disease (HVOD) occurred. During the episodic outbreak multiple hundred deaths were reported due to PAs intoxications. PAs contamination occurred through food items such as millet in the farm fields. This study has led to take interventional measures against the causative agents to cease the morbidity and mortality. The identified PAs possesses the 1:2 double bond in the pyrrole ring necessary for in vivo activation and subsequent liver intoxications. The presence of Angeloyl-platynecine, Angeloyl-retronecine, and the macrocyclic, Seneciphylline alkaloids in A. conyzoides L. is not known previously. Isolation of the different PAs were realized by column chromatography (CC) with silica gel, sephadex-LH-20 for size exclusion CC and cationexchanger (CE). PA detection was performed by TLC with Ehrlich reaction method of Mattocks and their identification with gas-chromatography/mass-spectrometry (GC-MS) equipped with standard PAs library. PA containing plants and compounds should be under the watchlist to prevent similar outbreaks worldwide.

Abstract No. 646 Natural history of transjugular intrahepatic portosystemic shunts: long-term analysis of survival and protective factors

To evaluate long-term survival in patients with portal hypertension treated with transjugular intrahepatic portosystemic shunts (TIPS) and to identify patient characteristics associated with improved survival. This is a multicenter retrospective cohort study. Patients who received TIPS between January 1, 2008 and December 31, 2014 were included in this study. Patient data was collected between the time of procedure and September 1, 2019. Statistical analysis was performed using SPSS (IBM, New York). 129 patients are included in this study, 84 males and 45 females, with a median age of 61. 32% of patients had chronic hepatitis C, 33% had a history of alcohol use disorder, and 19% of patients had nonalcoholic steatohepatitis (NASH). The remainder of patients had miscellaneous etiologies of cirrhosis including autoimmune biliary cirrhosis, hepatitis B, and cystic fibrosis. 77% of patients had variceal bleeding and 34% of patients had refractory ascites prior to their procedures. 14% of patients had a history of hepatic encephalopathy. The technical success rate was 91% and overall complication rate was 30%. 1-, 3-, 5-, 7-, and 10-year survival rates are as follows: 93%, 74%, 58%, 38%, and 15%. 19% of patients had at least one episode of ascites requiring therapeutic paracentesis and 16% of patients experienced variceal hemorrhage during the follow-up period. 28% of patients required revision to expand their TIPS and 4% of patients required revision to constrain their TIPS. 56% of patients had episodes of hepatic encephalopathy during the follow-up period requiring hospitalization. 25% of patients experienced a decline in renal function of at least one stage. 21% of patients underwent subsequent liver transplantation. Female sex, preprocedural variceal bleeding rather than ascites, and NASH etiology of cirrhosis were associated with higher rates of overall survival. TIPS are crucial for many patients with symptomatic portal hypertension. Female sex, preprocedural variceal bleeding rather than ascites, and NASH as etiology of cirrhosis are associated with increased rates of long-term survival.

Extended hypothermic oxygenated machine perfusion enables ex situ preservation of porcine livers for up to 24 hours.

Background & AimsEnd-ischemic hypothermic oxygenated machine perfusion (HOPE) of the donor liver for 1–2 h mitigates ischemia-reperfusion injury during subsequent liver transplantation. Extended preservation time may be preferred to facilitate difficult recipient hepatectomy or to optimize logistics. We therefore investigated whether end-ischemic dual HOPE (DHOPE) could extend preservation time for up to 24 h using a porcine liver reperfusion model.MethodsFollowing 30 min warm ischemia, porcine livers were subjected to 2 h static cold storage (SCS), followed by 2 h, 6 h, or 24 h DHOPE (n = 6 per group). Subsequent normothermic reperfusion was performed for 4 h using autologous blood. Two livers preserved by 24 h SCS served as additional controls. A proof of principle confirmation was carried out in 2 discarded human livers subjected to extended DHOPE. Hepatocellular and cholangiocyte injury and function were assessed. Oxidative stress levels and histology were compared between groups.ResultsPerfusion flows remained stable during DHOPE, regardless of duration. After normothermic reperfusion, livers perfused for 24 h by DHOPE had similar lactate clearance, blood pH, glucose, and alanine aminotransferase levels, and biliary pH, bicarbonate, and LDH levels, as livers perfused for 2 h and 6 h. Levels of malondialdehyde and high-mobility group box 1 in serum and liver parenchyma were similar for all groups. Histological analysis of bile ducts and liver parenchyma revealed no differences between the groups. Extended DHOPE in discarded human livers preserved hepatocellular and cholangiocyte function and histology after reperfusion. In contrast, livers preserved by 24 h SCS were non-functioning.ConclusionExtended end-ischemic DHOPE enabled successful preservation of porcine and discarded human donor livers for up to 24 h. Extended DHOPE enables safe extension of preservation time, which may facilitate allocation and transplantation from a logistical perspective, and further expand the donor pool.Lay summaryIt has been suggested that preserving liver grafts with a technique called (dual) hypothermic oxygenated machine perfusion ([D]HOPE) leads to better outcomes after transplantation than if livers are stored on ice, especially if an organ is of lesser quality. In this study, we showed that DHOPE could be used to preserve liver grafts for up to 24 h. This extended procedure could be used globally to facilitate transplantation and expand the donor pool.

Influence of primary tumour and patient factors on survival in patients undergoing curative resection and treatment for liver metastases from colorectal cancer.

BackgroundResection of the primary tumour is a prerequisite for cure in patients with colorectal cancer, but hepatic metastasectomy has been used increasingly with curative intent. This national registry study examined prognostic factors for radically treated primary tumours, including the subgroup of patients undergoing liver metastasectomy.MethodsPatients who had radical resection of primary colorectal cancer in 2009–2013 were identified in a population‐based Swedish colorectal registry and cross‐checked in a registry of liver tumours. Data on primary tumour and patient characteristics were extracted and prognostic impact was analysed.ResultsRadical resection was registered in 20 853 patients; in 38·7 per cent of those registered with liver metastases, surgery or ablation was performed. The age‐standardized relative 5‐year survival rate after radical resection of colorectal cancer was 80·9 (95 per cent c.i. 80·2 to 81·6) per cent, and the rate after surgery for colorectal liver metastases was 49·6 (46·0 to 53·2) per cent. Multivariable analysis identified lymph node status, multiple sites of metastasis, high ASA grade and postoperative complications after resection of the primary tumour as strong risk factors after primary resection and following subsequent liver resection or ablation. Age, sex and primary tumour location had no prognostic impact on mortality after liver resection.ConclusionLymph node status and complications have a negative impact on outcome after both primary resection and liver surgery. Older age and female sex were underrepresented in the liver surgical cohort, but these factors did not influence prognosis significantly.

Wischnewsky lesions in a morbidly obese man with cirrhosis, liver failure and cardiomegaly: can this be hypothermia?

Obesity is an increasingly prevalent co-morbidity that is associated with sudden unexpected death and is commonly encountered in post mortem practice. Due to the effects of increased body-habitus it is, however, uncommon to encounter a death in an obese individual from hypothermia, especially during non-winter seasons. This case documents a hypothermic death in a setting of morbid obesity and subsequent liver failure and cardiomegaly where widespread Wischnewsky lesions and slightly elevated beta-hydroxybutyrate were noted, with non-elevated blood sugar levels. In this rare case, the only identifiable predisposing factor to hypothermia was metabolic derangement resulting in altered energy metabolism.

Fibrotic liver has prompt recovery after ischemia-reperfusion injury.

Hepatic ischemia-reperfusion (I/R) is a major complication of liver resection, trauma, and liver transplantation; however, liver repair after I/R in diseased liver has not been studied. The present study sought to determine the manner in which the fibrotic liver repairs itself after I/R. Liver fibrosis was established in mice by CCl4 administration for 6 wk, and then liver I/R was performed to investigate liver injury and subsequent liver repair in fibrotic and control livers. After I/R, fibrotic liver had more injury compared with nonfibrotic, control liver; however, fibrotic liver showed rapid resolution of liver necrosis and reconstruction of liver parenchyma. Marked accumulation of hepatic stellate cells and macrophages were observed specifically in the fibrotic septa in early reparative phase. Fibrotic liver had higher numbers of hepatic stellate cells, macrophages, and hepatic progenitor cells during liver recovery after I/R than did control liver, but hepatocyte proliferation was unchanged. Fibrotic liver also had significantly greater number of phagocytic macrophages than control liver. Clodronate liposome injection into fibrotic mice after I/R caused decreased macrophage accumulation and delay of liver recovery. Conversely, CSF1-Fc injection into normal mice after I/R resulted in increased macrophage accumulation and concomitant decrease in necrotic tissue during liver recovery. In conclusion, fibrotic liver clears necrotic areas and restores normal parenchyma faster than normal liver after I/R. This beneficial response appears to be directly related to the increased numbers of nonparenchymal cells, particularly phagocytic macrophages, in the fibrotic liver.NEW & NOTEWORTHY This study is the first to reveal how diseased liver recovers after ischemia-reperfusion (I/R) injury. Although it was not completely unexpected that fibrotic liver had increased hepatic injury after I/R, a novel finding was that fibrotic liver had accelerated recovery and repair compared with normal liver. Enhanced repair after I/R in fibrotic liver was associated with increased expansion of phagocytic macrophages, hepatic stellate cells, and progenitor cells.

Late mortality and causes of death among long-term survivors after autologous hematopoietic stem cell transplantation.

By evaluating risks of late mortality and causes of death among long-term survivors after autologous hematopoietic stem cell transplantation (HSCT) in Japan, we clarified what we should focus on during follow-up to reduce them. The study cohort included 6,780 patients who had survived for ≥2 years after the first autologous HSCT performed from 1974 to 2012 for hematological diseases. With a median follow-up of 6.0 years among survivors, overall survival probabilities at 5 and 10 years after HSCT were 92% and 83%, respectively. Eight hundred thirty deaths occurred: 451, recurrent primary diseases; 87, subsequent solid cancers; 57, subsequent hematological malignancies; 55, infections; 41, respiratory diseases; 19, cardiovascular diseases; 15, liver diseases; 10, neurological diseases; and 7, kidney/genitourinary diseases (Except small numbers of other causes and missing). According to the log-rank test, the risk of overall mortality was remarkably increased among HSCT recipients compared with the that in the general Japanese population (observed/expected ratio [O/E]=5.4; 95% confidence interval [CI], 5.0-5.8). The risks of cause-specific mortality increased with infection (O/E=6.8; 95% CI, 5.1-8.8), subsequent solid cancers (O/E=1.4; 95% CI, 1.1-1.7), subsequent hematological malignancies (O/E=14.3; 95% CI, 10.8-18.5), kidney/genitourinary diseases (O/E=3.4; 95% CI, 1.4-7.1), respiratory disease (O/E=9.0; 95% CI, 6.5-1.2), and liver diseases (O/E=2.6; 95% CI, 1.4-4.2). Long-term survivors after autologous HSCT are at an increased risk of death due to secondary cancers, infections, and any organ diseases as well as recurrence compared to the general population. When monitoring these patients in the outpatient clinic, it is important for physicians to predict a change in the patient's condition and to start treatment earlier.

Liver organoids reproduce alpha-1 antitrypsin deficiency-related liver disease

Background and aimsAlpha-1 antitrypsin (AAT) is a product of SERPINA1 gene mainly expressed by hepatocytes. Clinically relevant mutations in the SERPINA1 gene, such as Z (Glu342Lys), results in an expression of misfolded AAT protein having high propensity to polymerize, accumulate in hepatocytes and thus to enhance a risk for hepatocyte damage and subsequent liver disease. So far, the relationship between the Z-AAT accumulation and liver cell damage remains not completely understood. We present three-dimensional organoid culture systems, as a novel tool for modeling Z-AAT-related liver diseases.MethodsWe have established liver organoids from liver biopsies of patients with homozygous (ZZ) and heterozygous (MZ) deficiency and normal (MM) genotypes of AAT. The features of these organoid models were characterized by analyzing AAT protein secretion and intracellular aggregation in MZ and ZZ genotypes as well as SERPINA1 expression in differentiated cultures.ResultsTranscriptional analysis of differentiated organoid cultures by RNA-Seq showed hepatocyte-specific gene expression profile. Genes, such as ALB, APOB, CYP3A4 and SERPINA1, were validated and confirmed through quantitative-PCR analysis. The organoids from MZ and ZZ cases showed intracellular aggregation and lower secretion of AAT protein, and lower expression of ALB and APOB, as typically seen in hepatocytes from Z-AAT deficiency patients. Furthermore, organoids responded to external stimulus. Treatment with oncostatin M, a well-known inducer of SERPINA1, increased expression of the full-length transcripts (AAT-1C) as well as the short transcript of AAT (AAT-ST1C4).ConclusionsLiver organoid model recapitulates the key features of Z-AAT deficiency and provides a useful tool for disease modeling.

Thymoquinone and curcumin modify inducible nitric oxide synthase, caspase 3, and thioredoxin immunohistochemical expression in acetaminophen hepatotoxicity.

Acetaminophen (APAP) hepatotoxicity is characterised by an extensive oxidative stress due to depletion of glutathione (GSH), which results in massive lipid peroxidation and subsequent liver injury. The current paradigm suggests that mitochondria are the main source of reactive oxygen species (ROS), which impair mitochondrial function and are responsible for cell signalling resulting in cell death. This study was designed to compare the potential impact of thymoquinone (THQ), and/or curcumin (CURC) on liver injury induced by APAP toxicity in rats. Serum levels of alanine transaminase, aspartate transaminase, total bilirubin, and total protein were measured. In addition, liver nitric oxide (NO), malondialdehyde, reduced glutathione (GSH), and superoxide dismutase (SOD) were estimated. Moreover, these biochemical parameters were confirmed by histopathological and immunohistochemical investigations for the expression of thioredoxin, iNOS and caspase 3. Acetaminophen toxicity elevated most of the above-mentioned parameters but decreased GSH, SOD, and total protein levels. Histologically, liver sections demonstrated liver injury characterised by hepatocellular necrosis with nuclear pyknosis, karyorrhexis and karyolysis. Immunohistochemical study revealed increased expression of iNOS and caspase 3 proteins, while the thioredoxin protein expression was decreased. Treatment with the THQ and CURC regulated the biochemical and histopathological alterations induced by APAP toxicity. It was concluded that the combination strategy of THQ and CURC might be considered as a potential antidote in combating liver injury induced by APAP with minimal side effects.

Effect of Different Adjuvants on the Longevity and Strength of Humoral and Cellular Immune Responses to the HCV Envelope Glycoproteins.

Infection by Hepatitis C virus (HCV) can lead to liver cirrhosis/hepatocellular carcinoma and remains a major cause of serious disease morbidity and mortality worldwide. However, current treatment regimens remain inaccessible to most patients, particularly in developing countries, and, therefore, the development of a novel vaccine capable of protecting subjects from chronic infection by HCV could greatly reduce the rates of HCV infection, subsequent liver pathogenesis, and in some cases death. Herein, we evaluated two different semi-synthetic archaeosome formulations as an adjuvant to the E1/E2 HCV envelope protein in a murine model and compared antigen-specific humoral (levels of anti-E1/E2 IgG and HCV pseudoparticle neutralization) and cellular responses (numbers of antigen-specific cytokine-producing T cells) to those generated with adjuvant formulations composed of mimetics of commercial adjuvants including a squalene oil-in-water emulsion, aluminum hydroxide/monophosphoryl lipid A (MPLA) and liposome/MPLA/QS-21. In addition, we measured the longevity of these responses, tracking humoral, and cellular responses up to 6 months following vaccination. Overall, we show that the strength and longevity of anti-HCV responses can be influenced by adjuvant selection. In particular, a simple admixed sulfated S-lactosylarchaeol (SLA) archaeosome formulation generated strong levels of HCV neutralizing antibodies and polyfunctional antigen-specific CD4 T cells producing multiple cytokines such as IFN-γ, TNF-α, and IL-2. While liposome/MPLA/QS-21 as adjuvant generated superior cellular responses, the SLA E1/E2 admixed formulation was superior or equivalent to the other tested formulations in all immune parameters tested.

Liver sympathetic nerve activity and steatosis.

Liver sympathetic nerve activity and steatosis.

Hepatotoxicity and the role of the gut-liver axis in rats after oral administration of titanium dioxide nanoparticles

BackgroundDue to its excellent physicochemical properties and wide applications in consumer goods, titanium dioxide nanoparticles (TiO2 NPs) have been increasingly exposed to the environment and the public. However, the health effects of oral exposure of TiO2 NPs are still controversial. This study aimed to illustrate the hepatotoxicity induced by TiO2 NPs and the underlying mechanisms. Rats were administered with TiO2 NPs (29 nm) orally at exposure doses of 0, 2, 10, 50 mg/kg daily for 90 days. Changes in the gut microbiota and hepatic metabolomics were analyzed to explore the role of the gut-liver axis in the hepatotoxicity induced by TiO2 NPs.ResultsTiO2 NPs caused slight hepatotoxicity, including clear mitochondrial swelling, after subchronic oral exposure at 50 mg/kg. Liver metabolomics analysis showed that 29 metabolites and two metabolic pathways changed significantly in exposed rats. Glutamate, glutamine, and glutathione were the key metabolites leading the generation of energy-related metabolic disorders and imbalance of oxidation/antioxidation. 16S rDNA sequencing analysis showed that the diversity of gut microbiota in rats increased in a dose-dependent manner. The abundance of Lactobacillus_reuteri increased and the abundance of Romboutsia decreased significantly in feces of TiO2 NPs-exposed rats, leading to changes of metabolic function of gut microbiota. Lipopolysaccharides (LPS) produced by gut microbiota increased significantly, which may be a key factor in the subsequent liver effects.ConclusionsTiO2 NPs could induce slight hepatotoxicity at dose of 50 mg/kg after long-term oral exposure. The indirect pathway of the gut-liver axis, linking liver metabolism and gut microbiota, played an important role in the underlying mechanisms.

Histopathological changes of acetaminophen-induced liver injury and subsequent liver regeneration in BALB/C and ICR mice.

Background and Aim:Laboratory mice are widely used as a research model to provide insights into toxicological studies of various xenobiotic. Acetaminophen (APAP) is an antipyretic and analgesic drug that is commonly known as paracetamol, an ideal hepatotoxicant to exhibit centrilobular necrosis in laboratory mice to resemble humans. However, assessment of histopathological changes between mouse strains is important to decide the optimal mouse model used in APAP toxicity study. Therefore, we aim to assess the histomorphological features of APAP-induced liver injury (AILI) in BALB/C and Institute of Cancer Research (ICR) mice.Materials and Methods:Twenty-five ICR mice and 20 BALB/C mice were used where five animals as control and the rest were randomly divided into four time points at 5, 10, 24 and 48 hours post-dosing (hpd). They were induced with 500 mg/kg APAP intraperitoneally. Liver sections were processed for hematoxylin-eosin staining and histopathological changes were scored based on grading methods.Results:Intense centrilobular damage was observed as early as 5 hpd in BALB/C as compared to ICR mice, which was observed at 10 hpd. The difference of liver injury between ICR and BALB/C mice is due to dissimilarity in the genetic line-up that related to different elimination pathways of APAP toxicity. However, at 24 hpd, the damage was markedly subsided and liver regeneration had taken place for both ICR and BALB/C groups with evidence of mitotic figures. This study showed that normal liver architecture was restored after the clearance of toxic insult.Conclusion:AILI was exhibited earlier in BALB/C than ICR mice but both underwent liver recovery at later time points.

METTL3-mediated m6A modification of HDGF mRNA promotes gastric cancer progression and has prognostic significance

ObjectiveN6-methyladenosine (m6A) RNA methylation and its associated methyltransferase METTL3 are involved in tumour initiation and progression via the regulation of RNA function. This study explored the biological function and clinical...