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Tissue Engineering and Regenerative... Dec 2022Liver inflammation is the main cause of severe liver diseases, including liver fibrosis, steatohepatitis, cirrhosis and hepatocellular carcinoma. Cell therapy topics are...
BACKGROUND
Liver inflammation is the main cause of severe liver diseases, including liver fibrosis, steatohepatitis, cirrhosis and hepatocellular carcinoma. Cell therapy topics are receiving increasingly more attention. The therapeutic applications of mesenchymal stem cells (MSC) have become one of the most discussed issues. While other stem cells have therapeutic effects, they have only one or two clinical applications. MSCs are responsible for repairing a variety of tissue injuries. Moreover, MSCs could be derived from several sources, including adipose tissue. MSCs are usually more abundant and easier to obtain compared to other stem cells.
METHODS
To prove the concept that MSCs have homing ability to the injured tissue and assist in tissue repair, we examined the effects of intravenous injected adipose-derived mesenchymal stem cells (ADSCs) in a N-nitrosodiethylamine (DEN)-induced liver injury rat model.
RESULTS
The significant repairing ability of ADSCs was observed. The levels of fibrosis, apoptosis, and tumorigenesis in the DEN-injured liver tissues all decreased after ADSC treatment. Furthermore, to enhance the therapeutic effects of ADSCs, we pretreated them with L-theanine, which promotes the hepatocyte growth factor secretion of ADSC, and therefore improved the healing effects on injured liver tissue.
CONCLUSION
ADSCs, especially L-theanine-pretreated ADSCs, have anti-inflammation, anti-apoptosis, and anti-tumorigenesis effects on the N-nitrosodiethylamine-induced liver injury rat model.
Topics: Rats; Animals; Mesenchymal Stem Cell Transplantation; Diethylnitrosamine; Chemical and Drug Induced Liver Injury, Chronic; Mesenchymal Stem Cells
PubMed: 36029414
DOI: 10.1007/s13770-022-00472-2 -
Oncotarget Dec 2016Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene...
Environmental disruption of molecular clocks promoted liver carcinogenesis and accelerated cancer progression in rodents. We investigated the specific role of clock gene Period 2 (Per2) for liver carcinogenesis and clock-controlled cellular proliferation, genomic instability and inflammation. We assessed liver histopathology, and determined molecular and physiology circadian patterns in mice on chronic diethylnitrosamine (DEN) exposure according to constitutive Per2 mutation. First, we found that Per2m/m liver displayed profound alterations in proliferation gene expression, including c-Myc derepression, phase-advanced Wee1, and arrhythmic Ccnb1 and K-ras mRNA expressions, as well as deregulated inflammation, through arrhythmic liver IL-6 protein concentration, in the absence of any DEN exposure. These changes could then make Per2m/m mice more prone to subsequently develop liver cancers on DEN. Indeed, primary liver cancers were nearly fourfold as frequent in Per2m/m mice as compared to wild-type (WT), 4 months after DEN exposure. The liver molecular clock was severely disrupted throughout the whole carcinogenesis process, including the initiation stage, i.e. within the initial 17 days on DEN. Per2m/m further exhibited increased c-Myc and Ccnb1 mean 24h expressions, lack of P53 response, and arrhythmic ATM, Wee1 and Ccnb1 expressions. DEN-induced tumor related inflammation was further promoted through increased protein concentrations of liver IL-6 and TNF-α as compared to WT during carcinogenesis initiation. Per2 mutation severely deregulated liver gene or protein expressions related to three cancer hallmarks, including uncontrolled proliferation, genomic instability, and tumor promoting inflammation, and accelerated liver carcinogenesis several-fold. Clock gene Per2 acted here as a liver tumor suppressor from initiation to progression.
Topics: Animals; Carcinogenesis; Circadian Rhythm; Diethylnitrosamine; Interleukin-6; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Mutation; Period Circadian Proteins; Tumor Necrosis Factor-alpha
PubMed: 27494874
DOI: 10.18632/oncotarget.11037 -
Applied Biochemistry and Biotechnology Oct 2023Thunbergia erecta L. contains cytotoxic and liver-protective compounds. Thunbergia erecta L. leaves were macerated in 70% aqueous ethanol, then fractionated with ethyl...
Thunbergia erecta L. contains cytotoxic and liver-protective compounds. Thunbergia erecta L. leaves were macerated in 70% aqueous ethanol, then fractionated with ethyl acetate (9.3 g) and butanol (12.7 g), and attenuated Den-induced liver cancer in a Wistar rat experimental model. Ethyl acetate and butanol fractions were chromatographed using column chromatography and solid-phase extraction (SPE); Vicenin-II (1), kaempferol (2), biochanin A, sissotrin 7-O-β-glucopyranoside (3), gentianose (4), acacetin 7-O-β-glucopyranoside (5), apigenin 7-O-β-glucopyranoside (6), and rosmarinic acid (7) were extracted, and their structures were determined using NMR spectroscopy and ESI-mass spectrometry. Sixty rats were divided into six groups (ten each): control group, Den group, doxorubicin/Den-treated group, butanol fraction/Den-treated group, and isolated acacetin 7-O-β-glucopyranoside/Den-treated group. The liver enzymes and proinflammatory biomarkers were used to estimate the liver function. In addition, liver tissues were collected for analysis of oxidative stress markers, gene expression, and histopathology. There is a significant increase in the levels of liver enzymes, AFP, and TNF-ἁ. This was conveyed by a significant increase of IL-1 and caspase-3, elevation of MDA and reduction of GSH, and suppression of Bcl2 and elevation of Bax expression. All parameters in butanol, ethyl acetate fractions, and isolated acacetin 7-O-β-glucopyranoside (major constituents) of T. erecta L. were significantly improved to values close to those of the control group.
Topics: Rats; Animals; Diethylnitrosamine; Rats, Wistar; Liver; Plant Leaves; Carcinogenesis; Butanols
PubMed: 36708488
DOI: 10.1007/s12010-022-04292-x -
Cell Death & Disease May 2018Liver cancer is one of the most lethal malignancies with very poor prognosis once diagnosed. The most common form of liver cancer is hepatocellular carcinoma (HCC). The...
Liver cancer is one of the most lethal malignancies with very poor prognosis once diagnosed. The most common form of liver cancer is hepatocellular carcinoma (HCC). The WW domain-containing oxidoreductase (WWOX) is a large gene that is often perturbed in a wide variety of tumors, including HCC. WWOX has been shown to act as a tumor suppressor modulating cellular metabolism via regulating hypoxia-inducible factor 1α (HIF-1α) levels and function. Given that WWOX is commonly inactivated in HCC, we set to determine whether specific targeted deletion of murine Wwox affects liver biology and HCC development. WWOX liver-specific knockout mice (Wwox ) showed more potent liver regeneration potential and enhanced proliferation as compared with their control littermates. Moreover, WWOX deficiency in hepatocytes combined with diethylnitrosamine treatment increased the tumor burden, which was associated with increased HIF1α levels and target gene transactivation. Inhibition of HIF1α by systemic treatment with digoxin significantly delayed HCC formation. Our work suggests that WWOX inactivation has a central role in promoting HCC through rewiring of cellular metabolism and modulating proliferation.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Diet, High-Fat; Diethylnitrosamine; Digoxin; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Hepatocytes; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Liver Neoplasms; Lymphatic Metastasis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prognosis; Signal Transduction; Tumor Burden; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 29724996
DOI: 10.1038/s41419-018-0510-4 -
Asian Pacific Journal of Cancer... Jul 2021This study was conducted to assess the therapeutic effect of Myrrh on Diethylnitrosamine (DEN)-induced hepatocarcinogenesis (HCC) in male albino rats.
BACKGROUND
This study was conducted to assess the therapeutic effect of Myrrh on Diethylnitrosamine (DEN)-induced hepatocarcinogenesis (HCC) in male albino rats.
METHODS
Fifty male albino rats were divided into five groups (10 rats each). Group 1 (control group) received distilled water. Group 2 (positive control) was injected intraperitoneally with DEN (55 mg/kg b.w) twice a week for two weeks, while group 3 (DOX) received doxorubicin i.p (10 mg/ kg b.w) after concomitant with DEN twice a week for four weeks. Groups 4 and 5 received a low dose of Myrrh (250 mg/kg b.w) and a high dose of Myrrh (500 mg/kg b.w) respectively daily for four weeks after the induction with DEN. The sera were used to estimate the liver enzymes (ALT, AST, and ALP), Alpha-fetoprotein (AFP), Total antioxidant capacity (TAC), and Tumor necrosis factor-ἁ (TNF-ἁ). Also, the liver tissues were collected to determine the oxidative stress markers in addition to the histopathological and immunohistochemical investigations.
RESULTS
The results showed that the induction of DEN causes a significant increase in the level of liver enzymes (ALT, AST, and ALP), AFP and TNF-ἁ as well as produce oxidative stress indicated by increasing of malondialdehyde (MDA) with the reduction in TAC and glutathione (GSH). Meanwhile, there are noticeable histopathological lesions with loss of hepatic architecture. This was accompanied by a significant increase of immunohistochemical markers; Caspase-3, vascular endothelial growth factor (VEGF), transforming growth factor β1(TGF- β1), and carcinoembryonic antigen (CEA) percentage area. The treatment of DEN rats with DOX reduced the alterations in most parameters. A marked amelioration of all parameters in a dose-dependent manner of Myrrh to the values almost near to those of the control group.
CONCLUSION
Our data revealed that Water extract of Myrrh (C. molmol) has a potential therapeutic effect in attenuation of HCC induced DEN.
Topics: Animals; Antioxidants; Biomarkers, Tumor; Carcinoma, Hepatocellular; Commiphora; Diethylnitrosamine; Doxorubicin; Liver Neoplasms, Experimental; Male; Oxidative Stress; Rats; Resins, Plant
PubMed: 34319038
DOI: 10.31557/APJCP.2021.22.7.2153 -
Theranostics 2021Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy...
Emerging evidence is demonstrating that rapid regeneration of remnant liver elicited by associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) may be attenuated in fibrotic livers. However, the molecular mechanisms responsible for this process are largely unknown. It is widely acknowledged that the TGFβ1 signaling axis plays a major role in liver fibrosis. Therefore, the aims of this study were to elucidate the underlying mechanism of liver regeneration during ALPPS with or without fibrosis, specifically focusing on TGFβ1 signaling. ALPPS was performed in rat models with -diethylnitrosamine-induced liver fibrosis and no fibrosis. Functional liver remnant regeneration and expression of TGFβ1 were analyzed during the ALPPS procedures. Adeno-associated virus-shTGFβ1 and the small molecule inhibitor LY2157299 (galunisertib) were used separately or in combination to inhibit TGFβ1 signaling in fibrotic rats. Liver regeneration following ALPPS was lower in fibrotic rats than non-fibrotic rats. TGFβ1 was a key mediator of postoperative regeneration in fibrotic liver. Interestingly, AAV-shTGFβ1 accelerated the regeneration of fibrotic functional liver remnant and improved fibrosis, while LY2157299 only enhanced liver regeneration. Moreover, combination treatment elicited a stronger effect. Inhibition of TGFβ1 accelerated regeneration of fibrotic liver, ameliorated liver fibrosis, and improved liver function following ALPPS. Therefore, TGFβ1 is a promising therapeutic target in ALPPS to improve fibrotic liver reserve function and prognosis.
Topics: Animals; Carbon Tetrachloride; Diethylnitrosamine; Hepatectomy; Hepatic Stellate Cells; Hepatocytes; Ligation; Liver; Liver Cirrhosis; Liver Regeneration; Portal Vein; Primary Cell Culture; Pyrazoles; Quinolines; Rats; Signal Transduction; Transforming Growth Factor beta1
PubMed: 33754025
DOI: 10.7150/thno.52102 -
Molecules (Basel, Switzerland) Feb 2023Therapeutics, based on small interfering RNA (siRNA), have demonstrated tremendous potential for treating cancer. However, issues such as non-specific targeting,...
Therapeutics, based on small interfering RNA (siRNA), have demonstrated tremendous potential for treating cancer. However, issues such as non-specific targeting, premature degradation, and the intrinsic toxicity of the siRNA, have to be solved before they are ready for use in translational medicines. To address these challenges, nanotechnology-based tools might help to shield siRNA and ensure its specific delivery to the target site. Besides playing a crucial role in prostaglandin synthesis, the cyclo-oxygenase-2 (COX-2) enzyme has been reported to mediate carcinogenesis in various types of cancer, including hepatocellular carcinoma (HCC). We encapsulated COX-2-specific siRNA in membrane lipid-based liposomes (subtilosomes) and evaluated their potential in the treatment of diethylnitrosamine (DEN)-induced hepatocellular carcinoma. Our findings suggested that the subtilosome-based formulation was stable, releasing COX-2 siRNA in a sustained manner, and has the potential to abruptly release encapsulated material at acidic pH. The fusogenic property of subtilosomes was revealed by FRET, fluorescence dequenching, content-mixing assay, etc. The subtilosome-based siRNA formulation was successful in inhibiting TNF-α expression in the experimental animals. The apoptosis study indicated that the subtilosomized siRNA inhibits DEN-induced carcinogenesis more effectively than free siRNA. The as-developed formulation also suppressed COX-2 expression, which in turn up-regulated the expression of wild-type p53 and Bax on one hand and down-regulated Bcl-2 expression on the other. The survival data established the increased efficacy of subtilosome-encapsulated COX-2 siRNA against hepatocellular carcinoma.
Topics: Animals; Carcinoma, Hepatocellular; Liver Neoplasms; Diethylnitrosamine; RNA, Small Interfering; Cyclooxygenase 2; Apoptosis; Carcinogenesis
PubMed: 36903437
DOI: 10.3390/molecules28052191 -
Journal of Oleo Science Sep 2022Hepatocellular Carcinoma (HCC) is the 5 most common type of cancer in all types of cancers, globally. It is well known that the frequency of inflammatory reaction and...
Hepatocellular Carcinoma (HCC) is the 5 most common type of cancer in all types of cancers, globally. It is well known that the frequency of inflammatory reaction and oxidative stress increases during the HCC. The goal of this study was to see if decalactone could prevent rats against HCC caused by diethylnitrosamine (DEN). Single intraperitoneal administration of DEN (200 mg/kg) used as inducer and weekly intraperitoneal injection of phenobarbital (8 mg/kg) was used as promotor for induction the HCC in rats. Serum alpha fetoprotein (AFP) was used for the confirmation of HCC. Different doses of decalactone (5, 10 and 15 mg/kg) were orally administered to the rats. The body weight was determined at regular time. The hepatic, non-hepatic, antioxidant markers and inflammatory mediators were scrutinized. All groups of animals were scarified and macroscopically examination of the liver tissue was performed and the weight of organ (hepatic tissue) were estimated. Decalactone increased body weight while also suppressing hepatic nodules and tissue weight. Decalactone treatment reduced AFP, total bilirubin, and direct bilirubin levels while increasing albumin and total protein levels in a dose-dependent manner. Decalactone reduced lipid peroxidation (LPO) and increased catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels significantly (p < 0.001) (SOD). Decalactone lowered the levels of significantly (p < 0.001) inflammatory cytokines and inflammatory markers in the liver. Based on the findings, we may conclude that decalactone inhibited HCC in DEN-induced HCC animals via reducing oxidative stress and inflammatory mediators.
Topics: Animals; Antioxidants; Bilirubin; Body Weight; Carcinoma, Hepatocellular; Diethylnitrosamine; Glutathione; Inflammation Mediators; Liver; Liver Neoplasms; Oxidative Stress; Plant Extracts; Rats; Rats, Wistar; Superoxide Dismutase; alpha-Fetoproteins
PubMed: 35965085
DOI: 10.5650/jos.ess22033 -
Nature Communications Apr 2015Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour...
Hepatocellular carcinoma (HCC) develops on the background of chronic hepatitis. Leukocytes found within the HCC microenvironment are implicated as regulators of tumour growth. We show that diethylnitrosamine (DEN)-induced murine HCC is attenuated by antibody-mediated depletion of hepatic neutrophils, the latter stimulating hepatocellular ROS and telomere DNA damage. We additionally report a previously unappreciated tumour suppressor function for hepatocellular nfkb1 operating via p50:p50 dimers and the co-repressor HDAC1. These anti-inflammatory proteins combine to transcriptionally repress hepatic expression of a S100A8/9, CXCL1 and CXCL2 neutrophil chemokine network. Loss of nfkb1 promotes ageing-associated chronic liver disease (CLD), characterized by steatosis, neutrophillia, fibrosis, hepatocyte telomere damage and HCC. Nfkb1(S340A/S340A)mice carrying a mutation designed to selectively disrupt p50:p50:HDAC1 complexes are more susceptible to HCC; by contrast, mice lacking S100A9 express reduced neutrophil chemokines and are protected from HCC. Inhibiting neutrophil accumulation in CLD or targeting their tumour-promoting activities may offer therapeutic opportunities in HCC.
Topics: Alkylating Agents; Animals; Calgranulin A; Calgranulin B; Carcinoma, Hepatocellular; Chemokine CXCL1; Chemokine CXCL2; Diethylnitrosamine; Liver Diseases; Liver Neoplasms, Experimental; Mice; Mice, Knockout; Mutation; NF-kappa B p50 Subunit; Neutrophils
PubMed: 25879839
DOI: 10.1038/ncomms7818 -
Genomics Jul 2023Differences in the gut microbiota and metabolic processes between males and females may explain differences in the risk of liver injury; however, the sex-specific...
Differences in the gut microbiota and metabolic processes between males and females may explain differences in the risk of liver injury; however, the sex-specific effects of antibiotics and probiotics on these relationships are not clear. We evaluated differences in the gut microbiota and the risk of liver injury between male and female rats after the oral administration of antibiotics or probiotics followed by a period of diethylnitrosamine treatment to chemically induce liver injuryusing high-throughput sequencing of fecal microbiota combined with histological analyses of liver and colon tissues. Our results suggest that the ratio of gram-positive to gram-negative bacteria in kanamycin-treated rats was significantly higher than that of other groups, and this difference persisted for the duration of the experiment. Antibiotics significantly changed the composition of the gut microbiota of experimental rats. Clindamycin caused more diethylnitrosamine-induced damage to livers of male rats. Probiotics did not influencethe gut microbiota; however, they hadprotective effects against liver injury induced by diethylnitrosamine, especially in female rats. These results strengthen our understanding of sex differences in the indirect effects of antibiotics or probiotics on metabolism and liver injury in hosts via the gut microbiota.
Topics: Female; Male; Rats; Animals; Anti-Bacterial Agents; Gastrointestinal Microbiome; Chemical and Drug Induced Liver Injury, Chronic; Diethylnitrosamine; Sex Characteristics; Probiotics
PubMed: 37217087
DOI: 10.1016/j.ygeno.2023.110647