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Photomicrograph of liver tissue section of HCCbearing rat treated with doxorubicin shows severe congestion in portal vein (PV) with degeneration in the hepatocytes (d) (H&E, 16×).
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The global burden of hepatocellular carcinoma is increasing; actually, it is estimated as 750,000 new cases annually. This study was initiated to emphasize the possibility that gallic acid could alleviate hepatocarcinogenesis in vivo. In this study, 40 rats were enrolled and distributed as follows; group 1 was set as negative control, while all of...
Context in source publication
Context 1
... the contrary, optical micro- graph of the liver tissue section of rat in HCC group treated with gallic acid shows congestion in the portal vein with inflammatory cell infiltration as well as multiple newly formed bile ductules (Figure 4). Optical micrograph of the cross-sectioned liver tissue of rat in HCC group treated with doxorubicin reveals severe congestion in the portal vein with a focal degeneration of hepatocytes ( Figure 5). ...
Citations
... Gallic acid (3,4,5-trihydroxy benzoic acid) is a polyhydroxy-phenolic compound extracted from the astringent Chinese medicine gallnut (Hsu et al. 2011), which has an inflammatory reduction, antioxidant, antineoplastic, antiviral, and antianxiety effects (Mori et al. 2020), especially in liver cancer (Sun et al. 2016;Aglan et al. 2017), cervical cancer (Zhao and Hu 2013), breast cancer (Wang et al. 2014), and other tumors. It has been reported that GA aggravates the imbalance of the redox status of tumor cells, causing ROS accumulation and tumor cell death (Tor et al. 2015;Alfei et al. 2020). ...
Hepatocellular carcinoma (HCC) has high morbidity and mortality, and effective therapies are lacking. Gallic acid (GA), a natural phenolic compound derived from plants, has been reported to prevent the onset and progression of various cancers. However, there is limited elaboration on the potential mechanisms and anticancer effects of GA on hepatocellular carcinoma. Inducing ferroptosis of tumor cells has become one of the most promising ways to eradicate tumor cells. However, the effect of GA on HCC ferroptosis remains unknown. We evaluated the impact of GA on cell viability, migration, and mitochondrial morphology in HepG2 cells. Our study identified a critical role of GA in inducing ferroptosis in HepG2 cells. Mechanistically, we found that GA could inhibit the expression of a ferroptosis-related protein SLC7A11 and GPX4 in HepG2, by blocking β‐catenin transport from nuclear to the cytoplasm, thus inducing the inactivation of the Wnt/β‐catenin pathway. Our study has confirmed that GA is a novel ferroptosis inducer of HC, suggesting GA could be a promising candidate for the clinical treatment of HCC.
... GA decreases the serum levels of alpha-fetoprotein, glypican-3, and signal transducer and activator of transcription 3 and increases serum levels of suppressors of cytokine signaling 3 when N-nitrosodiethylamine was used to induce hepatocellular carcinoma in rats. Additionally, GA significantly improves the instability of the liver tissue structure brought on by N-nitrosodiethylamine poisoning and results in a significant decrease in the gene expression levels of hepatic gamma glutamyl transferase and heat shock protein gp96 [103]. GA reduces the proliferation of hepatocellular carcinoma (HepG2) cells in a dose-dependent manner, without causing necrosis, and leads to a significant decrease in IL-8 levels and an increase in IL-10 and IL-12 levels [102]. ...
Cancer is one of the deadliest and most heterogeneous diseases. Cancers often develop drug resistance, which can lead to treatment failure or recurrence. Accordingly, anticancer compounds are essential for chemotherapy-resistant cancer cells. Phenolic compounds are of interest in the development of cancer drugs due to their medicinal properties and ability to target different molecular pathways. Gallic acid (GA), as one of the main components of phenol, which is abundantly present in plant compounds such as walnut, sumac, grapes, tea leaves, oak bark, and other plant compounds, has antitumor properties. GA can prevent cancer progression, cell invasion, and metastasis by targeting molecular pathways and is an effective complement to chemotherapy drugs and combating multidrug resistance (MDR). In this review, we discuss various mechanisms related to cancer, the therapeutic potential of GA, the antitumor properties of GA in various cancers, and the targeted delivery of GA with nanocarriers.
... Similarly, Quercetin inhibits hepatocellular carcinoma progression by down-regulation of the activation of JAK2 and STAT3. Gallic acid show strong antitumor potential in the treatment of cellular hepatocarcinoma in vivo and in vitro [49,50]. Nevertheless, clinical trials have not yet been conducted to confirm their effectiveness in humans. ...
Background
Liver hepatocellular carcinoma (LIHC) ranks sixth among the most common types of cancer with a high mortality rate. Cuproptosis is a newly discovered type of cell death in tumor, which is characterized by accumulation of intracellular copper leading to the aggregation of mitochondrial lipoproteins and destabilization of proteins. Thus, understanding the exact effects of cuproptosis-related genes in LIHC and determining their prognosticvalue is critical. However, the prognostic model of LIHC based on cuproptosis-related genes has not been reported.
Methods
Firstly, we downloaded transcriptome data and clinical information of LIHC patients from TCGA and GEO (GSE76427), respectively. We then extracted the expression of cuproptosis-related genes and established a prognostic model by lasso cox regression analysis. Afterwards, the prediction performance of the model was evaluated by Kaplan–Meier survival analysis and receiver operating characteristic curve (ROC). Then, the prognostic model and the expression levels of the three genes were validated using the dataset from GEO. Subsequently, we divided LIHC patients into two subtypes by non-negative matrix factorization (NMF) classification and performed survival analysis. We constructed a Sankey plot linking different subtypes and prognostic models. Next, we calculate the drug sensitivity of each sample from patients in the high-risk group and low-risk group by the R package pRRophetic. Finally, we verified the function of LIPT1 in LIHC.
Results
Using lasso cox regression analysis, we developed a prognostic risk model based on three cuproptosis-related genes (GCSH, LIPT1 and CDKN2A). Both in the training and in the test sets, the overall survival (OS) of LIHC patients in the low-risk group was significantly longer than that in the high-risk group. By performing NMF cluster, we identified two molecular subtypes of LIHC (C1 and C2), with C1 subtype having significantly longer OS and PFS than C2 subtype. The ROC analysis indicated that our model had a precisely predictive capacity for patients with LIHC. The multivariate Cox regression analysis indicated that the risk score is an independent predictor. Subsequently, we identified 71 compounds with IC50 values that differed between the high-risk and low-risk groups. Finally, we determined that knockdown of LIPT1 gene expression inhibited proliferation and invasion of hepatoma cells.
Conclusion
In this study, we developed a novel prognostic model for hepatocellular carcinoma based on cuproptosis-related genes that can effectively predict the prognosis of LIHC patients. The model may be helpful for clinicians to make clinical decisions for patients with LIHC and provide valuable insights for individualized treatment. Two distinct subtypes of LIHC were identified based on cuproptosis-related genes, with different prognosis and immune characteristics. In addition, we verified that LIPT1 may promote proliferation, invasion and migration of LIHC cells. LIPT1 might be a new potential target for therapy of LIHC.
... Among the emerging cancer treatments is gallic acid (GA) [102][103][104]. Studies have shown it suppresses hepatic cancer cell viability, proliferation, invasion, and angiogenesis [105][106][107][108]. ...
Human diseases such as cancer can be caused by aberrant epigenetic regulation. Polyphenols play a major role in mammalian epigenome regulation through mechanisms and proteins that remodel chromatin. In fruits, seeds, and vegetables, as well as food supplements, polyphenols are found. Compounds such as these ones are powerful anticancer agents and antioxidants. Gallic acid, kaempferol, curcumin, quercetin, and resveratrol, among others, have potent anti-tumor effects by helping reverse epigenetic changes associated with oncogene activation and tumor suppressor gene inactivation. The role dietary polyphenols plays in restoring epigenetic alterations in cancer cells with a particular focus on DNA methylation and histone modifications was summarized. We also discussed how these natural compounds modulate gene expression at the epigenetic level and described their molecular targets in cancer. It highlights the potential of polyphenols as an alternative therapeutic approach in cancer since they modulate epigenetic activity.
... 31 On the plus side, GA has been reported to be a potent antiproliferative agent against diethylnitrosamine (DEN)-induced HCC owing to its affinity to regulate signal transducer and activator of transcription 3 signaling pathway. 32,33 Consequently, GA may possess the potential to be a novel therapeutic compound for use in the treatment of HCC. Noteworthy, GA is hydrophilic, causing it difficult to penetrate the wall of cancer cells. ...
... 70 The proposed mechanism by which GA could recover AFP serum level may stem from the suppression of COX-2 gene expression, which is known to modulate the transcription of AFP. 33 Collectively, as AFP is indicative for HCC, the reduction of AFP suggested the inhibition in HCC development which is further supported by the improvement of liver functions of DEN + GA-GaNPs treated rats compared to their DEN counterparts (illustrated later). On the other hand, our results are also concomitant with Mohamed et al. 69 who reported that CDDP treatment of intoxicated rats showed a significant decrease in AFP level relative to their DEN counterparts. ...
Introduction: In the fight against cancer, cisplatin is most widely used as a clinical mainstay for the chemotherapy of various human cancers. Meanwhile, its cytotoxic profile, as well as drug resistance, limits its widespread application. The goal of precision medicine is to tailor an optimized therapeutic program based on the biology of the disease. Recently, nanotechnology has been demonstrated to be promising in this scenario. Objective: The current work provides a rationale for the design of an alternative oncology trial for the treatment of hepatocarcinogenesis using a novel eco-friendly nanocomplex, namely gallic acid-coated gallium nanoparticles. Moreover, the study tests whether the antineoplastic efficacy of gallic acid-coated gallium nanoparticles could be enhanced or not when it is administrated together with cisplatin. Methods: The work comprised a series of both in vitro and in vivo investigations. The in vivo therapeutic efficacy of such treatments, against diethylnitrosamine-induced hepatocarcinogenesis, was strictly evaluated by tracking target genes expressions, iron homeostasis, diverse bio-markers alterations, and lastly, routine paraclinical investigations were also assessed. Results: The in vitro biological evaluation of gallic acid-coated gallium nanoparticles in a HepG-2 cancer cell line established its superior cytotoxicity. Else more, the results of the in vivo experiment highlighted that gallic acid-coated gallium nanoparticles could diminish key hallmarks of cancer by ameliorating most of the investigated parameters. This was well-appreciated with the histopathological findings of the liver architectures of the treated groups. Conclusions: Our findings suggest that novel biogenic Ga-based nanocom-plexes may potentially present new hope for the development of alternative liver cancer therapeutics, which should attract further scientific interest.
... 31 On the plus side, GA has been reported to be a potent antiproliferative agent against diethylnitrosamine (DEN)-induced HCC owing to its affinity to regulate signal transducer and activator of transcription 3 signaling pathway. 32,33 Consequently, GA may possess the potential to be a novel therapeutic compound for use in the treatment of HCC. Noteworthy, GA is hydrophilic, causing it difficult to penetrate the wall of cancer cells. ...
... 70 The proposed mechanism by which GA could recover AFP serum level may stem from the suppression of COX-2 gene expression, which is known to modulate the transcription of AFP. 33 Collectively, as AFP is indicative for HCC, the reduction of AFP suggested the inhibition in HCC development which is further supported by the improvement of liver functions of DEN + GA-GaNPs treated rats compared to their DEN counterparts (illustrated later). On the other hand, our results are also concomitant with Mohamed et al. 69 who reported that CDDP treatment of intoxicated rats showed a significant decrease in AFP level relative to their DEN counterparts. ...
Introduction: In the fight against cancer, cisplatin is most widely used as a clinical mainstay for the chemotherapy of various human cancers. Meanwhile, its cytotoxic profile, as well as drug resistance, limits its widespread application. The goal of precision medicine is to tailor an optimized therapeutic program based on the biology of the disease. Recently, nanotechnology has been demonstrated to be promising in this scenario. Objective: The current work provides a rationale for the design of an alternative oncology trial for the treatment of hepatocarcinogenesis using a novel eco-friendly nanocomplex, namely gallic acid-coated gallium nanoparticles. Moreover, the study tests whether the antineoplastic efficacy of gallic acid-coated gallium nanoparticles could be enhanced or not when it is administrated together with cisplatin. Methods: The work comprised a series of both in vitro and in vivo investigations. The in vivo therapeutic efficacy of such treatments, against diethylnitrosamine-induced hepatocarcinogenesis, was strictly evaluated by tracking target genes expressions, iron homeostasis, diverse biomarkers alterations, and lastly, routine paraclinical investigations were also assessed. Results: The in vitro biological evaluation of gallic acid-coated gallium nanoparticles in a HepG-2 cancer cell line established its superior cytotoxicity. Else more, the results of the in vivo experiment highlighted that gallic acid-coated gallium nanoparticles could diminish key hallmarks of cancer by ameliorating most of the investigated parameters. This was well-appreciated with the histopathological findings of the liver architectures of the treated groups. Conclusions: Our findings suggest that novel biogenic Ga-based nanocomplexes may potentially present new hope for the development of alternative liver cancer therapeutics, which should attract further scientific interest.
... Furthermore, transforming growth factor-β (TGFβ) plays a vital role in the development and progression of HCC induced by DEN through induction of regulatory T cell (Treg) polarization [55], in which Treg cells play an important role in the regulation of immune response by prevention of tissue damage and inf lammation [56]. Glypican3 (GP3) was highly expressed in HCC [57], due to over expression of the c-Myc gene, where it is the primary regulator of GP3 through its direct binding to the GP3 promoter [58]. The high expression of GP3 can accelerate the epithelial-mesenchymal transition (EMT) of HCC cells through the activation of extracellular signalregulated kinases (ERK) [59], where EMT is involved in the spreading activity of cancer cells as well as drug resistance [60]. ...
Natural antioxidant products play a vital role in the treatment and prevention of cancer disease because they have no side effects. This study aimed to compare the chemoprotective effect of Spirulina platensis (SP) and garlic against hepatocellular carcinoma (HCC) in rats. This study was being done by using 60 male Wistar rats and divided into four groups. Group (I): normal group. Group (II): HCC group induced by injection of a single dose of DEN (200 mg/kg/I.P) and after 14 days injected CCl4 (1 mg/kg/I.P) 3 times/week/six weeks. Group (III): HCC group received SP orally at a dose (500 mg/kg). Group (IV): HCC group received garlic (250 mg/kg) orally. The results revealed that the Spirulina and garlic treatment have a significant decrease in Glutamate pyruvate transaminase, Glutamate oxaloacetate transaminase, GGT, LDH, and the Malondialdehyde (MDA) activity, and furthermore, a significant increase in the total protein level, the superoxide dismutase (SOD), and Catalase (CAT) activity nearly to normal activity. Furthermore, the hepatic expression of tumor necrosis factor (TNF-α), interleukin-6 (IL-6), inducible nitric oxide synthase, transforming growth factor-beta (TGF-β1), Heat Shock Protein glycoprotein 96 (HSPgp96), and Glypican 3 (GP3) were down regulated by the Spirulina and garlic treatment in comparison with those in HCC group. All findings reported that the chemoprotective of both Spirulina and garlic that have nearly the same effect may be due to antioxidant activity and inhibition of lipid peroxidation, amelioration of pro-inflammatory cytokine, HSPgp96, and GP3.
... Our results revealed the overexpression of GPC3 in the HCC-induced group compared with the level in controls. In addition, it was previously reported [65] that the serum level of GPC-3 was increased in NDEN-treated rats. Meanwhile, the administration of honey to HCC-induced rats decreased the (Table 1). ...
Hepatocellular carcinoma (HCC) is a serious threat to human health that has attracted substantial interest. The purpose of this study was to investigate the modulatory effect of bee honey against induced HCC by diethylnitrosamine/carbon tetrachloride (DEN/CCl4) in rats. HCC was induced by a single intraperitoneal dose of DEN (200 mg/kg B.W). Two weeks later, CCl4 (1 ml/kg) was intraperitoneally injected (three times a week). Bee honey was administered orally at 2 g/rat before and after the induction of HCC. The results showed that bee honey administration significantly increased body weight, decreased liver weight, and relative liver weight compared to those in the HCC-induced group. Moreover, a significant decrease in serum alpha-fetoprotein (AFP) as well as AST, ALT, GGT, ALP activities were observed in bee honey administration rats compared with those in HCC-induced group. Also, the hepatic MDA was significantly decreased; in addition, SOD, CAT, and GPx activities were significantly increased in groups treated with bee honey compared with those in the HCC group. The hepatic histopathology alterations caused by DEN/CCl4 injection were ameliorated by bee honey treatment. Likewise, the mRNA expression levels of tumor necrosis factor-alpha (TNF-α), transforming growth factor (TGF-β1), intracellular adhesion molecule-1 (ICAM-1), vascular cellular adhesion molecule-1 (VCAM-1), glypican (GP-3), thioredoxin (TRX), and glutaredoxin (GRX) were downregulated, and caspase-3 was upregulated by bee honey treatment compared with untreated HCC-induced group. In conclusion, bee honey has remarkable beneficial effects against HCC induced in rats through its antioxidant, anti-inflammatory, antifibrotic, and antimetastatic effects.
Practical Applications
The current study confirmed that honey has the potential to act as an antimetastatic factor. Bee honey supplementation either before or after combined injection of DEN/CCl4 exhibited inhibitory and ameliorative effects against DEN/CCl4-induced HCC through its antioxidant, antiproliferative, anti-metastatic, antifibrotic, and apoptosis properties. To our knowledge, this is the first study to describe the molecular mechanisms underlying honey’s effects against DEN/CCl4-induced HCC in rats.
... In addition, Glypican 3 (GP3) is highly related to the appearance and development of liver cancer, is used for diagnosis, and is an important target for HCC immunotherapy [41]. Our finding revealed that the expression level of GP3 was increased in HCC-induced rats, in agreement with another study [42], which documented an increased serum level of GP3 level in DEN-treated rats. All biochemical, pathological, and molecular analysis results of this study indicate the antitumor and hepatoprotective effects of the S-methyl methionine sulphonium chloride. ...
Liver disease, especially liver cancer, has become a threat facing the world. Now, antioxidant products are garnering great attention for the treatment and prevention of many diseases. S-Methyl methionine sulfonium chloride (MMSC) is a methionine derivative and is present in many vegetables and has anti-inflammatory effects and antioxidants. This is the first study aiming to investigate the antitumor activity of the MMSC. This study was carried out on 60 male Wistar albino rats (4–6 weeks old age) and divided into four groups, with the first group as normal control, second group as hepatocarcinoma induced by diethyl nitrosamine and carbon tetrachloride (DEN/CCL4) group, third group as normal rats treated with MMSC, and fourth group as hepatocellular carcinoma (HCC) induced rats treated with MMSC. Our findings revealed that MMSC administration after HCC induction significantly improved (p < 0.05) the liver function biomarkers, including AST, GGT, albumin, globulin, and albumin/globulin ratio (A/G), in comparison with those in the HCC group. Moreover, the histopathological changes of the liver tissue in the HCC group were improved by MMSC treatment. Likewise, the expression levels of tumor necrosis factor-alpha (TNF-α), induced nitric oxide synthase (iNOS), transforming growth factor (TGF-1β), and glypican 3 (GP3) were downregulated by MMSC treatment after HCC induction in comparison with those in the HCC-induced group. In conclusion, MMSC showed antitumor activity against HCC induction by DEN/CCl4 through decreasing lipid peroxide formation, the expression level of an inflammatory cytokines such as (TNF-α), immunoregulatory cytokines such as (TGF-1β), induced nitric oxide synthase, and glypican 3.
... Besides an elevation in ROS production and decrease in antioxidant status of the liver affected mitochondria function, accompanied with release of cytochrome-c (57) and leakage of hepatocellular enzymes to the extracellular space. GA, by suppressing lipid peroxidation and retaining the cell membrane, hindered the diffusion of hepatic enzymes into the plasma (58)(59)(60). The current results showed that administration of NAC has exert beneficial effects on liver enzymes which decrease the elevation of ALT and ALP, these results are similar to other researcher results (61,62). ...
This study was designed to investigate the ameliorative role of gallic acid (GA) and N-acetylcysteine (NAC) in reducing deleterious effect of sodium fluoride (NaF) such as, oxidative stress and hepatic dysfunction in adult male rats. Thirty adult male rats were randomly and equally divided into five groups, they were handled daily for 60 days, as follows: Control group (C), received tap water only, Sodium fluoride group (T1), received 100ppm of NaF in drinking tap water, gallic acid group (T2), rats in this group were injected intraperitoneal (i/p) 150 mg/kg/day/ of GA, N-acetylcysteine group (T3), animals in this group were administrated orally 25 mg/kg/day/of NAC, while the combination of GA and NAC were given to NaF treated group(T4) in the same previous mentioned doses and method of administration. Fasting blood sample were collected at the beginning and the end of the experiment and serum were collected for estimation of hepatic enzymes concentration and antioxidant status. After animal scarifying, samples from hepatic tissue were taken for measuring hepatic reduced glutathione (GSH)and malondialdehyde (MDA) concentration. The results showed that adminstration of NaF (T1group) caused hepatic damage manifested functionally by: significant increase in serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) concentrations, a case of oxidative stress as explained by depression in (GSH) and elevation in MDA concentration in serum and hepatic tissue. The current result also recorded that i/p injection of GA oral administration of NAC alone or in combination with NaF caused amelioration of all previously estimated parameters.
