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Biochemical Pharmacology Jul 2024Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, plays a critical role in...
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Pregnane X receptor (PXR), a xenobiotic-sensing nuclear receptor, plays a critical role in the metabolism of endogenous and exogenous substances in the liver. Here, we investigate whether PXR plays a role in pathogenesis of HCC. We show that liver tumors were developed in diethylnitrosamine (DEN)-treated in PXR knockout (KO) mice. Hepatic levels of prostaglandin F (PGF) and aldo-keto reductase family 1 member C18 (Akr1c18), a prostaglandin synthase of catalyzing reduction of PGH to PGF, were significantly elevated in DEN-treated PXR KO mice. Hepatic mRNA levels of alpha fetoprotein (AFP), cyclin D1 (Ccnd1), fibroblast growth factor 21 (FGF21), and inflammatory cytokine interleukin 6 (IL-6) were significantly increased in DEN-treated PXR KO mice. Other members of Akr1c family, liver metabolizing enzymes including Cyp1a2, Cyp2b10 and Cyp3a11, and bile acid synthesis enzyme Cyp7a1 mRNA levels were significantly decreased in DEN-treated PXR KO mice. Our findings revealed that PXR deficiency promoted DEN-induced HCC in mice via induction of Akr1c18 expression and PGF levels and the increased PGF levels synthetized by Akr1c18 enhanced hepatocytes proliferation and induced inflammatory cytokine production, which accelerated liver tumor development after DEN treatment, suggesting that PXR deficiency may create a microenvironment that is more prone to DEN-induced liver tumors and targeting PXR and Akr1c18 to reduce PGF biosynthesis may be a potential and novel therapeutic strategy for HCC.
Topics: Animals; Humans; Male; Mice; Carcinogenesis; Carcinoma, Hepatocellular; Diethylnitrosamine; Dinoprost; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Liver Neoplasms, Experimental; Mice, Inbred C57BL; Mice, Knockout; Pregnane X Receptor
PubMed: 38788959
DOI: 10.1016/j.bcp.2024.116309 -
Cell Death and Differentiation May 2024The pseudokinase mixed lineage kinase domain-like (MLKL) is an essential component of the activation of the necroptotic pathway. Emerging evidence suggests that MLKL...
The pseudokinase mixed lineage kinase domain-like (MLKL) is an essential component of the activation of the necroptotic pathway. Emerging evidence suggests that MLKL plays a key role in liver disease. However, how MLKL contributes to hepatocarcinogenesis has not been fully elucidated. Herein, we report that MLKL is upregulated in a diethylnitrosamine (DEN)-induced murine HCC model and is associated with human hepatocellular carcinomas. Hepatocyte-specific MLKL knockout suppresses the progression of hepatocarcinogenesis. Conversely, MLKL overexpression aggravates the initiation and progression of DEN-induced HCC. Mechanistic study reveals that deletion of MLKL significantly increases the activation of autophagy, thereby protecting against hepatocarcinogenesis. MLKL directly interacts with AMPKα1 and inhibits its activity independent of its necroptotic function. Mechanistically, MLKL serves as a bridging molecule between AMPKα1 and protein phosphatase 1B (PPM1B), thus enhancing the dephosphorylation of AMPKα1. Consistently, MLKL expression correlates negatively with AMPKα1 phosphorylation in HCC patients. Taken together, our findings highlight MLKL as a novel AMPK gatekeeper that plays key roles in inhibiting autophagy and driving hepatocarcinogenesis, suggesting that the MLKL-AMPKα1 axis is a potential therapeutic target for HCC.
PubMed: 38783090
DOI: 10.1038/s41418-024-01314-5 -
Journal of Asian Natural Products... May 2024In the current study, bioinformatics analysis of the hepatocellular carcinoma (HCC) dataset was conducted with the hepatoprotective effect of the Fuzheng Huayu (FZHY)...
In the current study, bioinformatics analysis of the hepatocellular carcinoma (HCC) dataset was conducted with the hepatoprotective effect of the Fuzheng Huayu (FZHY) capsule against the diethylnitrosamine-induced HCC progression analyzed. Eight cell clusters were defined and , , and , compounds of the FZHY capsule, inhibit HCC progression-related fibrosis by regulating the expression of and . Combined with the ameliorative effect of the FZHY capsule against liver dysfunctions and expression of PLAU and IGFBP3, our study confirmed the effect of the FZHY capsule on inhibiting the fibrosis-associated HCC progression regulating the expression of PLAU and IGFBP3.
PubMed: 38780602
DOI: 10.1080/10286020.2024.2355132 -
Drug Development Research Jun 2024Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The prevention and therapy for this deadly disease remain a global medical challenge. In this study, we...
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. The prevention and therapy for this deadly disease remain a global medical challenge. In this study, we investigated the effect of pantoprazole (PPZ) on the carcinogenesis and growth of HCC. Both diethylnitrosamine (DEN) plus CCl4-induced and DEN plus high fat diet (HFD)-induced HCC models in mice were established. Cytokines and cell proliferation-associated gene in the liver tissues of mice and HCC cells were analyzed. Cellular glycolysis and Na/H exchange activity were measured. The preventive administration of pantoprazole (PPZ) at a clinically relevant low dose markedly suppressed HCC carcinogenesis in both DEN plus CCl4-induced and HFD-induced murine HCC models, whereas the therapeutic administration of PPZ at the dose suppressed the growth of HCC. In the liver tissues of PPZ-treated mice, inflammatory cytokines, IL1, CXCL1, CXCL5, CXCL9, CXCL10, CCL2, CCL5, CCL6, CCL7, CCL20, and CCL22, were reduced. The administration of CXCL1, CXCL5, CCL2, or CCL20 all reversed PPZ-suppressed DEN plus CCL4-induced HCC carcinogenesis in mice. PPZ inhibited the expressions of CCNA2, CCNB2, CCNE2, CDC25C, CDCA5, CDK1, CDK2, TOP2A, TTK, AURKA, and BIRC5 in HCC cells. Further results showed that PPZ reduced the production of these inflammatory cytokines and the expression of these cell proliferation-associated genes through the inhibition of glycolysis and Na/H exchange. In conclusion, PPZ suppresses the carcinogenesis and growth of HCC, which is related to inhibiting the production of inflammatory cytokines and the expression of cell proliferation-associated genes in the liver through the inhibition of glycolysis and Na/H exchange.
Topics: Animals; Carcinoma, Hepatocellular; Glycolysis; Liver Neoplasms; Mice; Pantoprazole; Male; Cell Proliferation; Humans; Mice, Inbred C57BL; Carcinogenesis; Diethylnitrosamine; Cytokines; Cell Line, Tumor; Diet, High-Fat
PubMed: 38764200
DOI: 10.1002/ddr.22198 -
Gut May 2024Squalene epoxidase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in modulating the tumour...
OBJECTIVE
Squalene epoxidase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in modulating the tumour immune microenvironment in MASH-HCC remains unclear.
DESIGN
We established hepatocyte-specific transgenic (tg) and knockout mice, which were subjected to a choline-deficient high-fat diet plus diethylnitrosamine to induce MASH-HCC. SQLE function was also determined in orthotopic and humanised mice. Immune landscape alterations of MASH-HCC mediated by SQLE were profiled by single-cell RNA sequencing and flow cytometry.
RESULTS
Hepatocyte-specific tg mice exhibited a marked increase in MASH-HCC burden compared with wild-type littermates, together with decreased tumour-infiltrating functional IFN-γ and Granzyme B CD8 T cells while enriching Arg-1 myeloid-derived suppressor cells (MDSCs). Conversely, hepatocyte-specific knockout suppressed tumour growth with increased cytotoxic CD8 T cells and reduced Arg-1 MDSCs, inferring that SQLE promotes immunosuppression in MASH-HCC. Mechanistically, SQLE-driven cholesterol accumulation in tumour microenvironment underlies its effect on CD8 T cells and MDSCs. SQLE and its metabolite, cholesterol, impaired CD8 T cell activity by inducing mitochondrial dysfunction. Cholesterol depletion in vitro abolished the effect of SQLE-overexpressing MASH-HCC cell supernatant on CD8 T cell suppression and MDSC activation, whereas cholesterol supplementation had contrasting functions on CD8 T cells and MDSCs treated with SQLE-knockout supernatant. Targeting SQLE with genetic ablation or pharmacological inhibitor, terbinafine, rescued the efficacy of anti-PD-1 treatment in MASH-HCC models.
CONCLUSION
SQLE induces an impaired antitumour response in MASH-HCC via attenuating CD8 T cell function and augmenting immunosuppressive MDSCs. SQLE is a promising target in boosting anti-PD-1 immunotherapy for MASH-HCC.
PubMed: 38744443
DOI: 10.1136/gutjnl-2023-331117 -
Journal of Traditional and... May 2024Mulberry leaf has been recognized as a traditional Chinese medicinal plant, which was distributed throughout the Asia. The aqueous extract of mulberry leaf extract (MLE)...
Mulberry leaf has been recognized as a traditional Chinese medicinal plant, which was distributed throughout the Asia. The aqueous extract of mulberry leaf extract (MLE) has various biologically active components such as polyphenols and flavonoids. However, the inhibitory effect of MLE in hepatocarcinogenesis is poorly understood. In this study, we determined the role of MLE supplementation in preventing hepatocarcinogenesis in a carcinogen-initiated high-fat diet (HFD)-promoted Sprague-Dawley (SD) rat model. The rats were fed an HFD to induce obesity and spontaneous hepatomas by administering 0.01% diethylnitrosamine (DEN) in their drinking water for 12 weeks (HD group), and also to fed MLE through oral ingestion at daily doses of 0.5%, 1%, or 2%. At the end of the 12-week experimental period, the liver tumors were analyzed to identify markers of oxidative stress and antioxidant enzyme activities, and their serum was analyzed to determine their nutritional status and liver function. Histopathological analysis revealed that MLE supplementation significantly suppressed the severity and incidence of hepatic tumors. Furthermore, compared with the HFD + DEN groups, the expression of protein kinase C (PKC)-α and Rac family small GTPase 1 (Rac1) was lower in the MLE groups. These findings suggest that MLE prevents obesity-enhanced, carcinogen-induced hepatocellular carcinoma development, potentially through the protein kinase C (PKC)α/Rac1 signaling pathway. MLE might be an effective chemoprevention modality for nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH)-related hepatocarcinogenesis.
PubMed: 38707917
DOI: 10.1016/j.jtcme.2024.01.007 -
Environmental Toxicology May 2024Glycyrrhizic acid (GA) has effects on anti-hepatic fibrosis, anti-tumor and prevention from hepatocellular carcinoma (HCC) progression. Yet, the capacity of GA to...
Glycyrrhizic acid (GA) has effects on anti-hepatic fibrosis, anti-tumor and prevention from hepatocellular carcinoma (HCC) progression. Yet, the capacity of GA to ameliorate the advance of HCC pertinent to nonalcoholic fatty liver disease (NAFLD) remains to be clarified. We used the CCK-8 method to detect the optimal treatment concentration and time for L-02 cells, palmitic acid (PA)-induced L-02 cells and HepG2 cells, and selected 40 μM and 48 h to treat PA-induced L-02 cells and 60 μM for 24 h to treat HepG2 cells. Moreover, functional associations of HepG2 cells were elucidated through various assays. The results showed that GA demonstrated enhances lipid deposition and alleviates the inflammatory response in L-02 cells induced by palmitic acid. Simultaneously, we found that GA inhibits the proliferation, migration, and invasion while promoting apoptosis in HepG2 cells. In pursuit of constructing of HCC model rats, a combination of high-fat diets and diethylnitrosamine was utilized. The results showed that GA significantly decreased the liver index, body weight, liver weight, and the number of nodules in HCC model rats. Moreover, GA mitigated infiltration and heightened apoptosis in these rats. Mechanistically, GA notably attenuated the KKβ/NF-κB pathway in both HepG2 cells and the HCC model rats. In conclusion, GA functions as an inhibitor in the progression of NAFLD-related HCC cells, which might be relevant to the KKβ/NF-κB pathway. Therefore, GA is a potential drug for NAFLD-related HCC treatment.
PubMed: 38700384
DOI: 10.1002/tox.24295 -
Journal of Evidence-based Integrative... 2024Liver cancer is the most common cancer among males in Africa. The disease has a poor prognosis and its treatment is associated with toxicity and resistance. For this...
Liver cancer is the most common cancer among males in Africa. The disease has a poor prognosis and its treatment is associated with toxicity and resistance. For this reason, numerous herbal combinations are being subjected to anticancer screening to circumvent the shortcomings of the conventional anticancer drugs. In the current study, the anti-cancer effects of the chloroform root extract of the herb, Burm were investigated. Liver cancer was induced in mice by a single intraperitoneal injection of diethylnitrosamine (DEN) followed by oral administration of the promoter of carcinogenesis, 2-aminoacetyl fluorine that was mixed with the mice feed. The cytotoxicity of the root extract of on liver cancer cells was investigated using liver enzyme, histology, DNA fragmentation and caspases assays. Real time qPCR was conducted to evaluate the effect of the extract on apoptotic genes. The findings revealed that the extract of significantly decreased the progression of hepatocarcinogenesis and the toxicity-induced production of the liver enzymes, alanine and aspartate aminotransferases. The histological analyses of the liver tissues revealed evidence of apoptotic cell death. The extract also provoked significant ( < .05) expressions of caspase 9 protein and gene as well as other apoptotic genes (P53, P27, Apaf-1, cytochrome C, bax and bid). Therefore, we postulate that the chloroform root extract of induces apoptosis of liver cancer in mice.
Topics: Animals; Plant Extracts; Mice; Plant Roots; Chloroform; Male; Liver Neoplasms; Clausena; Carcinoma, Hepatocellular; Apoptosis; Humans; Antineoplastic Agents, Phytogenic; Liver; Diethylnitrosamine
PubMed: 38689490
DOI: 10.1177/2515690X241251558 -
JHEP Reports : Innovation in Hepatology May 2024Emerging evidence suggests that maternal obesity negatively impacts the health of offspring. Additionally, obesity is a risk factor for hepatocellular carcinoma (HCC)....
BACKGROUND & AIMS
Emerging evidence suggests that maternal obesity negatively impacts the health of offspring. Additionally, obesity is a risk factor for hepatocellular carcinoma (HCC). Our study aims to investigate the impact of maternal obesity on the risk for HCC development in offspring and elucidate the underlying transmission mechanisms.
METHODS
Female mice were fed either a high-fat diet (HFD) or a normal diet (ND). All offspring received a ND after weaning. We studied liver histology and tumor load in a N-diethylnitrosamine (DEN)-induced HCC mouse model.
RESULTS
Maternal obesity induced a distinguishable shift in gut microbial composition. At 40 weeks, female offspring of HFD-fed mothers (HFD offspring) were more likely to develop steatosis (9.43% 3.09%, 0.0023) and fibrosis (3.75% 2.70%, 0.039), as well as exhibiting an increased number of inflammatory infiltrates (4.8 1.0, 0.018) and higher expression of genes involved in fibrosis and inflammation, compared to offspring of ND-fed mothers (ND offspring). A higher proportion of HFD offspring developed liver tumors after DEN induction (79.8% 37.5%, 0.0084) with a higher mean tumor volume (234 3 μm, 0.0041). HFD offspring had a significantly less diverse microbiota than ND offspring (Shannon index 2.56 . 2.92, 0.0089), which was rescued through co-housing. In the principal component analysis, the microbiota profile of co-housed animals clustered together, regardless of maternal diet. Co-housing of HFD offspring with ND offspring normalized their tumor load.
CONCLUSIONS
Maternal obesity increases female offspring's susceptibility to HCC. The transmission of an altered gut microbiome plays an important role in this predisposition.
IMPACT AND IMPLICATIONS
The worldwide incidence of obesity is constantly rising, with more and more children born to obese mothers. In this study, we investigate the impact of maternal diet on gut microbiome composition and its role in liver cancer development in offspring. We found that mice born to mothers with a high-fat diet inherited a less diverse gut microbiome, presented chronic liver injury and an increased risk of developing liver cancer. Co-housing offspring from normal diet- and high-fat diet-fed mothers restored the gut microbiome and, remarkably, normalized the risk of developing liver cancer. The implementation of microbial screening and restoration of microbial diversity holds promise in helping to identify and treat individuals at risk to prevent harm for future generations.
PubMed: 38681863
DOI: 10.1016/j.jhepr.2024.101056 -
Life Sciences Apr 2024Hepatocellular Carcinoma (HCC) is renowned as a deadly primary cancer of hepatic origin. Sorafenib is the drug-of-choice for targeted treatment of unresectable end-stage...
AIMS
Hepatocellular Carcinoma (HCC) is renowned as a deadly primary cancer of hepatic origin. Sorafenib is the drug-of-choice for targeted treatment of unresectable end-stage HCC. Unfortunately, great proportion of HCC patients showed intolerance or unresponsiveness to treatment. This study assesses potency of novel ProTide; SH-PAN-19 against N-Nitrosodiethylamine (DEN)-induced HCC in male Wistar rats, compared to Sorafenib.
MAIN METHODS
Structural entity of the synthesized compound was substantiated via FT-IR, UV-Vis, H NMR and C NMR spectroscopic analysis. In vitro, SH-PAN-19 cytotoxicity was tested against 3 human cell lines; hepatocellular carcinoma; HepG-2, colorectal carcinoma; HCT-116 and normal fibroblasts; MRC-5. In vivo, therapeutic efficacy of SH-PAN-19 (300 mg/kg b.w./day) against HCC could be revealed and compared to that of Sorafenib (15 mg/kg b.w./day) by evaluating the morphometric, biochemical, histopathological, immunohistochemical and molecular key markers.
KEY FINDINGS
SH-PAN-19 was relatively safe toward MRC-5 cells (IC = 307.6 μg/mL), highly cytotoxic to HepG-2 cells (IC = 24.9 μg/mL) and prominently hepato-selective (TSI = 12.35). Oral LD of SH-PAN-19 was >3000 mg/kg b.w. DEN-injected rats suffered hepatomegaly, oxidative stress, elevated liver enzymes, hypoalbuminemia, bilirubinemia and skyrocketed AFP plasma titre. SH-PAN-19 alleviated the DEN-induced alterations in apoptotic, angiogenic and inflammatory markers. SH-PAN-19 produced a 2.5-folds increase in Caspase-9 and downregulated VEGFR-2, IL-6, TNF-α, TGFβ-1, MMP-9 and CcnD-1 to levels comparable to that elicited by Sorafenib. SH-PAN-19 resulted in near-complete pathological response versus partial response achieved by Sorafenib.
SIGNIFICANCE
This research illustrated that SH-PAN-19 is a promising chemotherapeutic agent capable of restoring cellular plasticity and could stop HCC progression.
PubMed: 38677390
DOI: 10.1016/j.lfs.2024.122669