Liver Toxicity Research Articles

Locoregional therapy for colorectal liver metastases awaiting transplantation: Balancing tumor control with liver toxicity.

Locoregional therapy for colorectal liver metastases awaiting transplantation: Balancing tumor control with liver toxicity.

Epicatechin ameliorates glucose intolerance and hepatotoxicity in sodium arsenite-treated mice

Arsenic is a metalloid found in the environment that causes toxic effects in different organs, mainly the liver. This study aimed to investigate the protective effects of epicatechin (EC), a natural flavonol, on glucose intolerance (GI) and liver toxicity caused by sodium arsenite (SA) in mice. Our findings showed that SA exposure led to the development of GI. Liver tissue damage and decreased pancreatic Langerhans islet size were also observed in this study. Mice exposed to SA exhibited hepatic oxidative damage, indicated by reduced antioxidant markers (such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione), along with elevated levels of thiobarbituric acid reactive substances. SA administration elevated the serum activities of liver enzymes alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Furthermore, notable increases in the levels of inflammatory and apoptotic markers (Toll-like receptor 4, nuclear factor-kappa B, tumor necrosis factor-α, nitric oxide, B-cell lymphoma-2, and cysteine aspartate-specific protease-3) were observed in the liver. Treatment of SA-exposed mice with EC considerably reversed these biochemical and histological changes. This study demonstrated the beneficial effects of EC in ameliorating SA-induced hyperglycemia and hepatotoxicity due to its ability to enhance the antioxidant system by modulating inflammation and apoptosis.

Pera orange juice (Citrus sinensis L. Osbeck) alters lipid metabolism and attenuates oxidative stress in the heart and liver of rats treated with doxorubicin

BackgroundDoxorubicin (DOX) is a highly effective chemotherapy drug widely used to treat cancer, but its use is limited due to multisystemic toxicity. Lipid metabolism is also affected by doxorubicin. Orange juice can reduce dyslipidemia in other clinical situations and has already been shown to attenuate cardiotoxicity. Our aim is to evaluate the effects of Pera orange juice (Citrus sinensis L. Osbeck) on mitigating lipid metabolism imbalance, metabolic pathways, and DOX induced cytotoxic effects in the heart and liver. MethodsTwenty-four male Wistar rats were allocated into 3 groups: Control (C); DOX (D); and DOX plus Pera orange juice (DOJ). DOJ received orange juice for 4 weeks, while C and D received water. At the end of each week, D and DOJ groups received 4 mg/kg/week DOX, intraperitoneal. At the end of 4 weeks animals were submitted to echocardiography and euthanasia. ResultsAnimals treated with DOX decreased water intake and lost weight over time. At echocardiography, DOX treated rats presented morphologic alterations in the heart. DOX increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, high density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides. It also reduced superoxide dismutase (SOD) activity, increased protein carbonylation in the heart and dihydroethidium (DHE) expression in the liver, decreased glucose transporter type 4 (GLUT4) and the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ1) in the heart, and reduced carnitine palmitoyltransferase I (CPT1) in the liver. ConclusionDOX caused dyslipidemia, liver and cardiac toxicity by increasing oxidative stress, and altered energy metabolic parameters in both organs. Despite not improving changes in left ventricular morphology, orange juice did attenuate oxidative stress and mitigate the metabolic effects of DOX.

Synthesis of dragonfruit-based silicon nanoparticles at room temperature and their application in the real-time fiber-optic detection of doxorubicin

Doxorubicin (DOX) has been extensively used in cancer chemotherapy as an antibiotic drug, but when DOX concentration exceeds the threshold value, irreversible liver toxicity and cardiotoxicity can be triggered. Therefore, it is a significant theme to detect DOX concentration of patient blood and metabolites for the optimization of drug dosage. Linear correlation between fluorescence quenching of silicon nanoparticles (SiNPs) and DOX concentration enables SiNPs to present good prospect to address this tricky issue. Inspired by these aspects, we put forward a novel method to synthesize dragonfruit-based SiNPs (DSiNPs) at room temperature, and leverage them in the fiber-optic sensing of urine DOX. Firstly, we investigate a simple and green synthesis method of DSiNPs emitting blue-green fluorescence through a one-step redox reaction at room temperature with organosilane as silicon source and fresh dragonfruit juice as reducing agent. Secondly, depending on optical characterization, we demonstrate mechanism of DSiNPs in the detection of DOX. Thirdly, a fiber-optic sensor is used to measure the fluorescence intensity of DSiNPs under diverse salt concentrations, pH values, and illumination time to explore the tolerance of DSiNPs. Fourthly, based on optimization of parameters and validation of specificity, we acquire linear response range of this method to DOX from 0 to 50 μM with detection limit of 3 μM. Finally, this method is leveraged in the detection of urine DOX, and obtained the recovery rates of 92.30 % and 107.30 %. This method holds excellent potential in the clinical analysis of anti-tumor drugs for the advantages of environmental friendliness and simple operation.

Hepatoprotective potential of coconut inflorescence sap against paracetamol induced toxicity in hep G2 cell lines

Coconut Inflorescence Sap (CIS) is the sweet, oyster-white colored, non-fermented juice obtained from the immature inflorescence of the Coconut tree. Acetaminophen (N-acetyl-p-aminophenol, or paracetamol) is one of the most frequently used drugs worldwide as an antipyretic or analgesic. HepG2 cell lines were used as an experimental model for studying in vitro hepatotoxicity induced by Paracetamol. The present study aims to identify biologically active compounds of CIS using LCMS analysis and to elucidate the ameliorative potential of CIS in alleviating paracetamol-induced hepatotoxicity. LC-MS analysis revealed the presence of 17 bioactive compounds. HepG2 cells were pretreated with Paracetamol (20 mM) for inducing toxicity, and Silymarin at a concentration of 50 μg/ml was used as a standard drug. The morphological analysis and MTT assay showed effective recovery from toxicity in cells treated with CIS in a dose-dependent manner. CIS at 25 μg/ml potentially showed the highest percentage of inhibitory activity against the toxicity induced by paracetamol. The treatment with paracetamol significantly increased the indicators of liver toxicity - LDH, SGOT, SGPT, and Glut.S Transferase in the media.CIS administration also increased the total protein levels, SOD, and Catalase activity. The morphological analysis, MTT assay, cytocompatibility studies, determination of enzymatic activities, etc., confirms the significant hepatoprotective efficacy of CIS.

Phytochemical Composition Antioxidant and Anti-Inflammatory Activity of Artemisia dracunculus and Artemisia abrotanum.

This study aimed to investigate the antioxidant and anti-inflammatory activities mechanism of Artemisia dracunculus (A. dracunculus) and Artemisia abrotanum (A. abrotanum) ethanol extracts in acute rat inflammation induced in Wistar male rats with turpentine oil. The characterization of the polyphenolic compounds in the extracts was conducted using UV-Vis and Fourier-transform infrared spectroscopy and high-performance liquid chromatography coupled with mass spectrometry techniques. The antioxidant activity of the extracts was evaluated in vitro by DPPH, FRAP, H2O2, and NO scavenging tests and in vivo by measuring the total oxidative status (TOS), total antioxidant capacity (TAC), oxidative stress index (OSI), 8-hydroxy-deoxyguanosine (8-Oxo-dG), advanced oxidation protein products (AOPP), malondialdehyde (MDA), nitric oxide (NO), 3-nitrotyrosine (3NT), and total thiols (SH). Inflammation was evaluated by measuring nuclear factor-kB-p65 (NfkB-p65) and NLRP3 inflammasome activation with IL-1β, IL-18, and gasdermin D. Liver and renal toxicity was determined following transaminases (ALT and AST), creatinine, and urea. The experimental results indicated that A. dracunculus and A. abrotanum ethanol extracts have moderate in vitro antioxidant activity and had in vivo antioxidant activity and an anti-inflammatory effect by NfkB-p65, IL-1b, IL-18, and gasdermin D serum level reduction. The antioxidant activity correlated with the chemical composition of the extracts. These results bring evidence-based use of A. dracunculus and A. abrotanum's in traditional and contemporary medicine.

Triazine herbicide prometryn alters epoxide hydrolase activity and increases cytochrome P450 metabolites in murine livers via lipidomic profiling

Oxylipins are a group of bioactive fatty acid metabolites generated via enzymatic oxygenation. They are notably involved in inflammation, pain, vascular tone, hemostasis, thrombosis, immunity, and coagulation. Oxylipins have become the focus of therapeutic intervention since they are implicated in many conditions, such as nonalcoholic fatty liver disease, cardiovascular disease, and aging. The liver plays a crucial role in lipid metabolism and distribution throughout the organism. Long-term exposure to pesticides is suspected to contribute to hepatic carcinogenesis via notable disruption of lipid metabolism. Prometryn is a methylthio-s-triazine herbicide used to control the growth of annual broadleaf and grass weeds in many cultivated plants. The amounts of prometryn documented in the environment, mainly waters, soil and plants used for human and domestic consumption are significantly high. Previous research revealed that prometryn decreased liver development during zebrafish embryogenesis. To understand the mechanisms by which prometryn could induce hepatotoxicity, the effect of prometryn (185 mg/kg every 48 h for seven days) was investigated on hepatic and plasma oxylipin levels in mice. Using an unbiased LC–MS/MS-based lipidomics approach, prometryn was found to alter oxylipins metabolites that are mainly derived from cytochrome P450 (CYP) and lipoxygenase (LOX) in both mice liver and plasma. Lipidomic analysis revealed that the hepatotoxic effects of prometryn are associated with increased epoxide hydrolase (EH) products, increased sEH and mEH enzymatic activities, and induction of oxidative stress. Furthermore, 9-HODE and 13-HODE levels were significantly increased in prometryn treated mice liver, suggesting increased levels of oxidation products. Together, these results support that sEH may be an important component of pesticide-induced liver toxicity.

Prenatal exposure to bisphenol AF causes toxicities in liver, spleen, and kidney tissues of SD rats

As a replacement for bisphenol A (BPA), bisphenol AF (BPAF) showed stronger maternal transfer and higher fetal accumulation than BPA. Therefore, concerns should be raised about the health risks of maternal exposure to BPAF during gestation on the offspring. In this study, SD rats were exposed to BPAF (0, 50, and 100 mg/kg/day) during gestation to investigate the bioaccumulation and adverse effects in liver, spleen, and kidney tissues of the offspring at weaning period. Bioaccumulation of BPAF in these tissues with concentrations ranging from 1.56 ng/mg (in spleen of males) to 55.44 ng/mg (in liver of females) led to adverse effects at different biological levels, including increased relative weights of spleen and kidneys, histopathological damage in liver, spleen, and kidney, organ functional damage in liver, spleen, and kidney, upregulated expression of genes related to lipid metabolism (in liver), oxidative stress response (in kidney), immunity and inflammatory (in spleen). Furthermore, dysregulated metabolomics was identified in spleen, with 217 differential metabolites screened and 9 KEGG pathways significantly enriched. This study provides a comprehensive insight into the systemic toxicities of prenatal exposure to BPAF in SD rats. Given the broad applications and widespread occurrence of BPAF, its safety should be re-considered.

Hesperetin alleviates aflatoxin B1 induced liver toxicity in mice: Modulating lipid peroxidation and ferritin autophagy

One of the ways Aflatoxin B1 damages the liver is through ferroptosis. Ferroptosis is characterized by the build-up of lipid peroxides and reactive oxygen species (ROS) due to an excess of iron. Dietary supplements have emerged as a promising strategy for treating ferroptosis in the liver. The flavonoid component hesperetin, which is mostly present in citrus fruits, has a number of pharmacological actions, such as those against liver fibrosis, cancer, and hyperglycemia. However, hesperetin's effects and mechanisms against hepatic ferroptosis are still unknown. In this study, 24 male C57BL/6 J mice were randomly assigned to CON, AFB1 (0.45 mg/kg/day), and AFB1+ hesperetin treatment groups (40 mg/kg/day). The results showed that hesperetin improved the structural damage of the mouse liver, down-regulated inflammatory factors (Cxcl1, Cxcl2, CD80, and F4/80), and alleviated liver fibrosis induced by aflatoxin B1. Hesperetin reduced hepatic lipid peroxidation induced by iron accumulation by up-regulating the levels of antioxidant enzymes (GPX4, GSH-Px, CAT, and T-AOC). It is worth noting that hesperetin not only improved lipid peroxidation but also maintained the dynamic balance of iron ions by reducing ferritin autophagy. Mechanistically, hesperetin's ability to regulate ferritin autophagy mostly depends on the PI3K/AKT/mTOR/ULK1 pathway. In AFB1-induced HepG2 cells, the addition of PI3K inhibitor (LY294002) and AKT inhibitor (Miransertib) confirmed that hesperetin regulated the PI3K/AKT/mTOR/ULK1 pathway to inhibit ferritin autophagy and reduced the degradation of ferritin in lysosomes. In summary, our results suggest that hesperetin not only regulates the antioxidant system but also inhibits AFB1-induced ferritin hyperautophagy, thereby reducing the accumulation of iron ions to mitigate lipid peroxidation. This work provides a fresh perspective on the mechanism behind hesperetin and AFB1-induced liver damage in mice.

Hepatoprotective activity of aqueous <i>Curcuma longa</i> rhizome extract against carbon tetrachloride-induced liver toxicity in adult Wistar rats

Hepatoprotective activity of aqueous <i>Curcuma longa</i> rhizome extract against carbon tetrachloride-induced liver toxicity in adult Wistar rats

Pyridaben inhibits cell cycle progression and delays early embryonic development in zebrafish (Danio rerio)

Pyridaben is a broad-spectrum, contact-killing acaricide that can be used to control a variety of harmful food and plant mites. Pyridaben displays cardiotoxicity and liver toxicity toward fish, but the effects on fish embryonic development have not been characterized. We exposed early zebrafish embryos to 20, 30, and 40 μg/L concentrations of pyridaben. The exposure caused developmental abnormalities, including delayed embryonic shield formation, yolk sac resorption, decreases in body length, reduced pigmentation, and delays in hatching. Pyridaben caused a significant increase in the transcription level of the endoderm marker foxa2, but the transcription levels of the ectoderm development marker foxb1a and the mesoderm development marker snaila were not significantly altered. The transcription levels of the genes SOX17 in early embryos were significantly reduced. After exposure to pyridaben, catalase (CAT) activity and glutathione (GSH) content were increased, and cyclin D1, that is involved in early embryonic development, was abnormally expressed. This study shows that pyridaben causes anomalous development in zebrafish embryos by interfering with the cell cycle order of early embryonic development and inducing excessive oxidative stress. Colivelin, an agonist of the STAT3 signaling pathway, acted as a salvage drug to restore the cell cycle order during embryonic development following exposure to pyridaben. Thus, the toxic effects may be caused by pyridaben’s regulation of the STAT3 signaling pathway.

Evaluation of the Efficacy of Tofacitinib, a JAK Inhibitor, in Alleviating Sepsis-Induced Multiple Organ Dysfunction Syndrome.

Sepsis, a life-threatening condition triggered by an uncontrolled response to infection, results in a systemic inflammatory response syndrome (SIRS) and the failure of multiple organs leading to multiple organ dysfunction (MODS). In the present study, we investigated the therapeutic potential of tofacitinib (TOFA), an FDA-approved inhibitor of JAK1 and JAK3 against sepsis, using a mouse model induced by cecal ligation puncture (CLP). Swiss albino mice were employed to replicate the CLP-induced sepsis model and were randomly divided into four groups: control, CLP, 150 mg/kg TOFA, and 300 mg/kg TOFA. Six hours after the last TOFA dose, we collected blood and tissue samples from the liver, lungs, kidneys, and spleen for histological analysis. Blood samples were used to assess granulocyte and lymphocyte percentages. Throughout the experiment, we monitored body weight and short-term survival. Our comparative histological analysis revealed that 150 mg/kg TOFA had a protective effect against multiple organ damage. Conversely, the study highlighted the harmful effects of 300 mg/kg TOFA, primarily due to liver and renal toxicity within this group. In summary, our findings demonstrate that tofacitinib at an optimal dose of 150 mg/kg showed promise as a potential therapeutic intervention for sepsis-induced multiple organ failure. However, caution is warranted when considering higher dosages.

Hepatic cell junctions: Pulling a double-duty.

Cell junctions, including anchoring, occluding and communicating junctions, play an indispensable role in the structural and functional organization of multicellular tissues, including in liver. Specifically, hepatic cell junctions mediate intercellular adhesion and communication between liver cells. The establishment of the hepatic cell junction network is a prerequisite for normal liver functioning. Hepatic cell junctions indeed support liver-specific features and control essential aspects of the hepatic life cycle. This review paper summarizes the role of cell junctions and their components in relation to liver physiology, thereby also discussing their involvement in hepatic dysfunctionality, including liver disease and toxicity.

Impact of chlorogenic acid on submandibular salivary gland and liver of albino rats exposed to sodium nitrite

AimThe aim of the present study is to show how sodium nitrite alters the histology of submandibular salivary glands and livers of Albino rats, as well as how chlorogenic acid may have therapeutic benefits.MethodsA sample size of thirty male Sprague Dawley Albino rats weighing between 100 and 150 g (5-6 weeks old) was randomly allocated into 3 equal groups. Group I: rats were used as controls and were given phosphate buffer solution, whereas Group II: rats were given an 80 mg/kg sodium nitrites (SN) daily dissolved in distilled water. The rats in Group III were given a daily dose of 80 mg/kg SN dissolved in distilled water and after 6 hours each rat received 50 mg/mL freshly prepared chlorogenic acid (CGA) every other day. For 12 weeks, all treatment modalities will be administered orally, every day. After the experiment, all rats were euthanized. Samples from salivary glands and livers were processed and stained with H&E and interleukin 6 (IL 6). Malondialdehyde (MDA) and superoxide dismutase (SOD) enzymes were detected using an ELISA assay.ResultsGroups III had nearly comparable findings to Group I regarding histological pattern with normal submandibular glands and livers features. Group III salivary gland treated with CGA exhibited higher SOD levels (20.60±4.81 U/g) in comparison to the SN group, and lower MDA levels (111.58±28.28 nmol/mg) in comparison to the SN treated samples. In comparison to the SN group, CGA treatment significantly reduced MDA levels in liver samples (167.56±21.17 nmol/mg) and raised SOD (30.85±6.77 U/g).ConclusionsChlorogenic acid has a protective effect against salivary gland and liver toxicity induced by SN in rats. This was mediated via the anti-inflammatory and antioxidative properties of CGA and the restoration of oxidant/antioxidant balance in rat salivary gland and liver.

Compound probiotics and glycyrrhizic acid alleviate DON-induced liver damage linked to the alteration of lipid metabolism in piglets

Compound probiotics are capable of effectively breaking down mycotoxins, and glycyrrhizic acid (GA) exhibits hepatoprotective properties. However, the protective efficacy and the underlying mechanism of combined intervention of GA and probiotics (GAP) on ameliorating Deoxynivalenol (DON)-induced liver toxicity remains unclear. This experiment involved 120 weaned piglets, encompassing the control group, the DON group, and the GPD group (E. faecalis and S. cerevisiae + GA + DON). Results showed that GAP significantly mitigated DON-related liver damage and oxidative stress. Furthermore, GAP inhibited the Nrf2/MAPK/NF-κB pathway, ultimately decreasing liver inflammation and apoptosis. Additionally, GAP significantly enhanced the expressions of ZO-1, GLUT2, PePT1, ASCT2, Occludin and Claudin-1. Moreover, metabolomics analysis revealed that GAP modulated lipid metabolism and mitigated liver damage by elevating serum levels of metabolites, such as phosphatidylcholine, phosphatidylethanolamine, and 3-amino-4-hydroxybenzoic acid. The research provides a theoretically based framework for using GAP to combat DON-induced hepatotoxicity in piglets.

Carrier cascade target delivery of 5-aminolevulinic acid nanoplatform to enhance antitumor efficiency of photodynamic therapy against lung cancer

5-Aminolevulinic acid (5-ALA) is a prodrug of porphyrin IX (PpIX). Disadvantages of 5-ALA include poor stability, rapid elimination, poor bioavailability, and weak cell penetration, which greatly reduce the clinical effect of 5-ALA based photodynamic therapy (PDT). Presently, a novel targeting nanosystem was constructed using gold nanoparticles (AuNPs) as carriers loaded with a CSNIDARAC (CC9)-targeting peptide and 5-ALA via Au-sulphur and ionic bonds, respectively, and then wrapped in polylactic glycolic acid (PLGA) NPs via self-assembly to improve the antitumor effects and reduce the side effect. The successful preparation of ALA/CC9@ AuNPs-PLGA NPs was verified using ultraviolet-visible, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The analyses revealed good sphericity with a particle size of approximately140 nm, Zeta potential of 10.11 mV, and slow-controlled release characteristic in a weak acid environment. Confocal microscopy revealed targeting of NCL-H460 cells by NPs by actively internalising CC9 and avoiding the phagocytic action of RAW264.7 cells, and live fluorescence imaging revealed targeting of tumours in tumour-bearing mice. Compared to free 5-ALA, the nanosystem displayed amplified anticancer activity by increasing production of PpIX and reactive oxygen species to induce mitochondrial pathway apoptosis. Antitumor efficacy was consistently observed in three-dimensionally cultured cells as the loss of integrity of tumour balls. More potent anti-tumour efficacy was demonstrated in xenograft tumour models by decreased growth rate and increased tumour apoptosis. Histological analysis showed that this system was not toxic, with lowered liver toxicity of 5-ALA. Thus, ALA/CC9@AuNPs-PLGA NPs deliver 5-ALA via a carrier cascade, with excellent effects on tumour accumulation and PDT through passive enhanced permeability and retention action and active targeting. This innovative strategy for cancer therapy requires more clinical trials before being implemented.

The hepatoprotective potential of tannic acid against doxorubicin-induced hepatotoxicity: Insights into its antioxidative, anti-inflammatory, and antiapoptotic mechanisms.

Doxorubicin (DOX), which is frequently used in cancer treatment, has limited clinical use due to adverse effects on healthy tissues, especially the liver. Therefore, it is necessary to research the molecular basis of DOX-induced organ and tissue damage and protective agents. In this study, we aimed to examine the protective effects of tannic acid (TA) against DOX-induced hepatoxicity in experimental rat models. Rats were randomly divided into four experimental groups: the untreated control, DOX, TA, and cotreatment (DOX + TA) groups. We investigated the antioxidant system's main components and oxidative stress indicators. Moreover, we examined alterations in the mRNA expression of critical regulators that modulate apoptosis, inflammation, and cell metabolism to better understand the underlying factors of DOX-induced liver toxicity. The results showed that DOX exposure caused an increase in MDA levels and a significant depletion of GSH content in rat liver tissues. Consistent with oxidative stress-related metabolites, DOX was found to significantly suppress both mRNA expression and enzyme activities of antioxidant system components. Moreover, DOX exposure had significant adverse effects on regulating the other regulatory genes studied. However, it was determined that TA could alleviate many of the negative changes caused by DOX. The results of the present study indicated that TA might be considered a versatile candidate that could prevent DOX-induced hepatotoxicity, possibly by preserving cell physiology, viability, and especially redox balance.

Novel Inhibition of Central Carbon Metabolism Pathways by Rac and CDC42 inhibitor MBQ167 and Paclitaxel.

Triple negative breast cancer (TNBC) represents a therapeutic challenge in which standard chemotherapy is limited to paclitaxel. MBQ167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ167 in combination with paclitaxel in TNBC preclinical models, as a prelude to safety trials of this combination in patients with advanced breast cancer. Individual MBQ167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared with paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB231 and MDA-MB468), individual MBQ167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, whereas MBQ167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ167 and paclitaxel decreased established lung metastases by ∼80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ167 and paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action.

A double-blind, randomized control trial to investigate the therapeutic potential of garlic scapes for high apoprotein E levels in a high-Fat diet-induced hypercholesteremic rat model.

Hypercholesteremia is the main contributor to metabolic diseases, including obesity, hypertension, and diabetes, which are the primary global sources of morbidity and death rates. Garlic scapes, a member of the Allium sativum family and a rich source of antioxidants, are utilized in various cuisine preparations due to their unique flavors and tastes. The current study examined garlic scape powder's effect on apoprotein E and its ability to decrease cholesterol. In an invivo experiment, normal, healthy Wistar albino rats (weeks) were divided into a negative control group (NC, n = 10) and a high-fat diet-raised group (n = 50) until they achieved cholesterol ≥250 mg/dL. Hypercholesteremic rats were further divided randomly into five groups: positive control (PC), standard group (fenofibrate 20 mg/kg bwt), and treatment groups G1, G2, and G3 that were administered with garlic scape powder 400 mg, 800 mg, and 1200 mg/kg bwt orally, respectively, for 3 months. The blood samples were examined for cholesterol, triglycerides, high-density lipoproteins (HDLs), low-density lipoproteins, apoprotein E, albumin levels, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). The liver tissues of the rats were subjected to histopathology. The lipid profile was assessed using serum kit techniques, whereas an ELISA kit was used to evaluate apoprotein E, and a serum kit was used to estimate ALT and AST. In comparison to all other groups except NC, the highest dose of 1200 mg/kg bwt of garlic scapes significantly (p ≤ .05) increased serum insulin (13.66 ± 0.72 μU/mL), apoprotein E levels (6.08 ± 0.10 mg/dL), HDL (42.1 ± 1.81 mg/dL), and reduce TG (88.7 ± 1.64 mg/dL) and decreased overall cholesterol levels (67.9 ± 1.17 mg/dL). Except for NC, all treatment groups had significantly (p ≤ .05) lower ALT and AST values than PC. To sum up, powdered garlic scapes may be a great way to avoid hyperlipidemia, which raises the risk of cardiovascular illnesses. ALT and AST levels were significantly (p ≤ .05) reduced in all treatment groups compared to PC, except for NC. In conclusion, garlic scape powder may be an excellent source to prevent hyperlipidemia, a risk factor for cardiovascular diseases. In addition, powdered garlic scapes supplementation at high doses may be used as an alternative natural source in functional foods to halt hyperlipidemia without liver toxicity in the long term.

Arsenic induces hepatotoxicity in chickens via PANoptosis pathway

Environmental pollution caused by arsenic or its compounds is called arsenic pollution. Arsenic pollution mainly comes from people's mining and smelting of arsenic compounds. In addition, the widespread use of arsenic compounds, such as the use and production of arsenic-containing pesticides, is also a source of arsenic contamination. Arsenic contamination leads to an increased risk of arsenic exposure, and the multi-organ toxicity induced by arsenic exposure is a global health problem. As a non-mammalian vertebrate with high nutrient levels, chickens readily absorb and accumulate arsenic from their food. Relevant studies have shown that arsenic exposure induces hepatotoxicity in chickens, and there has been a steady stream of research into the specific mechanisms involved. PANoptosis, a newly discovered and unique mode of programmed cell death (PCD) characterized by both apoptosis, cellular pyroptosis, and necroptosis. There are no studies to indicate whether chicken liver toxicity due to arsenic is associated with PANoptosis. Therefore, we established chicken animal models and chicken primary hepatocyte models exposed to different arsenic concentrations to dissect the role and mechanism of PANoptosis in arsenic exposure-induced hepatotoxicity in chickens. Our histopathological results showed that arsenic treatment caused dose-dependent damage to chicken liver structure. Meanwhile, different doses of arsenic treatment groups caused significant up-regulation of the protein level of ZBP1, a key factor of PANoptosis. And then consequently triggered the abnormal gene and protein expression levels of apoptosis-associated factors (Caspase-8, Caspase-7, Caspase-3), cellular pyroptosis-associated factors (NLRP3, ASC, GSDMD) and necroptosis-associated factors (RIPK1, RIPK3, MLKL). In conclusion, our study revealed that PANoptosis is involved in arsenic-induced chicken hepatotoxicity. Our findings provide a new perspective on the pathogenesis of arsenic exposure-induced hepatotoxicity in chickens.