Si-Wu-Tang attenuates hepatocyte PANoptosis and M1 polarization of macrophages in non-alcoholic fatty liver disease by influencing the intercellular transfer of mtDNA.

ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) represents a burgeoning challenge for public health with potential progression to malignant liver diseases. PANoptosis, an avant-garde conceptualization of cell deaths, is closely associated with mitochondrial damage and linked to multiple liver disorders. Si-Wu-Tang (SWT), a traditional Chinese herbal prescription renowned for regulating blood-related disorders and ameliorating gynecological and hepatic diseases, has been demonstrated to alleviate liver fibrosis by regulating bile acid metabolism and immune responses. AIM OF THE STUDY: However, the mechanisms by which mtDNA is released from PANoptotic hepatocytes, triggering macrophage activation and hepatitis and whether this process can be reversed by SWT remain unclear. MATERIALS AND METHODS: Here, sophisticated RNA-sequencing complemented by molecular approaches were applied to explore the underlying mechanism of SWT against NAFLD in methionine/choline-deficient diet (MCD)-induced mice and relative in vitro models. RESULTS: We revealed that SWT profoundly repaired mitochondrial dysfunction, blocked mitochondrial permeability transition and mtDNA released to the cytoplasm, subsequently reversing hepatocyte PANoptosis and macrophage polarization both in MCD-stimulated mice and in vitro. Mechanically, loaded lipids dramatically promoted the opening of mPTP and oligomerization of VDAC2 to orchestrate mtDNA release, which was combined with ZBP1 to promote hepatocyte PANoptosis and also taken by macrophages to trigger M1 polarization via the FSTL1 and PKM2 combination. SWT effectively blocked NOXA signaling and reversed all these detrimental outcomes. CONCLUSION: Our findings show that SWT protects against hepatitis-mediated hepatocyte PANoptosis and macrophage M1 polarization by influencing intrahepatic synthesis, release and intercellular transfer of mtDNA, suggesting a potential therapeutic strategy for ameliorating NAFLD.

Corticosteroid-resistant immune-related adverse events: a systematic review.

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.

Liuweiwuling Tablet relieves the inflammatory transformation of hepatocellular carcinoma by inhibiting the PI3K/AKT/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Liuweiwuling Tablet (LWWL) is a patented Chinese medicine approved by the Chinese National Medical Products Administration (NMPA). Clinically, it is used to treat a range of liver diseases that precede hepatocellular carcinoma (HCC), including hepatitis, liver fibrosis and cirrhosis. LWWL is hypothesized to inhibit the inflammatory transformation of HCC, which may have a positive impact on the prevention and treatment of HCC. However, its exact mechanism of action remains unknown. AIM OF THE STUDY: To investigate how LWWL is effective in the treatment of HCC and to validate the pathways involved in this process. MATERIALS AND METHODS: An in vivo model of HCC induced by diethylnitrosamine (DEN) was established to study the effect of LWWL on the development of HCC. The rat serum was analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (γ-GT). The rat liver tissues were stained with hematoxylin and eosin (HE) and Masson's trichrome for pathological analysis. Rat liver tissue was subjected to transcriptome sequencing. Expression of inflammatory and liver fibrosis-related factors in bone marrow-derived macrophages (BMDMs) and LX-2 cells was detected by QRT-PCR, ELISA and Western blot (WB). The expression of apoptosis and stemness genes in HepG2 and Huh7 cells was assessed through flow cytometry and QRT-PCR. Transcriptomics, network pharmacology, WB, and QRT-PCR were employed to validate the mechanisms associated with the amelioration of HCC development by LWWL. RESULTS: LWWL significantly reduced the severity of hepatitis and liver fibrosis, the expression of tumor stemness genes, and the incidence of HCC. In addition, LWWL inhibited the release of inflammatory substances and nuclear accumulation of P65 protein in BMDMs as well as the conversion of LX-2 cells to fibroblasts. LWWL inhibited the proliferation of HepG2 and Huh7 cells, including the initiation of apoptosis and the reduction of stemness gene expression. Importantly, LWWL regulates the PI3K/AKT/NF-κB pathway, which affects hepatic inflammation and cancer progression. CONCLUSION: LWWL inhibited the occurrence and development of HCC by modulating the severity of hepatitis and liver fibrosis, indicating the potential clinical relevance of LWWL in preventing and treating HCC.

Network pharmacology and molecular docking technology for exploring the effect and mechanism of Radix Bupleuri and Radix Paeoniae Alba herb-pair on anti-hepatitis: A review.

The Radix Bupleuri and Radix Paeoniae Alba herb-pair (RRH) are the most classic compatible drug pair for the treatment of hepatitis. However, the underlying mechanism remains unclear. Therefore, network pharmacology and molecular docking were conducted to investigate the prospective therapeutic constituents, targets, and pharmacological mechanisms of RRH in the treatment of hepatitis. The active components of RRH from the TCMSP database and disease-related targets from the OMIM, PharmGkb, GeneCards, TTD, and DrugBank databases were identified. The "drug-target-disease" network diagram and protein-protein interaction (PPI) network were constructed using Cytoscape (v3.8.0) and Online STRING 11.0. GO and KEGG pathway enrichment analyses were performed using R version 4.1.2, and molecular docking was performed to verify the results. We placed 176 overlapping cross genes into Online STRING 11.0 and obtained 14 core targets. A "Component-Target-GO-KEGG" network diagram was constructed, which was composed of 7 components, 14 targets, 10 biological processes, and 10 signal pathways. A total of 2413 GO biological processes and 174 KEGG pathways were explored for hepatitis treatment. Quercetin, kaempferol, isorhamnetin, and beta-sitosterol, which are the main bioactive components, were employed to bind the disease's hub targets, ensuring fulfillment of spatial and energy matching. The anti-hepatitis mechanism of RRH may be associated with several targets including RELA, AKT1, JUN, MAPK1, TP53, CCND1, MYC, NFKBIA, CDKN1A, and their respective signaling pathways. The main bioactive components in RRH, including quercetin, kaempferol, isorhamnetin, and beta-sitosterol, were used to bind the hub targets of the disease, which may provide insights into drug development for hepatitis.

Acute liver failure and aplastic crisis due to anorexia nervosa in an adolescent girl: a case report.

Anorexia nervosa (AN) has a high mortality rate due to the widespread organ dysfunction caused by the underlying severe malnutrition. Malnutrition-induced hepatitis is common among individuals with AN especially as body mass index decreases, while acute liver failure and aplastic crisis related to coagulation disease and encephalopathy rarely occur in AN patients. The supervised increase of caloric intake can quickly improve the elevated aminotransferases caused by starvation and aplastic crisis. This current case report describes a 12-year-old adolescent girl who was admitted with a 3-month history of weight loss. Within 3 months, she had lost 10 kg of weight. The girl was diagnosed with AN, acute liver failure, severe malnutrition with emaciation, electrolyte disorder, bradycardia and aplastic crisis. She was gradually supplemented with vitamins and enteral nutrition to avoid refeeding syndrome. After treatment, her liver function and haematopoietic function returned to normal. In conclusion, acute liver failure and aplastic crisis are rare but potentially life-threatening complications of AN, which could be improved by supervised feeding and timely rehydration. AN should be considered as the potential aetiology of acute liver failure and aplastic crisis.

Alleviating effect of selenium-enriched Lactobacillus plantarum 6076 on dextran sulfate sodium-induced colitis and liver inflammation in mice.

The aim of this study is to investigate the alleviating effect of selenium-enriched Lactobacillus plantarum (SL) 6076 on colitis and liver inflammation induced by sodium dextran sulfate (DSS) in mice and its potential molecular mechanisms. Lactobacillus plantarum (LA) was cultured for 3 generations on MRS medium containing sodium selenite to generate SL. LA (3.2 × 1011 CFU mL-1), low selenium Lactobacillus plantarum (LS) (3.9 × 1010 CFU mL-1, 0.35 mg mL-1 Se) and high selenium Lactobacillus plantarum (HS) (2.8 × 1010 CFU mL-1, 0.52 mg mL-1 Se) were continuously fed to mice for 21 d to observe their effects on DSS-induced colitis and liver inflammation in mice. The composition of gut microbiota was detected through high-throughput 16S rRNA sequencing, and inflammatory cytokines, oxidative stress parameters, and serum biochemical indicators were measured in the colon and liver using quantitative polymerase chain reaction (qPCR) and biochemical analysis methods. The results showed that SL alleviated inflammation symptoms in the colon and liver, reduced the expression of inflammatory factors in the colon and liver, regulated oxidative stress responses in the colon, downregulated NF-κB-P65 pathway factors, and altered the composition and structure of the gut microbiota. In summary, DSS-induced colitis may cause liver inflammation, and SL had a significant relieving effect on both colon and liver inflammation. The intervention effect of SL was better than that of LA, while HS was better than LS. SL had a significant alleviating effect on DSS-induced colitis, and may exert its therapeutic effect by downregulating NF-κB-P65 signaling pathways and regulating the structure of intestinal microbiota. This study provides a new approach for the treatment of colitis.

Rhabdomyolysis or Severe Acute Hepatitis Associated with the Use of Red Yeast Rice Extracts: an Update from the Adverse Event Reporting Systems.

PURPOSE OF REVIEW: Elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) are a major risk factor for atherosclerotic cardiovascular disease (ASCVD), and lowering LDL-C reduces the risk of cardiovascular adverse events. Among natural approaches known for their lipid-lowering properties, red yeast rice (RYR) has a cholesterol-lowering effect due to the presence of bioactive components (monacolins) that act by inhibiting the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. In August 2018, the European Food Safety Authority (EFSA) concluded in its assessment of the use of RYR (further amended in June 2022) that monacolins from RYR raise significant safety concerns when used as a food supplement at a dose of 10 mg/day. In particular, individual cases of serious adverse effects of monacolins from RYR have been reported at intakes as low as 3 mg/day. The EFSA Panel pointed out several uncertainties regarding the available data. RECENT FINDINGS: We conducted an in-depth and updated analysis of the serious adverse events, with a focus on rhabdomyolysis and acute hepatitis, associated with the consumption of RYR. An analysis of the Food and Drug Administration reporting systems revealed a very small number of cases of rhabdomyolysis or severe acute hepatitis associated with RYR use. In addition, only a few case reports of these serious adverse events associated with RYR use have been published. Based on data from adverse event reporting systems and available case reports, the occurrence of rhabdomyolysis or severe acute hepatitis that could be associated with the use of RYR appears to be extremely rare compared to the occurrence with statins, which is rare to common.

Hibiscus-cisplatin combination treatment decreases liver toxicity in rats while increasing toxicity in lung cancer cells via oxidative stress- apoptosis pathway.

Cisplatin (CIS) is a broad-spectrum anti-carcinogen that causes cytotoxic effects both in normal and cancer cells. The purpose of this study was to test whether Hibiscus sabdariffa (HS) extract can reduce CIS-induced hepatotoxicity in rodents and to assess its anticancer activity in vitro. Treatment with HS extract at daily doses of 500 mg/kg before and after a single dose of CIS (10 mg/kg) reduced hepatotoxicity in Wistar male albino rats. HS extract reduced activity of hepatic damage marker enzymes ( i.e. alanine and aspartate aminotransferases), necrosis, and apoptosis in liver tissues of CIS-treated rats. This hepatic protection was associated with reduced oxidative stress in liver tissues. The antioxidant effects of HS were manifested as a normalization of malondialdehyde levels and glutathione levels which were all raised after CIS-induction. In addition, HS treatment resulted in a decrease of catalase, and superoxide dismutase activity. The combined effects of CIS and HS were also studied in two human lung cancer cell lines (A549 and H460). Treatment with HS (20 µg /mL) enhanced the cytotoxic activity of CIS both in A549 and H460 cell lines. Interestingly, HS increased CIS-induced apoptosis and oxidative stress more clearly in A549 cells indicating that HS extract in combination with CIS could increase the efficacy of CIS in the treatment of cancer.

Nervonic acid improves liver inflammation in a mouse model of Parkinson's disease by inhibiting proinflammatory signaling pathways and regulating metabolic pathways.

BACKGROUND: Nervonic acid (NA) - a type of bioactive fatty acid that is found in natural sources - can inhibit inflammatory reactions and regulate immune system balance. Therefore, the use of NA for the treatment of neurodegenerative diseases has received considerable attention. Our previous study found that NA inhibited inflammatory responses in the brain of Parkinson's disease (PD) mouse models. In addition to the brain, PD is also associated with visceral organ dysfunction, especially impaired liver function. Thus, studying the role of NA in PD-mediated inflammation of the liver is particularly important. METHODS: A combined transcriptome and metabolomic approach was utilized to investigate the anti-inflammatory effects of NA on the liver of PD mice. Inflammatory signaling molecules and metabolic pathway-related genes were examined in the liver using real-time PCR and western blotting. RESULTS: Liver transcriptome analysis revealed that NA exerted anti-inflammatory effects by controlling several pro-inflammatory signaling pathways, such as the down-regulation of the tumor necrosis factor and nuclear factor kappa B signaling pathways, both of which were essential in the development of inflammatory disease. In addition, liver metabolomic results revealed that metabolites related to steroid hormone biosynthesis, arachidonic acid metabolism, and linoleic acid metabolism were up-regulated and those related to valine, leucine, and isoleucine degradation pathways were down-regulated in NA treatment groups compared with the PD model. The integration of metabolomic and transcriptomic results showed NA significantly exerted its anti-inflammatory function by regulating the transcription and metabolic pathways of multiple genes. Particularly, linoleic acid metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis were the crucial pathways of the anti-inflammatory action of NA. Key genes in these metabolic pathways and key molecules in inflammatory signaling pathways were also verified, which were consistent with transcriptomic results. CONCLUSION: These findings provide novel insights into the liver protective effects of NA against PD mice. This study also showed that NA could be a useful dietary element for improving and treating PD-induced liver inflammation.

Blockade of C5aR1 alleviates liver inflammation and fibrosis in a mouse model of NASH by regulating TLR4 signaling and macrophage polarization.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is an advanced form of chronic fatty liver disease, which is a driver of hepatocellular carcinoma. However, the roles of the C5aR1 in the NASH remain poorly understood. Here, we aimed to investigate the functions and mechanisms of the C5aR1 on hepatic inflammation and fibrosis in murine NASH model. METHODS: Mice were fed a normal chow diet with corn oil (ND + Oil), a Western diet with corn oil (WD + Oil) or a Western diet with carbon tetrachloride (WD + CCl4) for 12 weeks. The effects of the C5a-C5aR1 axis on the progression of NASH were analyzed and the underlying mechanisms were explored. RESULTS: Complement factor C5a was elevated in NASH mice. C5 deficiency reduced hepatic lipid droplet accumulation in the NASH mice. The hepatic expression levels of TNFα, IL-1ß and F4/80 were decreased in C5-deficient mice. C5 loss alleviated hepatic fibrosis and downregulated the expression levels of α-SMA and TGFß1. C5aR1 deletion reduced inflammation and fibrosis in NASH mice. Transcriptional profiling of liver tissues and KEGG pathway analysis revealed that several pathways such as Toll-like receptor signaling, NFκB signaling, TNF signaling, and NOD-like receptor signaling pathway were enriched between C5aR1 deficiency and wild-type mice. Mechanistically, C5aR1 deletion decreased the expression of TLR4 and NLRP3, subsequently regulating macrophage polarization. Moreover, C5aR1 antagonist PMX-53 treatment mitigated the progression of NASH in mice. CONCLUSIONS: Blockade of the C5a-C5aR1 axis reduces hepatic steatosis, inflammation, and fibrosis in NASH mice. Our data suggest that C5aR1 may be a potential target for drug development and therapeutic intervention of NASH.

A Case Report of Acute Hepatitis Involving the Medicinal Herb Tinospora cordifolia Along with Other Variables.

This is a 54-year-old woman from Germany of central European origin who developed an acute hepatitis while orally taking Ayurvedic herbal remedies, among those was the medicinal herb Tinospora cordifolia. She took the plant powders from July 1, 2021, to October 1, 2021, with the intention of relieving the symptoms of her subjectively irritated gastrointestinal tract. The patient's main symptoms of acute hepatitis were progressively increasing general fatigue, nausea, and exhaustion. During an inpatient hospital admission from November 4, 2021, to November 9, 2021, she was under clinical observation, but no specific therapeutic measures were deemed necessary; however, blood chemistry showed an acute toxic hepatitis. There was no clinical or laboratory evidence of acute liver failure. Aminotransferase values decreased to normal values on December 14, 2021, by themselves. This case report contributes to the ongoing discussion about the potential risks of triggering an acute hepatitis due to the intake of herbal remedies from the Tinospora genus in rare cases, differentiating other involved risk factors. The case also shows that causality assignments are not trivial in the context of multivariate clinical scenarios. In the case of known hepatic metabolism-associated risk factors, T. cordifolia should be used with more caution based on available case reports. At the same time, no hasty and exaggerated prejudgments should be made about this medicinal herb, which has been very successfully used in traditional South Asian systems of medicine for many centuries.

Molecular imaging of liver inflammation using an anti-VCAM-1 nanobody.

To date, a biopsy is mandatory to evaluate parenchymal inflammation in the liver. Here, we evaluated whether molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) could be used as an alternative non-invasive tool to detect liver inflammation in the setting of chronic liver disease. To do so, we radiolabeled anti-VCAM-1 nanobody (99mTc-cAbVCAM1-5) and used single-photon emission computed tomography (SPECT) to quantify liver uptake in preclinical models of non-alcoholic fatty liver disease (NAFLD) with various degree of liver inflammation: wild-type mice fed a normal or high-fat diet (HFD), FOZ fed a HFD and C57BL6/J fed a choline-deficient or -supplemented HFD. 99mTc-cAbVCAM1-5 uptake strongly correlates with liver histological inflammatory score and with molecular inflammatory markers. The diagnostic power to detect any degree of liver inflammation is excellent (AUROC 0.85-0.99). These data build the rationale to investigate 99mTc-cAbVCAM1-5 imaging to detect liver inflammation in patients with NAFLD, a largely unmet medical need.

Astragaloside IV plays a role in reducing radiation-induced liver inflammation in mice by inhibiting thioredoxin-interacting protein/nod-like receptor protein 3 signaling pathway.

OBJECTIVE: To investigate the efficacy of Astragaloside IV (AS-IV) on radiation-induced liver inflammation in mice. METHODS: The mice were divided into normal group, dimethyl sulfoxide solvent group, irradiation group (IR), irradiation + AS-IV (20 mg/kg) group (IR+AS-20) and irradiation + AS-IV (40 mg/kg) group (IR+AS-40). One month after intraperitoneal injection of AS-IV, the mice were irradiated with 8Gry Co60γ, the blood was collected for biochemical analysis, and the liver was collected for hematoxylin-eosin staining, immunofluorescence and electron microscopic observation, oxidative stress, and Western blot analysis. RESULTS: The AS-IV treatment significantly ameliorated the pathological morphology of liver and reduced the alanine aminotransferase and aspertate amino-transferase levels in serum induced by radiation; AS-IV treatment also significantly reduced the expression of inflammatory factors tumor necrosis factor alpha and interleukin 6 and antagonized malonaldehyde content and superoxide dismutase activity in liver caused by radiation; in addition, AS-IV treatment can significantly inhibited the positive expression of thioredoxin-interacting protein (TXNIP) and nod-like receptor protein 3 (NLRP3) inflammasome in liver tissue after radiation; The expression of TXNIP, NLRP3 inflammasome, apoptosis-associated speck-like protein containing a CARD, cysteinyl aspartate-specific proteinase 1 and interleukin 1beta in the AS-IV prevention group decreased significantly compared to the radiation group. CONCLUSIONS: These findings suggested that Co60γ radiation can cause structural and functional damage to the liver, which may be related to the NLRP3 mediated inflammatory pathway; AS-IV may play a protective role by inhibiting the TXNIP/NLRP3 inflammasome signaling pathway in the radiation-induced liver injury model.

Corydalis saxicola Bunting: A Review of Its Traditional Uses, Phytochemistry, Pharmacology, and Clinical Applications.

Corydalis saxicola Bunting (CSB), whose common name in Chinese is Yanhuanglian, is a herb in the family Papaveraceae. When applied in traditional Chinese medicine, it is used to treat various diseases including hepatitis, abdominal pain, and bleeding haemorrhoids. In addition, Corydalis saxicola Bunting injection (CSBI) is widely used against acute and chronic hepatitis. This review aims to provide up-to-date information on the botanical distribution, description, traditional uses, phytochemistry, pharmacology, and clinical applications of CSB. A comprehensive review was implemented on studies about CSB from several scientific databases, such as SciFinder, Elsevier, Springer, ACS Publications, Baidu Scholar, CNKI, and Wanfang Data. Phytochemical studies showed that 81 chemical constituents have been isolated and identified from CSB, most of which are alkaloids. This situation indicates that these alkaloids would be the main bioactive substances and that they have antitumour, liver protective, antiviral, and antibacterial pharmacological activities. CSBI can not only treat hepatitis and liver cancer but can also be used in combination with other drugs. However, the relationships between the traditional uses and modern pharmacological actions, the action mechanisms, quality standards, and the material basis need to be implemented in the future. Moreover, the pharmacokinetics of CSBI in vivo and the toxicology should be further investigated.

Lycopene modulates hepatic toxicity and testicular injury induced by etoposide in male rats.

OBJECTIVE: Lycopene (C40H56), a carotenoid found in red colour fruits, is known as a powerful antioxidant that protects cells from damage caused by reactive oxygen species (ROS). Etoposide inhibits topoisomerase II activity and restricts the development of cancer cells, though it establishes oxidative stress. To study the effect of lycopene (Ly) against hepatotoxicity and testis injury induced by etoposide in male rats. ANIMALS: Forty male Wister albino rats. SETTINGS: The experiment lasted for seven consecutive weeks including one week as acclimatization time. DESIGN: The experiment was in a completely randomized design with a 2×2 factorial arrangement. INTERVENTION(S): The animals were grouped as follow: No etoposide injection and no lycopene (control), lycopene supplementation (LY), etoposide injection (ET), and rats with etoposide injection and lycopene supplement (ET+LY). MAIN OUTCOME MEASURE(S): At the end of the experiment, rats were sacrificed by cervical dislocation. Blood samples were harvested and analyzed for serum alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), low-density lipoprotein-Cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), total cholesterol (TC), Total Protein (TP), glucose (GLU) and testosterone. The left testis was manipulated for histological examination. RESULT(S): The result of experiment showed that rats with etoposide injection had higher ALT, AST, and ALP than the control rats. In contrast co-treated rats (ET+LY) significantly modulated the levels of the hepatic parameters. Administration of lycopene increased testosterone concentration and germinal epithelium of seminiferous tubules in testes rats. CONCLUSION(S): Lycopene might be a promising agent with hepatoprotective effect in restoring testis injury induced by etoposide in rats.

Ameliorative effects of quercetin against hepatic toxicity of oral sub-chronic co-exposure to aluminum oxide nanoparticles and lead-acetate in male rats.

The present study was designed to evaluate the probable ameliorative role of quercetin (QCN) against oxidative hepatotoxicity induced by aluminum oxide nanoparticles (Al2O3NPs) with a diameter < 30 nm and lead acetate (Pb) co-exposure in adult male Sprague-Dawley rats. Rats were weighed and allocated to seven groups (n = 10 each) and were treated orally via orogastric gavage for 60 successive days: rats of the 1st group were kept as control given distilled water (1 ml/kg), rats of the 2nd group received 2 ml/kg BW/day corn oil; rats of the 3rd group were administered 20 mg/kg BW QCN/day; rats of the 4th group received 100 mg/kg BW Al2O3NPs; rats of the 5th group received 50 mg/kg BW Pb; rats of the 6th group co-received Al2O3NPs and Pb at the same previous doses; and rats of the 7th group were co-administered Al2O3NPs, Pb, and QCN at the same previous doses. At the end of the experiment, serum levels of alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total, direct, indirect bilirubin, triglycerides, total cholesterol, HDL, VLDL, and LDL were estimated. The hepatic oxidative stress biomarkers as superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GPx), were also evaluated. Finally, the histopathological and histomorphometric evaluations and the residues of Al and Pb in hepatic tissues were assessed. Al2O3NPs and/or Pb exposure significantly elevated lipid peroxidation levels and considerably altered the hepatic biochemical parameters; nevertheless, QCN significantly reduced hepatic enzymes compared to toxicant exposed groups. Additionally, QCN significantly improved Al2O3NPs-afforded liver tissue damage, as established in microscopic findings on the liver in the group treated with Al2O3NPs + Pb. Conclusively, QCN could be a candidate natural agent to safeguard the liver versus the co-harmful impacts of Al2O3NPs and Pb toxicity.

Novel graph-based machine-learning technique for viral infectious diseases: application to influenza and hepatitis diseases.

BACKGROUND: Most infectious diseases are caused by viruses, fungi, bacteria and parasites. Their ability to easily infect humans and trigger large-scale epidemics makes them a public health concern. Methods for early detection of these diseases have been developed; however, they are hindered by the absence of a unified, interoperable and reusable model. This study seeks to create a holistic and real-time model for swift, preliminary detection of infectious diseases using symptoms and additional clinical data. MATERIALS AND METHODS: In this study, we present a medical knowledge graph (MKG) that leverages multiple data sources to analyse connections between different nodes. Medical ontologies were used to enhance the MKG. We applied various graph algorithms to extract key features. The performance of multiple machine-learning (ML) techniques for influenza and hepatitis detection was assessed, selecting multi-layer perceptron (MLP) and random forest (RF) models due to their superior outcomes. The hyperparameters of both graph-based ML models were automatically fine-tuned. RESULTS: Both the graph-based MLP and RF models showcased the least loss and error rates, along with the most specific, accurate recall, precision and F1 scores. Their Matthews correlation coefficients were also optimal. When compared with existing ML techniques and findings from the literature, these graph-based ML models manifested superior detection accuracy. CONCLUSIONS: The graph-based MLP and RF models effectively diagnosed influenza and hepatitis, respectively. This underlines the potential of graph data science in enhancing ML model performance and uncovering concealed relationships in the MKG.

Hepatoprotective effect of methanolic extract of Iris florentina L. on paracetamol-induced liver toxicity in rats.

Despite of plethora of research on hepatoprotective potential of medicinal plants, there is still need to discover potential plants with hepatoprotective activity. Iris florentina L. is a medicinal plant with traditional claims but ignored investigation regarding its hepatoprotective effects. The current study is aimed to investigate the hepatoprotective potential of I. florentina L. methanolic extract on paracetamol (PCM)-induced liver injury. The phytochemical and HPLC screening was done which showed the presence of potential constituents including flavonoids and phenols. For investigating the hepatoprotective effect of I. florentina L. methanolic extract, rats were given five different treatments for seven consecutive days. The normal control (group 1) was administered with normal saline, group 2 (Diseased) received paracetamol and group 3 (Standard) was given silymarin as reference drug. In group 4 and 5 (Treated), I. florentina L. methanolic extract (250 and 500mg/kg) were administered. Different serum biomarkers and histopathological studies were performed to assess the recovery caused by PCM in comparison to diseased group. The treatment of I. florentina methanolic extract significantly improve the serum biomarkers and restored the hepatic injury towards normal, indicating the hepatoprotective potential. Thus, we can conclude that I. florentina have significantly reversed the damage caused by paracetamol in hepatotoxic rat model due to their potential phytochemical constituents.

The significance of thymoquinone administration on liver toxicity of diazinon and cholinesterase activity; a recommendation for prophylaxis among individuals at risk.

BACKGROUND: Diazinon (DZN), a widely used chemical herbicide for controlling agricultural pests, is an important organophosphorus pesticide and an environmental pollutant which induces toxic effects on living organisms during long-term exposure. Thymoquinone (TQ) is a phytochemical bioactive compound with antioxidant and anti-inflammatory properties. We aimed to evaluate the protective effects of TQ against DZN-induced hepatotoxicity through alleviating oxidative stress and enhancing cholinesterase (ChE) enzyme activity. METHODS: Rats were randomly divided into six groups (n = 8); a negative control group receiving corn oil; a group only receiving DZN (20 mg/kg/day); a group treated with TQ (10 mg/kg/day), and three treatment groups as TQ + DZN, receiving different doses of TQ (2.5, 5, and 10 mg/kg/day). All experimental animals were orally treated for 28 consecutive days. The levels of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactic acid dehydrogenase (LDH) were determined. In addition, ChE activity and histopathological changes were evaluated. RESULTS: The results showed that DZN decreased GSH level (p < 0.01) and SOD activity (p < 0.01) in parallel to an increase in MDA level (p < 0.01) and increased the activity of AST, ALT, ALP, and LDH (p < 0.01) in comparison to the negative control group. Our findings demonstrated that TQ administration could diminish hepatotoxicity and reduce oxidative damage in DZN-treated rats, which could be linked to its antioxidant and free radical scavenging properties. It was also observed that TQ 10 mg/kg remarkably increased the activity of acetylcholinesterase, butyrylcholinesterase, and SOD enzymes, elevated GSH, decreased MDA, and reduced pathological alternations of the liver induced by DZN. CONCLUSION: Thymoquinone 10 mg/kg increased the activity of plasma and blood cholinesterases and reduced DZN-induced alternations of the liver. Improvement of butyryl- and acetylcholinesterase activity suggests that maybe TQ supplement could be beneficial as pre-exposure prophylaxis among farm workers spraying pesticides.