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Mohamed Azar KAH, Ezhilarasan D, Karthick M, Shree Harini K, Kumar V. Coleus vettiveroides Root Extract Protects Against Thioacetamide-Induced Chronic Liver Injury by Inhibiting NF-κB Signaling Pathway. ENVIRONMENTAL TOXICOLOGY 2025; 40:723-736. [PMID: 39705085 DOI: 10.1002/tox.24465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 08/05/2024] [Accepted: 12/08/2024] [Indexed: 12/22/2024]
Abstract
The roots of Coleus vettiveroides (CV) have been traditionally used in Indian medicinal systems such as Ayurveda and Siddha for its antioxidant, anti-inflammatory, and antidiabetic effects. This study examines the antifibrotic potential of CV ethanolic root extract (CVERE) against thioacetamide (TAA)-induced liver fibrosis in Wistar rats. TAA was administered via i.p., thrice weekly for 11 weeks to induce liver fibrosis in rats. In separate groups, rats were administered with TAA and were concurrently treated with CVERE 125 mg/kg, CVERE 250 mg/kg, and silymarin (SIL) 100 mg/kg. Liver marker enzymes of hepatotoxicity, oxidative stress markers, proinflammatory marker gene expression (TNF-α, NF-κB, COX, and ILs), fibrotic marker gene expression (collagen I and III), immune histochemical expression of fibrosis marker proteins, and histopathologic changes were analyzed. TAA administration led to a significant (p < 0.001) increase in the serum level of hepatotoxic marker enzymes. The TAA-treated group showed higher levels (p < 0.001) of MDA and reduced activities of SOD and CAT in the liver. TAA administration increased CYP2E1 expression, proinflammatory, and fibrotic marker gene expressions in rat liver. The histopathology of the liver confirms TAA-induced architectural distortion and fibrotic changes. CVERE and SIL simultaneous treatments significantly protected against TAA-induced oxidative stress, inflammation, and liver fibrosis. In conclusion, CVERE inhibited TAA-induced liver fibrosis through downregulation of TAA metabolic activation, redox imbalance, and inflammation through repression of the NF-κB pathway.
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Affiliation(s)
- Kadmad Abdul Hameed Mohamed Azar
- Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India
| | - Devaraj Ezhilarasan
- Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India
| | - Munusamy Karthick
- Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India
| | - Karthik Shree Harini
- Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India
| | - Venkatesan Kumar
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha, Saudi Arabia
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Zhang X, Zhang L, Zhou L, Tao H, Chen Z. BRCC3 aggravates pulpitis by activating the NF-κB signaling pathway in dental pulp cells. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167698. [PMID: 39880291 DOI: 10.1016/j.bbadis.2025.167698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 12/18/2024] [Accepted: 01/23/2025] [Indexed: 01/31/2025]
Abstract
BRCA1/BRCA2-containing complex subunit 3 (BRCC3) has been proved to exert pro-inflammatory effect in various inflammatory diseases through different mechanisms, but its involvement in pulpitis remains unclear. This study aims to investigate the regulatory role and mechanisms of BRCC3 in modulating dental pulp cell inflammation and pulpitis progression. The expression of BRCC3 was observed to be elevated in human/mouse pulpitis samples and lipopolysaccharide-stimulated human dental pulp cells (hDPCs). Manipulation of BRCC3 expression revealed that BRCC3 facilitated the expression of pro-inflammatory cytokines and apoptosis of hDPCs. RNA-sequencing and gene set enrichment analysis were utilized to explore the downstream signaling pathways related to BRCC3 functions. Dual luciferase reporter assay, western blot, and immunofluorescence staining were conducted for further validation. The results demonstrated that BRCC3 expedited IκBα phosphorylation and degradation, as well as p65 phosphorylation and nuclear translocation in hDPCs, ultimately activating the nuclear factor kappa B (NF-κB) signaling pathway. Moreover, conditional knockout of Brcc3 in mouse dental pulp cells effectively impeded the expression of IL-6, recruitment of immune cells, and necrosis of inflamed pulp tissue after 1 day and 1 week of pulp exposure. The level of p-p65 in Brcc3 conditional knockout mice was lower than the control mice, indicating the inhibition of NF-κB. Taken together, BRCC3 promotes pulpitis by activating the NF-κB signaling pathway in dental pulp cells.
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Affiliation(s)
- Xinye Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China
| | - Lu Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China; Department of Cariology and Endodontology, School & Hospital of Stomatology, Wuhan University, China
| | - Linfang Zhou
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China
| | - Huangheng Tao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China; Center for Cariology, Endodontics and Periodontics, School & Hospital of Stomatology, Wuhan University, China.
| | - Zhi Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, China; Department of Cariology and Endodontology, School & Hospital of Stomatology, Wuhan University, China.
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Zheng S, Xue T, Xue C, Li S, Zao X, Li X, Cao X, Du H, Qi W, Seetoh WS, Wang W, Zhang P, Ye Y. Regulatory mechanisms of signaling pathways in liver cancer treatment with traditional Chinese medicine. JOURNAL OF ETHNOPHARMACOLOGY 2025; 342:119386. [PMID: 39848414 DOI: 10.1016/j.jep.2025.119386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 01/25/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese Medicine (TCM), as a longstanding therapeutic approach, offers unique advantages and potential in the treatment of liver cancer. Recent studies have highlighted its role in preventing liver cancer progression by modulating key signaling pathways. TCM's multi-component, multi-target, and multi-pathway mechanisms of action have garnered significant attention in the medical community for their ability to address complex diseases like liver cancer. AIM OF THE STUDY This review examines the current status and challenges in the application of TCM to regulate specific signaling pathways, including PI3K/Akt, NF-κB, TGF-β, Wnt/β-Catenin, and Notch, in liver cancer treatment. The goal is to further elucidate the critical roles of these pathways in liver cancer progression and provide new insights into the modern scientific interpretation of TCM. MATERIALS AND METHODS Literature was retrieved from PubMed and Web of Science databases using keywords such as "traditional Chinese medicine," "Chinese medicine," and "signaling pathway." The articles reviewed span from 2004 to 2024. RESULTS TCM demonstrates significant therapeutic and preventive effects in liver cancer by modulating signaling pathways involved in tumorigenesis. These pathways influence processes such as cell growth, invasion, proliferation, and inflammatory responses, contributing to the anti-cancer effects of TCM. CONCLUSION By modulating key signaling pathways such as PI3K/Akt, NF-κB, TGF-β, Wnt/β-Catenin, and Notch, TCM plays an important role in both the treatment and prevention of liver cancer, offering a promising therapeutic approach grounded in traditional practices and modern scientific understanding.
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Affiliation(s)
- Shihao Zheng
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Beijing University of Chinese Medicine, 100102, China.
| | - Tianyu Xue
- Hebei Provincial Hospital of Traditional Chinese Medicine, 050000, China
| | - Chengyuan Xue
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Beijing University of Chinese Medicine, 100102, China
| | - Size Li
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Beijing University of Chinese Medicine, 100102, China
| | - Xiaobin Zao
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China
| | - Xiaoke Li
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 100029, China
| | - Xu Cao
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 100029, China
| | - Hongbo Du
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 100029, China
| | - Wenying Qi
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Beijing University of Chinese Medicine, 100102, China
| | - Wei Song Seetoh
- Beijing University of Chinese Medicine, 100102, China; School of Biological Sciences, Nanyang Technological University, 637551, China
| | - Wei Wang
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Beijing University of Chinese Medicine, 100102, China
| | - Peng Zhang
- Department of Spleen and Gastroenterology, Dongfang Hospital, Beijing University of Chinese Medicine, 100078, China.
| | - Yongan Ye
- Department of Spleen and Gastroenterology, Dongzhimen Hospital, Beijing University of Chinese Medicine, 100007, China; Liver Diseases Academy of Traditional Chinese Medicine, Beijing University of Chinese Medicine, 100029, China.
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Saponara I, Aloisio Caruso E, Cofano M, De Nunzio V, Pinto G, Centonze M, Notarnicola M. Anti-Inflammatory and Anti-Fibrotic Effects of a Mixture of Polyphenols Extracted from "Navelina" Orange in Human Hepa-RG and LX-2 Cells Mediated by Cannabinoid Receptor 2. Int J Mol Sci 2025; 26:512. [PMID: 39859241 PMCID: PMC11765147 DOI: 10.3390/ijms26020512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/03/2025] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Navelina oranges (Citrus sinensis) are rich in phytonutrients and bioactive compounds, especially flavonoids like hesperidin. This study investigates the anti-inflammatory and anti-fibrotic properties of hesperidin (HE) and a polyphenol mixture from Navelina oranges (OE) in human hepatocytes (Hepa-RG) and hepatic stellate cells (LX-2), in order to elucidate the underlying molecular mechanisms. In Hepa-RG cells, HE treatment increased expression of cannabinoid receptor 2 (CB2R), which was associated with down-regulation of p38 mitogen-activated protein kinases (p38 MAPK) but had minimal impact on cyclooxygenase-2 (COX-2) and transforming growth factor-β (TGF-β) levels. Conversely, OE treatment not only enhanced CB2R levels and reduced p38 MAPK, but also promoted a significant reduction in both COX-2 and TGF-β levels, suggesting that OE might be more effective in mitigating inflammatory and fibrotic processes than HE. In LX-2 cells, HE treatment caused a notable decrease in both COX-2 and TGF-β levels, reflecting its efficacy in targeting fibrosis-associated inflammation. OE treatment, on the other hand, reduced Nuclear Factor-Kappa B p65 (NF-κB) expression, a critical transcription factor involved in inflammatory responses, though it did not significantly affect COX-2. LX-2 cells induced to fibrosis with TGF-β and treated with HE and OE showed a reduction in the expression levels of several fibrosis markers. In addition, HE and OE showed antioxidant effects by increasing protein levels of Cu, Zn superoxide dismutase (SOD1), Mn superoxide dismutase (SOD2) and catalase (CAT) and influencing the state of lipid peroxidation. Further research is needed to explore the effects of the treatments in activated hepatic stellate cells and in vivo liver disease models.
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Affiliation(s)
| | | | | | | | | | | | - Maria Notarnicola
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS “Saverio de Bellis”, 70013 Castellana Grotte, Italy; (I.S.); (E.A.C.); (M.C.); (V.D.N.); (G.P.); (M.C.)
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Mansour DF, Hashad IM, Rady M, Abd-El Razik AN, Saleh DO. Diosmin and Coenzyme q10: Synergistic histopathological and functional protection against doxorubicin-induced hepatorenal injury in rats. Toxicol Rep 2024; 13:101848. [PMID: 39703765 PMCID: PMC11655815 DOI: 10.1016/j.toxrep.2024.101848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/23/2024] [Accepted: 11/29/2024] [Indexed: 12/21/2024] Open
Abstract
Doxorubicin (DOX) is a cytotoxic anthracycline used to treat a variety of cancers. Cardiotoxicity, hepatotoxicity, and nephrotoxicity are adverse effects of DOX, that limit prognosis. The study aims to determine if diosmin (DIOS) and coenzyme Q10 (CoQ10) alone or in combination protect rats against DOX-induced liver and kidney damage. Adult male rats were assigned randomly in five groups. An intraperitoneal injection of DOX (2.5 mg/kg) was given to the DOX group every other day for three weeks, whereas a normal control group received the vehicle. Diosmin group received oral DIOS (100 mg/kg), Co-Q10 group received oral CoQ10 (10 mg/kg) and combination group received oral DIOS and CoQ10 daily for three weeks concomitantly with DOX. Sera and tissues were obtained 24 hours after last DOX injection. Serum aspartate transaminase (AST), alanine transaminase (ALT), creatinine, urea, total bilirubin and direct bilirubin were detected with hepatic and renal reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa-B (NF-κB). Histopathology and morphometry of liver and kidney were assessed. DOX exerted significant hepatorenal toxicity via elevation of liver and kidney functions, inducing oxidative stress by reducing GSH and elevating MDA, triggering renal and hepatic TNF-α and NF-kB. DIOS and CoQ10 modulated hepatic and renal functions, oxidative stress and inflammatory biomarkers. DIOS-CoQ10 combination treatment showed significant improvement in histopathology of liver and kidney along with morphometry compared to DOX group. In conclusion, combining DIOS and CoQ10 exhibited synergistic protective activity against DOX-induced hepatic and renal insult via their antioxidant and anti-inflammatory properties.
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Affiliation(s)
- Dina F. Mansour
- Pharmacology Department, Medical Research and Clinical Studies Institute - National Research Centre, Dokki, Giza 12622, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Galala University, Mount Ataka, Suez, Egypt
| | - Ingy M. Hashad
- Department of Biochemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Mona Rady
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, The German University in Cairo, Cairo, Egypt
- Faculty of Biotechnology, German International University, New Administrative Capital, Cairo, Egypt
| | - Amira N. Abd-El Razik
- Pathology Department, Medical Research and Clinical Studies Institute - National Research Centre, Dokki, Giza 12622, Egypt
| | - Dalia O. Saleh
- Pharmacology Department, Medical Research and Clinical Studies Institute - National Research Centre, Dokki, Giza 12622, Egypt
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Zhu J, Zhao H, Aierken A, Zhou T, Menggen M, Gao H, He R, Aimulajiang K, Wen H. Ghrelin is involved in regulating the progression of Echinococcus Granulosus-infected liver lesions through suppression of immunoinflammation and fibrosis. PLoS Negl Trop Dis 2024; 18:e0012587. [PMID: 39436864 PMCID: PMC11495594 DOI: 10.1371/journal.pntd.0012587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 09/30/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Cystic Echinococcosis (CE) is a zoonotic disease causing fibrosis and necrosis of diseased livers caused by infection with Echinococcus granulosus (E.g). There is evidence that E.g is susceptible to immune escape and tolerance when host expression of immunoinflammation and fibrosis is suppressed, accelerating the progression of CE. Ghrelin has the effect of suppressing immunoinflammation and fibrosis, and whether it is involved in regulating the progression of E.g-infected liver lesions is not clear. METHODS Serum and hepatic Ghrelin levels were observed in E.g-infected mice (4, 12 and 36 weeks) and compared with healthy control groups. Co-localization analysis is performed between protein expression of Ghrelin in and around the hepatic lesions of E.g-infected 12-week mice and protein expression of different hepatic histiocytes by mIHC. HepG2 cells and protoscoleces (PSCs) protein were co-cultured in vitro, as well as PSCs were alone in vitro, followed by exogenously administered of Ghrelin and its receptor blocker, [D-Lys3]-GHRP-6, to assess their regulatory effects on immunoinflammation, fibrosis and survival rate of PSCs. RESULTS Serum Ghrelin levels were increased in E.g-infected 4- and 12-week mice, and reduced in 36-week mice. E.g-infected mice consistently recruited Ghrelin in and around the hepatic lesions, which was extremely strongly co-localized with the protein expression of hepatic stellate cells (HSCs), T cells and the TGF-β1/Smad3 pathway. The secretion of Ghrelin was increased with increasing concentrations of PSCs protein in HepG2 cells culture medium. Moreover, Ghrelin could significantly inhibit the secretion of IL-2, INF-γ and TNF-α, as well as the expression of Myd88/NF-κB and TGF-β1/Smad3 pathway protein, and promoted the secretion of IL-4 and IL-10. Blocking Ghrelin receptor could significantly inhibit PSCs growth in in vitro experiment. CONCLUSION Ghrelin is highly expressed in the early stages of hepatic E.g infection and may be involved in regulating the progression of liver lesions by suppression immunoinflammation and fibrosis.
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Affiliation(s)
- Jiang Zhu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Hongqiong Zhao
- College of Veterinary Medicine, Xinjiang Agricultural University, Xinjiang, China
| | - Aili Aierken
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Tanfang Zhou
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Meng Menggen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Huijing Gao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Rongdong He
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Kalibixiati Aimulajiang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China
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Zhang WQ, Sun JX, Lan ST, Sun XM, Guo YJ, Wen BC, Chen J, Liu G. Regulation of Fuzheng Huayu capsule on inhibiting the fibrosis-associated hepatocellular carcinogenesis. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2024; 26:1219-1238. [PMID: 38780602 DOI: 10.1080/10286020.2024.2355132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 05/09/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024]
Abstract
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 tanshinone IIA, arachidonic acid, and quercetin, compounds of the FZHY capsule, inhibit HCC progression-related fibrosis by regulating the expression of PLAU and IGFBP3. 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 via regulating the expression of PLAU and IGFBP3.
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Affiliation(s)
- Wen-Qi Zhang
- Key Laboratory of Medical Cell Biology, Department of Achievement Transformation, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Jia-Xin Sun
- Key Laboratory of Medical Cell Biology, Department of Achievement Transformation, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Shu-Ting Lan
- Key Laboratory of Medical Cell Biology, Department of Achievement Transformation, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Xiao-Mei Sun
- Key Laboratory of Medical Cell Biology, Department of Achievement Transformation, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Yi-Jing Guo
- Key Laboratory of Medical Cell Biology, Department of Achievement Transformation, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Bi-Chao Wen
- Key Laboratory of Medical Cell Biology, Department of Achievement Transformation, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Jie Chen
- Key Laboratory of Medical Cell Biology, Department of Achievement Transformation, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
| | - Gang Liu
- Key Laboratory of Medical Cell Biology, Department of Achievement Transformation, Affiliated Hospital of Inner Mongolia Medical University, Hohhot 010050, China
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Zhang Y, Ren L, Tian Y, Guo X, Wei F, Zhang Y. Signaling pathways that activate hepatic stellate cells during liver fibrosis. Front Med (Lausanne) 2024; 11:1454980. [PMID: 39359922 PMCID: PMC11445071 DOI: 10.3389/fmed.2024.1454980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Liver fibrosis is a complex process driven by various factors and is a key feature of chronic liver diseases. Its essence is liver tissue remodeling caused by excessive accumulation of collagen and other extracellular matrix. Activation of hepatic stellate cells (HSCs), which are responsible for collagen production, plays a crucial role in promoting the progression of liver fibrosis. Abnormal expression of signaling pathways, such as the TGF-β/Smads pathway, contributes to HSCs activation. Recent studies have shed light on these pathways, providing valuable insights into the development of liver fibrosis. Here, we will review six signaling pathways such as TGF-β/Smads that have been studied more in recent years.
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Affiliation(s)
- Youtian Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Long Ren
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yinting Tian
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Xiaohu Guo
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Fengxian Wei
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Yawu Zhang
- The Second Hospital of Lanzhou University, Lanzhou, China
- The Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China
- The Laboratory of Hepatic-Biliary-Pancreatic, The Second Hospital of Lanzhou University, Lanzhou, China
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9
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Emad D, Bayoumi AMA, Gebril SM, Ali DME, Waz S. Modulation of keap-1/Nrf2/HO-1 and NF-ĸb/caspase-3 signaling pathways by dihydromyricetin ameliorates sodium valproate-induced liver injury. Arch Biochem Biophys 2024; 758:110084. [PMID: 38971420 DOI: 10.1016/j.abb.2024.110084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/30/2024] [Accepted: 07/03/2024] [Indexed: 07/08/2024]
Abstract
Nuclear factor erythroid factor 2 (Nrf2) is the key regulatory of the antioxidant response elements. Also, Nrf2 interacts with nuclear factor kappa B (NF-ĸB) to inhibit subsequent inflammatory cascade. Activation of Nrf2 signaling ameliorates drug-induced liver injury. Sodium valproate (SVP) is an anti-epilepsy drug with a hepatotoxic adverse effect that restricts its clinical use. In this study, coadministration of Dihydromyricetin (DHM), a natural flavonoid, with SVP to rats upregulated gene expression of Nrf2 and its downstream gene, heme oxygenase 1 (HO-1), while suppressed the Nrf2 repressor, Keap-1. Additionally, DHM led to downregulation of proinflammatory factors in liver tissues, including NF-ĸB, interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α). This was accompanied by a decrease in the proapoptotic protein (cleaved caspase-3) expression level. Furthermore, biochemical and histopathological studies showed that DHM treatment improved liver function and lipid profile while decreased inflammatory cell infiltration, congestion, and hepatocellular damage. According to our knowledge, prior research has not examined the protective effect of DHM on the liver injury induced by SVP. Consequently, this study provides DHM as a promising herbal medication that, when used with SVP, can prevent its induced hepatotoxicity owing to its potential anti-oxidative, anti-inflammatory, and anti-apoptotic properties.
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Affiliation(s)
- Doaa Emad
- Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag, Egypt.
| | - Asmaa M A Bayoumi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, 61511, Egypt.
| | - Sahar M Gebril
- Department of Histology and Cell biology, Faculty of Medicine, Sohag University, Sohag, Egypt.
| | | | - Shaimaa Waz
- Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, 61511, Egypt.
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10
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Vadizadeh A, Salehcheh M, Kalantar H, Khorsandi L, Rashno M, Mahdavinia M. Cannabidiol attenuates arsenic-induced nephrotoxicity via the NOX4 and NF-κB pathways in mice. Res Pharm Sci 2024; 19:447-458. [PMID: 39399730 PMCID: PMC11468165 DOI: 10.4103/rps.rps_51_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 07/16/2024] [Accepted: 08/12/2024] [Indexed: 10/15/2024] Open
Abstract
Background and purpose Cannabidiol (CBD) is a phenolic terpene compound with anticancer, antioxidant, anti-inflammatory, antibacterial, neuroprotective, and anticonvulsant properties. Since the effects of CBD on sodium arsenite (As)-induced nephrotoxicity have not been fully determined, this study investigated the effect of CBD on As-induced nephrotoxicity by evaluating the NOX4 and NF-kB pathways in mice. Experimental approach 48 male mice were divided into six groups (8 each) including group 1, receiving saline for 14 days; group 2, receiving CBD (10 mg/kg, intraperitoneally) from the 7th to the 14th day; group 3, receiving As (10 mg/kg) for 14 days by gavage; and treatment groups 4-6, receiving CBD (2.5, 5, and 10 mg/kg, i.p.) 1.5 h before As (10 mg/kg by gavage, for 14 days) from the 7th to the 14th day. Mice were anesthetized after overnight fasting on day 15, and the blood sample was collected from their hearts. The level of antioxidants and pro-inflammatory factors, the expression of ROS and TNF-α, NF-kB, NOX4, iNOS, cleaved PARP, and caspase-3 proteins were measured and histological studies were performed. Findings/Results Exposure to As significantly increased kidney markers, oxidative stress, apoptosis, and inflammation in mice kidney tissue, and pretreatment with CBD reversed these changes. In addition, CBD significantly decreased the expression of NF-kB and NOX4, and the levels of pro-inflammatory factors and the expression of cleaved PARP and increased the level of antioxidants. Conclusion and implications CBD ameliorated As-induced nephrotoxicity related to inhibiting oxidative stress, inflammation, and apoptosis, potentially through the NF-kB/Nox4 pathway.
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Affiliation(s)
- Ali Vadizadeh
- Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Student Research Committee, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
| | - Maryam Salehcheh
- Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hadi Kalantar
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Layasadat Khorsandi
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Rashno
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Masoud Mahdavinia
- Department of Toxicology, Faculty of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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11
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Gao S, An Z, Zhang Q, Sun Q, Huang Q, Shi L, Liu W, Gou X, Li Y, Xin X, Feng Q. Danggui-Shaoyao-San protects against non-alcoholic steatohepatitis via modulation of hepatic APP protein, Lysosomal CTSB release, and NF-κB activation. Heliyon 2024; 10:e34213. [PMID: 39114010 PMCID: PMC11305236 DOI: 10.1016/j.heliyon.2024.e34213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 07/02/2024] [Accepted: 07/05/2024] [Indexed: 08/10/2024] Open
Abstract
Background Non-alcoholic steatohepatitis (NASH), an escalating global health concern, is a primary factor behind cirrhosis, liver transplantation, and hepatocellular carcinoma. Effective treatments remain elusive. Danggui-Shaoyao-San (DGSY), a classic famous prescription employed in treating NASH, could hold promise, although its molecular underpinnings are still under investigation. This study undertakes an exploration of the impacts of DGSY on NASH and seeks to illuminate the mechanisms at play. Methods UHPLC-Q-Orbitrap HRMS was employed to identify compounds within DGSY. Mice underwent a 25-week regimen of HFHC diet and high-sugar water, with 4 weeks of DGSY treatment for efficacy and pathogenic mechanism exploration in vivo. L02 cells were cultured with 0.2 mM FFA for 24 h, exposed to DGSY at 1 mg/ml and 2 mg/ml for efficacy and pathogenic mechanism exploration in vitro. Using online databases, we sought potential targets for NASH treatment, and through PPI networks, identified key targets. Expression levels of genes and proteins were examined by western blotting, RT-PCR, and immunofluorescence staining. Results Thirty-four compounds were identified within DGSY. DGSY brought about marked reductions in biochemical indicators and yielded significant improvements in NASH mice histological features. Additionally, it mitigated hepatic steatosis and inflammation both in vivo and in vitro. The top 10 targets from two network pharmacology analyses, one focusing on structural prediction and the other on literature mining, identified APOE and APP as potential therapeutic targets for DGSY in NASH treatment. PCR validation confirmed that DGSY reduced APP expression after treatment, and further investigation revealed that DGSY significantly suppressed hepatic APP and Aβ expression, indicating its effectiveness in treating NASH. Furthermore, it inhibited Aβ-induced Cathepsin B lysosomal release, reducing hepatic inflammation. Conclusion Danggui-Shaoyao-San has anti-steatohepatitis effects in ameliorating hepatic APP protein expression, reducing hepatic lysosomal CTSB release, and suppressing hepatic NF-κB activation. The study provided a more theoretical basis for the future clinical application of DGSY.
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Affiliation(s)
- Siting Gao
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ziming An
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qian Zhang
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qinmei Sun
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qian Huang
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lei Shi
- Department of Clinical Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, China
| | - Xiaojun Gou
- Central Laboratory, Baoshan District Hospital of Integrated Traditional Chinese and Western Medicine of Shanghai, Shanghai, China
| | - Yajuan Li
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xin Xin
- Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, China
| | - Qin Feng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Shanghai University of Traditional Chinese Medicine, Ministry of Education, Shanghai, China
- Central Laboratory, ShuGuang Hospital Affiliated to Shanghai University of Chinese Traditional Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
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12
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Chandra Shill M, El-Nashar HAS, Prova Mollick P, Nath Acharyya R, Afrin S, Hossain H, Halder S, Torequl Islam M, Bhuia MS, Reza HM, El-Shazly M, Mubarak MS. Longevity Spinach (Gynura procumbens) Ameliorated Oxidative Stress and Inflammatory Mediators in Cisplatin-Induced Organ Dysfunction in Rats: Comprehensive in vivo and in silico Studies. Chem Biodivers 2024; 21:e202301719. [PMID: 38361048 DOI: 10.1002/cbdv.202301719] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 02/01/2024] [Accepted: 02/15/2024] [Indexed: 02/17/2024]
Abstract
This study focused to assess the efficacy of Gynura procumbens (GP) leaf extract against cisplatin (CP)-induced hepatorenal complications in Wister albino rats. Additionally, it aims to detect polyphenolic compounds using high-performance liquid chromatography with diode-array detection (HPLC-DAD). The rats were treated intraperitoneally with CP (7.5 mg/kg) to mediate hepatorenal damage. They were then treated with GP extract (75 and 150 mg/kg, P.O.) for 7 consecutive days. Although GP extract significantly ameliorated CP-mediated hepatorenal biomarkers like alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen (BUN) levels in a dose-dependent manner, GP extract at 150 mg/kg dose normalized hepatorenal biomarkers ALP (45.11 U/L), ALT (34 U/L), AST (29 U/L), creatinine (10.3 mg/dl) and BUN (11.19 mg/dl) while comparing to control and disease group. Similarly, though it significantly reduced CP-induced oxidative stress inducers, including nitric oxide (NO) and advanced oxidative protein products (AOPP), higher dose (150 mg/kg) exhibited better activity in reducing NO (281.54 mmol/gm tissue in liver and 52.73 mmol/gm tissue in the kidney) and AOPP (770.95 mmol/mg protein in liver and 651.90 mmol/mg protein in the kidney). Besides, it showed better enhancement in the antioxidant enzymes superoxide dismutase, and glutathione levels at a higher dose (150 mg/kg). Histopathological studies showed that CP caused collagen accumulation in the liver and kidney tissues. GP extract drained the collagen mass and acted against hepatorenal damage. Ellagic acid, gallic acid, quercetin hydrate, kaempferol, and rutin hydrate were revealed in GP extract. In-silico modelling showed good docking scores of the polyphenolic compounds with molecular targets including CYP4502E1, NF-κB, caspase-3, and TNF-α. GP could be an effective therapeutic option for management of anticancer drugs' complications like CP-induced organ damage, although clinical studies are required to establish herbal formulation.
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Affiliation(s)
- Manik Chandra Shill
- Department of Pharmaceutical Sciences, North South University, Dhaka, 1229, Bangladesh
| | - Heba A S El-Nashar
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt
| | | | | | - Silvia Afrin
- Department of Pharmaceutical Sciences, North South University, Dhaka, 1229, Bangladesh
| | - Hemayet Hossain
- Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka, 1205, Bangladesh
| | - Shimul Halder
- Department of Pharmaceutical Technology, Dhaka University, Dhaka, 1000, Bangladesh
| | - Muhammad Torequl Islam
- Pharmacy Discipline, Khulna University, Khulna, 9208, Bangladesh
- Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- Bioluster Research Center, Gopalganj, 8100, Dhaka, Bangladesh
| | - Md Shimul Bhuia
- Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, Bangladesh
- Bioluster Research Center, Gopalganj, 8100, Dhaka, Bangladesh
| | - Hasan Mahmud Reza
- Department of Pharmaceutical Sciences, North South University, Dhaka, 1229, Bangladesh
| | - Mohamed El-Shazly
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt
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13
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Yang B, Lin Y, Huang Y, Shen YQ, Chen Q. Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases. Redox Biol 2024; 70:103032. [PMID: 38232457 PMCID: PMC10827563 DOI: 10.1016/j.redox.2024.103032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/03/2023] [Accepted: 01/04/2024] [Indexed: 01/19/2024] Open
Abstract
Thioredoxin (Trx) is a compact redox-regulatory protein that modulates cellular redox state by reducing oxidized proteins. Trx exhibits dual functionality as an antioxidant and a cofactor for diverse enzymes and transcription factors, thereby exerting influence over their activity and function. Trx has emerged as a pivotal biomarker for various diseases, particularly those associated with oxidative stress, inflammation, and aging. Recent clinical investigations have underscored the significance of Trx in disease diagnosis, treatment, and mechanistic elucidation. Despite its paramount importance, the intricate interplay between Trx and cellular senescence-a condition characterized by irreversible growth arrest induced by multiple aging stimuli-remains inadequately understood. In this review, our objective is to present a comprehensive and up-to-date overview of the structure and function of Trx, its involvement in redox signaling pathways and cellular senescence, its association with aging and age-related diseases, as well as its potential as a therapeutic target. Our review aims to elucidate the novel and extensive role of Trx in senescence while highlighting its implications for aging and age-related diseases.
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Affiliation(s)
- Bowen Yang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Yumeng Lin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Yibo Huang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Ying-Qiang Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China
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14
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Ragab SMM, Almohaimeed HM, Alghriany AAI, Khalil NSA, Abd-Allah EA. Protective effect of Moringa oleifera leaf ethanolic extract against uranyl acetate-induced testicular dysfunction in rats. Sci Rep 2024; 14:932. [PMID: 38195615 PMCID: PMC10776666 DOI: 10.1038/s41598-023-50854-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 12/27/2023] [Indexed: 01/11/2024] Open
Abstract
Uranyl acetate (UA) is used in civilian and military applications, predisposing it to wide dispersion in ecosystems. Using high-performance liquid chromatography, gas chromatography-mass spectrometry, and 2,2-Diphenyl-1-picrylhydrazyl scavenging radical analysis, we confirmed that Moringa oleifera leaf ethanolic extract (MLEE) is rich in biologically active phytochemicals. Thus, this study aims to investigate the possible defensive effect of MLEE against UA-induced testicular dysfunction. To achieve this, rats were divided randomly and evenly into three groups for 14 days. The control group received no treatment, while the UA group received a single intraperitoneal injection of UA at a dose of 5 mg/kg BW dissolved in saline on the 12th day of the experiment, followed by no treatment the following day. The MLEE + UA group received daily oral administration of MLEE (300 mg/kg BW) dissolved in distilled water before exposure to UA intoxication. The disruption observed in the pituitary-gonadal axis of UA-intoxicated rats was characterized by a significant decrease in luteinizing hormone, follicle-stimulating hormone, testosterone, and estradiol 17beta levels. Additionally, there was a notable increase in malondialdehyde and a decrease in catalase, superoxide dismutase, reduced glutathione, and nitric oxide, accompanied by an up-regulation in the immuno-expression of nuclear factor-kappa B, indicating a disturbance in the redox balance. The TUNEL assay confirmed a substantial rise in apoptotic cell numbers in the UA group. Testicular histopathological changes, excessive collagen deposition, and reduced glycogen content were evident following UA exposure. However, supplementation with MLEE effectively countered these mentioned abnormalities. MLEE is proposed to combat the toxicological molecular targets in the UA-affected testis by restoring the balance between oxidants and antioxidants while obstructing the apoptotic cascade. MLEE contains an abundance of redox-stabilizing and cytoprotective phytochemicals that have the potential to counteract the mechanistic pathways associated with UA exposure. These findings encourage further research into other plausible protective aspects of Moringa oleifera against the UA challenge.
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Affiliation(s)
- Sohair M M Ragab
- Laboratory of Physiology, Department of Zoology and Entomology, Faculty of Sciences, Assiut University, Assiut, Egypt
| | - Hailah M Almohaimeed
- Department of Basic Science, College of Medicine, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671, Saudi Arabia
| | | | - Nasser S Abou Khalil
- Department of Basic Medical Sciences, Faculty of Physical Therapy, Merit University, Sohag, Egypt.
- Department of Medical Physiology, Faculty of Medicine, Assiut University, Assiut, 71526, Egypt.
| | - Elham A Abd-Allah
- Department of Zoology, Faculty of Science, New Valley University, El-Kharga, Egypt
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15
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Zhu J, Zhou T, Menggen M, Aimulajiang K, Wen H. Ghrelin regulating liver activity and its potential effects on liver fibrosis and Echinococcosis. Front Cell Infect Microbiol 2024; 13:1324134. [PMID: 38259969 PMCID: PMC10800934 DOI: 10.3389/fcimb.2023.1324134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/15/2023] [Indexed: 01/24/2024] Open
Abstract
Ghrelin widely exists in the central nervous system and peripheral organs, and has biological activities such as maintaining energy homeostasis, regulating lipid metabolism, cell proliferation, immune response, gastrointestinal physiological activities, cognition, memory, circadian rhythm and reward effects. In many benign liver diseases, it may play a hepatoprotective role against steatosis, chronic inflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress and apoptosis, and improve liver cell autophagy and immune response to improve disease progression. However, the role of Ghrelin in liver Echinococcosis is currently unclear. This review systematically summarizes the molecular mechanisms by which Ghrelin regulates liver growth metabolism, immune-inflammation, fibrogenesis, proliferation and apoptosis, as well as its protective effects in liver fibrosis diseases, and further proposes the role of Ghrelin in liver Echinococcosis infection. During the infectious process, it may promote the parasitism and survival of parasites on the host by improving the immune-inflammatory microenvironment and fibrosis state, thereby accelerating disease progression. However, there is currently a lack of targeted in vitro and in vivo experimental evidence for this viewpoint.
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Affiliation(s)
- Jiang Zhu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Tanfang Zhou
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Meng Menggen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Kalibixiati Aimulajiang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
- Department of Hepatobiliary and Hydatid Disease, Digestive and Vascular Surgery Center Therapy Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
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16
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Islam MM, Islam MM, Rahman MA, Ripon MAR, Hossain MS. Gut microbiota in obesity and related complications: Unveiling the complex interplay. Life Sci 2023; 334:122211. [PMID: 38084672 DOI: 10.1016/j.lfs.2023.122211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/24/2023] [Accepted: 10/24/2023] [Indexed: 12/18/2023]
Abstract
In recent years, the obesity epidemic has escalated into a serious public health catastrophe that is only getting worse. However, research into the pathophysiological pathways behind the obesity development and the illnesses that it is associated with is ongoing. In the last decades, it is now clear that the gut microbiota plays a significant role in the genesis and progression of obesity and obesity-related illnesses, particularly changes in its metabolites and composition as obesity progresses. Here, we provide a summary of the processes by which variations in gut metabolite levels and the composition of gut microbiota affect obesity and associated disorders. The bacteria residing in the gut release several chemicals that influence the appetite control, metabolism, and other systems. Since it can either encourage or restrict the deposition of fat in several different ways, the gut microbiota's role in obesity is debatable. Additionally, we go over potential therapeutic approaches that could be utilized to alter gut microbiota composition and focus on the important metabolic pathways associated with obesity and metabolic disorders linked to obesity.
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Affiliation(s)
- Md Monirul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Md Mahmodul Islam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Md Abdur Rahman
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Md Abdur Rahman Ripon
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh
| | - Mohammad Salim Hossain
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali 3814, Bangladesh.
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Zwierz M, Chabowski A, Sztolsztener K. α-Lipoic acid - a promising agent for attenuating inflammation and preventing steatohepatitis in rats fed a high-fat diet. Arch Biochem Biophys 2023; 750:109811. [PMID: 37926405 DOI: 10.1016/j.abb.2023.109811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/23/2023] [Accepted: 11/02/2023] [Indexed: 11/07/2023]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder affecting a significant part of the global population. This study aimed to investigate the potential therapeutic effects of α-lipoic acid (α-LA) on the inflammatory response during simple steatosis development and progression into steatohepatitis. The study used the MASLD model in male Wistar rats that were fed a standard diet or a high-fat diet (HFD) for 8 weeks. Throughout the entire experiment, half of the animals received α-LA supplementation. The hepatic activity of pro-inflammatory n-6 and anti-inflammatory n-3 polyunsaturated fatty acid (PUFA) pathways and the concentration of arachidonic acid (AA) in selected lipid fractions were determined by the gas-liquid chromatography (GLC). The hepatic expression of proteins from inflammatory pathway was measured by the Western blot technique. The level of eicosanoids, cytokines and chemokines was assessed by the ELISA or multiplex assay kits. The results showed that α-LA supplementation attenuated the activity of n-6 PUFA pathway in FFA and DAG and increased the activity of n-3 PUFA pathway in PL, TAG and DAG. In addition, the administration of α-LA decreased the concentration of AA in DAG and FFA, indicating its potential protective effect on the deterioration of simple hepatic steatosis. The supplementation of α-LA also increased the expression of COX-1 and COX-2 with the lack of significant changes in prostaglandins profile. We observed an increase in the expression of 12/15-LOX, which was reflected in an increase in lipoxin A4 (LXA4) level. A decrease in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines was also noticed in the liver of rats treated with HFD and α-LA. Our observations confirm that α-LA treatment has potential protective effects on inflammation development in the MASLD model. We believe that α-LA has a preventive impact when it comes to the progression of simple steatosis lesions to steatohepatitis.
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Affiliation(s)
- Mateusz Zwierz
- Department of Physiology, Medical University of Bialystok, Mickiewicz Str. 2C, 15-222, Bialystok, Poland.
| | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Mickiewicz Str. 2C, 15-222, Bialystok, Poland.
| | - Klaudia Sztolsztener
- Department of Physiology, Medical University of Bialystok, Mickiewicz Str. 2C, 15-222, Bialystok, Poland.
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18
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Aghaei F, Wong A, Zargani M, Sarshin A, Feizolahi F, Derakhshan Z, Hashemi M, Arabzadeh E. Effects of swimming exercise combined with silymarin and vitamin C supplementation on hepatic inflammation, oxidative stress, and histopathology in elderly rats with high-fat diet-induced liver damage. Nutrition 2023; 115:112167. [PMID: 37611505 DOI: 10.1016/j.nut.2023.112167] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 06/23/2023] [Accepted: 07/17/2023] [Indexed: 08/25/2023]
Abstract
OBJECTIVES The aim of this study was to demonstrate that swimming exercise combined with silymarin and vitamin C supplementation improves hepatic inflammation, oxidative stress, and liver histopathology in elderly rats with high-fat diet-induced liver damage. METHODS Forty elderly male Wistar rats were randomly assigned to five groups (n = 8 in each): a normal diet (control), a high-fat diet (HFD), HFD + silymarin and vitamin C supplementation (HFD+Sup), HFD + swimming exercise (HFD+Exe), and HFD+Sup+Exe group (HFD+Sup+Exe). The non-alcoholic fatty liver model was induced for 6 wk in the HFD groups. After 6 wk of consuming an HFD, a daily supplemental gavage was administered to rats as an intervention along with HFD in the supplement groups for 8 wk. Moreover, rats in the exercise groups were subjected to swimming exercise training 5 d/wk for the same period. RESULTS The combination of swimming training and supplementation caused significant decreases in liver inflammatory biomarkers tumor necrosis factor-α and interleukin-1β while increasing total antioxidant capacity and peroxisome proliferator-activated receptor α (P < 0.05). CONCLUSION In elderly rats with liver injury caused by an HFD, the combination of exercise and silymarin with vitamin C supplementation effectively reduced oxidative stress, liver inflammation, fat accumulation, and regulated liver enzymes.
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Affiliation(s)
- Fariba Aghaei
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Alexei Wong
- Department of Health and Human Performance, Marymount University, Arlington, Virginia, USA
| | - Mehdi Zargani
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Amir Sarshin
- Clinical Care and Health Promotion Research Center, Karaj branch, Islamic Azad University, Karaj, Iran
| | - Foad Feizolahi
- Clinical Care and Health Promotion Research Center, Karaj branch, Islamic Azad University, Karaj, Iran
| | - Zhila Derakhshan
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Mohammadreza Hashemi
- Department of Exercise Physiology, Karaj Branch, Islamic Azad University, Karaj, Iran
| | - Ehsan Arabzadeh
- Exercise Physiology Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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Chang Y, Guo T, Zhu B, Liu Y. A novel nomogram for predicting microvascular invasion in hepatocellular carcinoma. Ann Hepatol 2023; 28:101136. [PMID: 37479060 DOI: 10.1016/j.aohep.2023.101136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 06/07/2023] [Accepted: 07/05/2023] [Indexed: 07/23/2023]
Abstract
INTRODUCTION AND OBJECTIVES In hepatocellular carcinoma (HCC), the prognosis of patients with microvascular invasion (MVI) is poor. Therefore, in this study, we established and evaluated the performance of a novel nomogram to predict MVI in patients with HCC. MATERIALS AND METHODS We retrospectively obtained clinical data of 497 patients with HCC who underwent hepatectomy at Liaoning Cancer Hospital from November 1, 2018, to November 4, 2021. The patients (n = 497) were randomized in a 7:3 ratio into the training cohort (TC, n = 349) and the validation cohort (VC, n = 148). We performed Least Absolute Shrinkage and Selection Operator (LASSO) and univariate as well as multivariate logistic regression analyses (ULRA, MRLA) on patients in the TC to identify factors independently predicting MVI. RESULTS Preoperative FIB-4, AFU, AFP levels, liver cirrhosis, and non-smooth tumor margin were independent risk factors for preoperative MVI prediction. The C-index of the TC, VC, and the entire cohort was 0.846, 0.786, and 0.829, respectively. The calibration curves demonstrated the outstanding agreement between predicted MVI incidences by our model and the actual MVI risk. Decision curve analysis (DCA) confirmed the significance of our predictive model in clinical settings. The Kaplan-Meier (KM) survival curve showed that the recurrence-free survival (RFS) and overall survival (OS) of patients in the high-MVI risk group were poor compared to those in the low-MVI risk group. CONCLUSIONS We constructed and evaluated the performance of the novel nomogram for predicting MVI risk. Our predictive model could adequately predict MVI risk and aid clinicians in selecting appropriate therapeutic strategies for patients.
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Affiliation(s)
- Yuan Chang
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, PR China
| | - Tianyu Guo
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, PR China
| | - Bo Zhu
- Department of Cancer Prevention and Treatment, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No. 44 Xiaoheyan Road, Dadong District, Shenyang 110042, PR China
| | - Yefu Liu
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, No.44 Xiaoheyan Road, Dadong District, Shenyang 110042, PR China.
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20
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Jin J, Kouznetsova VL, Kesari S, Tsigelny IF. Synergism in actions of HBV with aflatoxin in cancer development. Toxicology 2023; 499:153652. [PMID: 37858775 DOI: 10.1016/j.tox.2023.153652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/30/2023] [Accepted: 10/16/2023] [Indexed: 10/21/2023]
Abstract
Aflatoxin B1 (AFB1) is a fungal metabolite found in animal feeds and human foods. It is one of the most toxic and carcinogenic of aflatoxins and is classified as a Group 1 carcinogen. Dietary exposure to AFB1 and infection with chronic Hepatitis B Virus (HBV) make up two of the major risk factors for hepatocellular carcinoma (HCC). These two major risk factors raise the probability of synergism between the two agents. This review proposes some collaborative molecular mechanisms underlying the interaction between AFB1 and HBV in accelerating or magnifying the effects of HCC. The HBx viral protein is one of the main viral proteins of HBV and has many carcinogenic qualities that are involved with HCC. AFB1, when metabolized by CYP450, becomes AFB1-exo-8,9-epoxide (AFBO), an extremely toxic compound that can form adducts in DNA sequences and induce mutations. With possible synergisms that exist between HBV and AFB1 in mind, it is best to treat both agents simultaneously to reduce the risk by HCC.
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Affiliation(s)
- Joshua Jin
- IUL Scientific Program, San Diego, CA, USA
| | - Valentina L Kouznetsova
- San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA, USA; BiAna, La Jolla, CA, USA; Curescience Institute, San Diego, CA, USA
| | | | - Igor F Tsigelny
- San Diego Supercomputer Center, University of California at San Diego, La Jolla, CA, USA; BiAna, La Jolla, CA, USA; Curescience Institute, San Diego, CA, USA; Department of Neurosciences, University of California at San Diego, La Jolla, CA, USA.
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21
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Tammam MA, Pereira F, Aly O, Sebak M, Diab YM, Mahdy A, El-Demerdash A. Investigating the hepatoprotective potentiality of marine-derived steroids as promising inhibitors of liver fibrosis. RSC Adv 2023; 13:27477-27490. [PMID: 37711373 PMCID: PMC10498675 DOI: 10.1039/d3ra04843h] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 08/27/2023] [Indexed: 09/16/2023] Open
Abstract
It has been reported that organic extracts derived from soft corals belonging to the genus Sarcophyton have exhibited a wide range of therapeutic characteristics. Based on biochemical and histological techniques, we aimed to assess the hepatoprotective role of the organic extract and its principal steroidal contents derived from the Red Sea soft coral Sarcophyton glaucum on acetaminophen-induced liver fibrosis in rats. Serum liver function parameters (ALT, AST, ALP and total bilirubin) were quantified using a spectrophotometer, and both alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) levels were determined by using enzyme-linked immunosorbent assay (ELISA) kits while transformed growth factor beta (TGF-β) and tumor necrosis factor α (TNF-α) in liver tissue homogenate were determined using ELISA, and TGF-β and TNF-α gene expression in liver tissue was determined using real-time PCR following extraction and purification. Histopathological alterations in hepatic tissue were also examined under a microscope. In order to prioritize the isolation and characterization of the most promising marine steroids from the organic extract of the Red Sea soft coral Sarcophyton glaucum as hepatoprotective agents, a computational approach was employed. This approach involved molecular docking (MDock) and analysis of the structure-activity relationship (SAR) against glutathione-S-transferase (GST) and Cu-Zn human superoxide dismutase (Cu-ZnSOD) enzymes. Although the major role in the detoxification of foreign chemicals and toxic metabolites of GST and SOD enzymes is known, there is a lack of knowledge about the mode of action of the hepatoprotective process and those of the targets involved. The present study investigated the multiple interactions of a series of marine steroids with the GST and SOD enzymes, in order to reveal insights into the process of hepatoprotection.
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Affiliation(s)
- Mohamed A Tammam
- Department of Biochemistry, Faculty of Agriculture, Fayoum University Fayoum 63514 Egypt
| | - Florbela Pereira
- LAQV REQUIMTE, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa 2829516 Caparica Portugal
| | - Omnia Aly
- Department of Medical Biochemistry, National Research Centre Cairo 12622 Egypt
| | - Mohamed Sebak
- Microbiology and Immunology Department, Faculty of Pharmacy, Beni-Suef University Egypt
| | - Yasser M Diab
- Department of Biochemistry, Faculty of Agriculture, Fayoum University Fayoum 63514 Egypt
| | - Aldoushy Mahdy
- Department of Zoology, Faculty of Science, Al-Azhar University (Assiut Branch) Assiut 71524 Egypt
| | - Amr El-Demerdash
- Division of Organic Chemistry, Department of Chemistry, Faculty of Sciences, Mansoura University Mansoura 35516 Egypt
- Department of Biochemistry and Metabolism, the John Innes Centre Norwich Research Park Norwich NR4 7UH UK
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22
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Fan Z, Sun X, Chen X, Liu H, Miao X, Guo Y, Xu Y, Li J, Zou X, Li Z. C-C motif chemokine CCL11 is a novel regulator and a potential therapeutic target in non-alcoholic fatty liver disease. JHEP Rep 2023; 5:100805. [PMID: 37555008 PMCID: PMC10404559 DOI: 10.1016/j.jhepr.2023.100805] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is characterised by accelerated lipid deposition, aberrant inflammation, and excessive extracellular matrix production in the liver. Short of effective intervention, NAFLD can progress to cirrhosis and hepatocellular carcinoma. In the present study we investigated the involvement of the C-C motif ligand 11 (CCL11) in NAFLD pathogenesis. METHODS NAFLD was induced by feeding mice with a high-fat high-carbohydrate diet. CCL11 targeting was achieved by genetic deletion or pharmaceutical inhibition. The transcriptome was analysed using RNA-seq. RESULTS We report that CCL11 expression was activated at the transcription level by free fatty acids (palmitate) in hepatocytes. CCL11 knockdown attenuated whereas CCL11 treatment directly promoted production of pro-inflammatory/pro-lipogenic mediators in hepatocytes. Compared with wild-type littermates, CCL11 knockout mice displayed an ameliorated phenotype of NAFLD when fed a high-fat high-carbohydrate diet as evidenced by decelerated body weight gain, improved insulin sensitivity, dampened lipid accumulation, reduced immune cell infiltration, and weakened liver fibrosis. RNA-seq revealed that interferon regulatory factor 1 as a mediator of CCL11 induced changes in hepatocytes. Importantly, CCL11 neutralisation or antagonism mitigated NAFLD pathogenesis in mice. Finally, a positive correlation between CCL11 expression and NAFLD parameters was identified in human patients. CONCLUSIONS Our data suggest that CCL11 is a novel regulator of NAFLD and can be effectively targeted for NAFLD intervention. IMPACT AND IMPLICATIONS Non-alcoholic fatty liver disease (NAFLD) precedes cirrhosis and hepatocellular carcinoma. In this paper we describe the regulatory role of CCL11, a C-C motif ligand chemokine, in NAFLD pathogenesis. Our data provide novel insights and translational potential for NAFLD intervention.
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Affiliation(s)
- Zhiwen Fan
- Department of Pathology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| | - Xinyue Sun
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Xuelian Chen
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Huimin Liu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
| | - Xiulian Miao
- College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Yan Guo
- College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Yong Xu
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
- College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical School, Nanjing, China
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
| | - Xiaoping Zou
- Department of Gastroenterology, Taikang Xianlin Drum Tower Hospital Affiliated with Nanjing University Medical School, Nanjing, China
- Department of Gastroenterology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, China
| | - Zilong Li
- State Key Laboratory of Natural Medicines, Department of Pharmacology, China Pharmaceutical University, Nanjing, China
- College of Life Sciences and Institute of Biomedical Research, Liaocheng University, Liaocheng, China
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23
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Papadakos SP, Arvanitakis K, Stergiou IE, Lekakis V, Davakis S, Christodoulou MI, Germanidis G, Theocharis S. The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks? Cancers (Basel) 2023; 15:2795. [PMID: 37345131 PMCID: PMC10216531 DOI: 10.3390/cancers15102795] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 06/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Ioanna E. Stergiou
- Pathophysiology Department, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Vasileios Lekakis
- Department of Gastroenterology, Laiko General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Spyridon Davakis
- First Department of Surgery, Laiko General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Maria-Ioanna Christodoulou
- Tumor Immunology and Biomarkers Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus;
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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24
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Jiang G, Wang B, Wang Y, Kong H, Wang Y, Gao P, Guo M, Li W, Zhang J, Wang Z, Niu J. Structural characteristics of a novel Bletilla striata polysaccharide and its activities for the alleviation of liver fibrosis. Carbohydr Polym 2023; 313:120781. [PMID: 37182941 DOI: 10.1016/j.carbpol.2023.120781] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 02/26/2023] [Accepted: 02/28/2023] [Indexed: 03/19/2023]
Abstract
Liver fibrosis has proven to be the main predisposing factor for liver cirrhosis and liver cancer; however, an effective treatment remains elusive. Polysaccharides, with low toxicity and a wide range of bioactivities, are strong potential candidates for anti-hepatic fibrosis applications. For this study, a new low molecular weight neutral polysaccharide (B. striata glucomannan (BSP)) was extracted and purified from Bletilla striata. The structure of BSP was characterized and its activities for alleviating liver fibrosis in vivo were further evaluated. The results revealed that the structural unit of BSP was likely →4)-β-D-Glcp-(1 → 4)-β-D-Manp-(1 → 4)-β-D-2ace-Manp-(1 → 4)-β-D-Manp-(1 → 4)-β-D-Glcp-(1 → 4)-β-D-Manp-(1 → 4)-β-D-Manp-(1 → 4)-β-D-3ace-Manp-(1→, with a molecular weight of only 58.5 kDa. Additionally, BSP was observed to attenuate the passive impacts of liver fibrosis in a manner closely related to TLR2/TLR4-MyD88-NF-κB signaling pathway conduction. In summary, the results of this study provide theoretical foundations for the potential applications of BSP as an anti-liver fibrosis platform.
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25
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A novel mechanistic approach for the anti-fibrotic potential of rupatadine in rat liver via amendment of PAF/NF-ĸB p65/TGF-β1 and hedgehog/HIF-1α/VEGF trajectories. Inflammopharmacology 2023; 31:845-858. [PMID: 36811777 PMCID: PMC10140091 DOI: 10.1007/s10787-023-01147-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 01/25/2023] [Indexed: 02/24/2023]
Abstract
Hepatic fibrosis is one of the major worldwide health concerns which requires tremendous research due to the limited outcomes of the current therapies. The present study was designed to assess, for the first time, the potential therapeutic effect of rupatadine (RUP) in diethylnitrosamine (DEN)-induced liver fibrosis and to explore its possible mechanistic actions. For the induction of hepatic fibrosis, rats were treated with DEN (100 mg/kg, i.p.) once weekly for 6 consecutive weeks, and on the 6th week, RUP (4 mg/kg/day, p.o.) was administered for 4 weeks. Treatment with RUP ameliorated changes in body weights, liver indices, liver function enzymes, and histopathological alterations induced by DEN. Besides, RUP amended oxidative stress, which led to the inhibition of PAF/NF-κB p65-induced inflammation, and, subsequently, prevention of TGF-β1 elevation and HSCs activation as indicated by reduced α-SMA expression and collagen deposition. Moreover, RUP exerted significant anti-fibrotic and anti-angiogenic effects by suppressing Hh and HIF-1α/VEGF signaling pathways. Our results highlight, for the first time, a promising anti-fibrotic potential of RUP in rat liver. The molecular mechanisms underlying this effect involve the attenuation of PAF/NF-κB p65/TGF-β1 and Hh pathways and, subsequently, the pathological angiogenesis (HIF-1α/VEGF).
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26
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Wei YY, Wang HR, Fan YM, Gu JH, Zhang XY, Gong XH, Hao ZH. Acute liver injury induced by carbon tetrachloride reversal by Gandankang aqueous extracts through nuclear factor erythroid 2-related factor 2 signaling pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 251:114527. [PMID: 36628874 DOI: 10.1016/j.ecoenv.2023.114527] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/25/2022] [Accepted: 01/07/2023] [Indexed: 06/17/2023]
Abstract
The aims of this study were to evaluated the effect and underlying mechanism of Gandankang (GDK) aqueous extract in alleviating the acute liver injury induced by carbon tetrachloride (CCl4) in vivo and in vitro. Mice were divided into 5 groups (n = 8) for acute (Groups: control, 0.3 % CCl4, BD (Bifendate), 1.17, 2.34 and 4.68 mg/kg GDK) liver injury study. 10 µL/g CCl4 with corn oil were injected interperitoneally (i.p) expect the control group. HepG2 cells were used in vitro study. The results showed GDK can effectively inhibit liver damage and restore the structure and function of the liver. In mechanism, GDK inhibited CCl4-induced liver fibrosis and blocked the NF-κB pathway to effectively inhibit the hepatic inflammatory response; and inhibited CCl4-induced oxidative stress by upregulating the Keap1/Nrf2 pathway-related proteins and promoting the synthesis of several antioxidants. Additionally, it inhibited ferroptosis in the liver by regulating the expression of ACSl4 and GPX4. GDK reduced lipid peroxide generation in vitro by downregulating the production of reactive oxygen species and Fe2+ aggregation, thereby inhibiting ferroptosis and alleviating CCl4-induced hepatocyte injury. In conclusion, we describe the potential complex mechanism underlying the effect of GDK against acute liver injury.
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Affiliation(s)
- Yuan-Yuan Wei
- Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, China
| | - Hui-Ru Wang
- Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, China
| | - Yi-Meng Fan
- Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, China
| | - Jin-Hua Gu
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, China; China Institute of Veterinary Drug Control, Beijing 100081, China
| | - Xiu-Ying Zhang
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, China; China Institute of Veterinary Drug Control, Beijing 100081, China
| | - Xu-Hao Gong
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, China; China Institute of Veterinary Drug Control, Beijing 100081, China
| | - Zhi-Hui Hao
- Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China; Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, China.
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27
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Comerford SA, Hinnant EA, Chen Y, Hammer RE. Hepatic ribosomal protein S6 (Rps6) insufficiency results in failed bile duct development and loss of hepatocyte viability; a ribosomopathy-like phenotype that is partially p53-dependent. PLoS Genet 2023; 19:e1010595. [PMID: 36656901 PMCID: PMC9888725 DOI: 10.1371/journal.pgen.1010595] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 01/31/2023] [Accepted: 12/26/2022] [Indexed: 01/20/2023] Open
Abstract
Defective ribosome biogenesis (RiBi) underlies a group of clinically diverse human diseases collectively known as the ribosomopathies, core manifestations of which include cytopenias and developmental abnormalities that are believed to stem primarily from an inability to synthesize adequate numbers of ribosomes and concomitant activation of p53. The importance of a correctly functioning RiBi machinery for maintaining tissue homeostasis is illustrated by the observation that, despite having a paucity of certain cell types in early life, ribosomopathy patients have an increased risk for developing cancer later in life. This suggests that hypoproliferative states trigger adaptive responses that can, over time, become maladaptive and inadvertently drive unchecked hyperproliferation and predispose to cancer. Here we describe an experimentally induced ribosomopathy in the mouse and show that a normal level of hepatic ribosomal protein S6 (Rps6) is required for proper bile duct development and preservation of hepatocyte viability and that its insufficiency later promotes overgrowth and predisposes to liver cancer which is accelerated in the absence of the tumor-suppressor PTEN. We also show that the overexpression of c-Myc in the liver ameliorates, while expression of a mutant hyperstable form of p53 partially recapitulates specific aspects of the hepatopathies induced by Rps6 deletion. Surprisingly, co-deletion of p53 in the Rps6-deficient background fails to restore biliary development or significantly improve hepatic function. This study not only reveals a previously unappreciated dependence of the developing liver on adequate levels of Rps6 and exquisitely controlled p53 signaling, but suggests that the increased cancer risk in ribosomopathy patients may, in part, stem from an inability to preserve normal tissue homeostasis in the face of chronic injury and regeneration.
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Affiliation(s)
- Sarah A. Comerford
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Elizabeth A. Hinnant
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Yidong Chen
- Department of Population Health Sciences, University of Texas Health San Antonio, San Antonio, Texas, United States of America
- Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, Texas. United States of America
| | - Robert E. Hammer
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
- * E-mail:
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28
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Shiragannavar VD, Sannappa Gowda NG, Puttahanumantharayappa LD, Karunakara SH, Bhat S, Prasad SK, Kumar DP, Santhekadur PK. The ameliorating effect of withaferin A on high-fat diet-induced non-alcoholic fatty liver disease by acting as an LXR/FXR dual receptor activator. Front Pharmacol 2023; 14:1135952. [PMID: 36909161 PMCID: PMC9995434 DOI: 10.3389/fphar.2023.1135952] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 02/07/2023] [Indexed: 02/25/2023] Open
Abstract
Introduction: Non-alcoholic fatty liver disease (NAFLD) incidence has been rapidly increasing, and it has emerged as one of the major diseases of the modern world. NAFLD constitutes a simple fatty liver to chronic non-alcoholic steatohepatitis (NASH), which often leads to liver fibrosis or cirrhosis, a serious health condition with limited treatment options. Many a time, NAFLD progresses to fatal hepatocellular carcinoma (HCC). Nuclear receptors (NRs), such as liver X receptor-α (LXR-α) and closely associated farnesoid X receptor (FXR), are ligand-inducible transcription factors that regulate various metabolism-associated gene expressions and repression and play a major role in controlling the pathophysiology of the human liver. Withaferin A is a multifaceted and potent natural dietary compound with huge beneficial properties and plays a vital role as an anti-inflammatory molecule. Methods: In vivo: Swill albino mice were fed with western diet and sugar water (WDSW) for 12, 16, and 20 weeks with suitable controls. Post necropsy, liver enzymes (AST, ALT, and ALP) and lipid profile were measured by commercially available kits using a semi-auto analyzer in serum samples. Liver histology was assessed using H&E and MTS stains to check the inflammation and fibrosis, respectively, using paraffin-embedded sections and mRNA expressions of these markers were measured using qRT-PCR method. TGF-β1 levels in serum samples were quantified by ELISA. In vitro: Steatosis was induced in HepG2 and Huh7 cells using free fatty acids [Sodium Palmitate (SP) and Oleate (OA)]. After induction, the cells were treated with Withaferin A in dose-dependent manner (1, 2.5, and 5 μM, respectively). In vitro steatosis was confirmed by Oil-Red-O staining. Molecular Docking: Studies were conducted using Auto Dock Vina software to check the binding affinity of Withaferin-A to LXR-α and FXR. Results: We explored the dual receptor-activating nature of Withaferin A using docking studies, which potently improves high-fat diet-induced NAFLD in mice and suppresses diet-induced hepatic inflammation and liver fibrosis via LXR/FXR. Our in vitro studies also indicated that Withaferin A inhibits lipid droplet accumulation in sodium palmitate and oleate-treated HepG2 and Huh7 cells, which may occur through LXR-α and FXR-mediated signaling pathways. Withaferin A is a known inhibitor of NF-κB-mediated inflammation. Intriguingly, both LXR-α and FXR activation inhibits inflammation and fibrosis by negatively regulating NF-κB. Additionally, Withaferin A treatment significantly inhibited TGF-β-induced gene expression, which contributes to reduced hepatic fibrosis. Discussion: Thus, the LXR/ FXR dual receptor activator Withaferin A improves both NAFLD-associated liver inflammation and fibrosis in mouse models and under in vitro conditions, which makes Withaferin A a possibly potent pharmacological and therapeutic agent for the treatment of diet-induced NAFLD.
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Affiliation(s)
- Varsha D Shiragannavar
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Nirmala G Sannappa Gowda
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Lakshana D Puttahanumantharayappa
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Shreyas H Karunakara
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Smitha Bhat
- Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysore, Karnataka, India
| | - Shashanka K Prasad
- Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education and Research, Mysore, Karnataka, India.,Bioactive Compound Laboratory, Faculty of Agriculture, Chiang Mai University, Chiang Mai, Thailand
| | - Divya P Kumar
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
| | - Prasanna K Santhekadur
- Department of Biochemistry, Center of Excellence in Molecular Biology and Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education and Research, Mysore, India
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Silva BRS, Jara CP, Sidarta-Oliveira D, Velloso LA, Velander WH, Araújo EP. Downregulation of the Protein C Signaling System Is Associated with COVID-19 Hypercoagulability-A Single-Cell Transcriptomics Analysis. Viruses 2022; 14:2753. [PMID: 36560757 PMCID: PMC9785999 DOI: 10.3390/v14122753] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/14/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022] Open
Abstract
Because of the interface between coagulation and the immune response, it is expected that COVID-19-associated coagulopathy occurs via activated protein C signaling. The objective was to explore putative changes in the expression of the protein C signaling network in the liver, peripheral blood mononuclear cells, and nasal epithelium of patients with COVID-19. Single-cell RNA-sequencing data from patients with COVID-19 and healthy subjects were obtained from the COVID-19 Cell Atlas database. A functional protein-protein interaction network was constructed for the protein C gene. Patients with COVID-19 showed downregulation of protein C and components of the downstream protein C signaling cascade. The percentage of hepatocytes expressing protein C was lower. Part of the liver cell clusters expressing protein C presented increased expression of ACE2. In PBMC, there was increased ACE2, inflammatory, and pro-coagulation transcripts. In the nasal epithelium, PROC, ACE2, and PROS1 were expressed by the ciliated cell cluster, revealing co-expression of ACE-2 with transcripts encoding proteins belonging to the coagulation and immune system interface. Finally, there was upregulation of coagulation factor 3 transcript in the liver and PBMC. Protein C could play a mechanistic role in the hypercoagulability syndrome affecting patients with severe COVID-19.
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Affiliation(s)
- Bruna Rafaela Santos Silva
- Nursing School, University of Campinas, Tessalia Vieira de Camargo, 126, Campinas 13084-970, Brazil
- Laboratory of Cell Signalling, Obesity and Comorbidities Center, OCRC, University of Campinas, Carl Von Linnaeus, s/n, Campinas 13084-864, Brazil
| | - Carlos Poblete Jara
- Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, NE 68588-0643, USA
| | - Davi Sidarta-Oliveira
- Laboratory of Cell Signalling, Obesity and Comorbidities Center, OCRC, University of Campinas, Carl Von Linnaeus, s/n, Campinas 13084-864, Brazil
- School of Medical Sciences, University of Campinas, Tessalia Vieira de Camargo, 126, Campinas 13083-887, Brazil
| | - Licio A. Velloso
- Laboratory of Cell Signalling, Obesity and Comorbidities Center, OCRC, University of Campinas, Carl Von Linnaeus, s/n, Campinas 13084-864, Brazil
- School of Medical Sciences, University of Campinas, Tessalia Vieira de Camargo, 126, Campinas 13083-887, Brazil
| | - William H. Velander
- Department of Chemical and Biomolecular Engineering, University of Nebraska, Lincoln, NE 68588-0643, USA
| | - Eliana P. Araújo
- Nursing School, University of Campinas, Tessalia Vieira de Camargo, 126, Campinas 13084-970, Brazil
- Laboratory of Cell Signalling, Obesity and Comorbidities Center, OCRC, University of Campinas, Carl Von Linnaeus, s/n, Campinas 13084-864, Brazil
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30
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Zhou Y, Li Z, Xu M, Zhang D, Ling J, Yu P, Shen Y. O-GlycNacylation Remission Retards the Progression of Non-Alcoholic Fatty Liver Disease. Cells 2022; 11:cells11223637. [PMID: 36429065 PMCID: PMC9688300 DOI: 10.3390/cells11223637] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/04/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease spectrum associated with insulin resistance (IR), from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC). O-GlcNAcylation is a posttranslational modification, regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Abnormal O-GlcNAcylation plays a key role in IR, fat deposition, inflammatory injury, fibrosis, and tumorigenesis. However, the specific mechanisms and clinical treatments of O-GlcNAcylation and NAFLD are yet to be elucidated. The modification contributes to understanding the pathogenesis and development of NAFLD, thus clarifying the protective effect of O-GlcNAcylation inhibition on liver injury. In this review, the crucial role of O-GlcNAcylation in NAFLD (from NAFL to HCC) is discussed, and the effect of therapeutics on O-GlcNAcylation and its potential mechanisms on NAFLD have been highlighted. These inferences present novel insights into the pathogenesis and treatments of NAFLD.
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Affiliation(s)
- Yicheng Zhou
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, Nanchang 330031, China
| | - Minxuan Xu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Deju Zhang
- Food and Nutritional Sciences, School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
| | - Jitao Ling
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
| | - Peng Yu
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
- Correspondence: (P.Y.); (Y.S.)
| | - Yunfeng Shen
- Department of Endocrinology and Metabolism, the Second Affiliated Hospital of Nanchang University, Branch of Nationlal Clinical Research Center for Metabolic Diseases, Institute for the Study of Endocrinology and Metabolism in Jiangxi Province, Nanchang 330006, China
- Correspondence: (P.Y.); (Y.S.)
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31
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Wei Y, Wang H, Zhang Y, Gu J, Zhang X, Gong X, Hao Z. Comprehensive Effect of Carbon Tetrachloride and Reversal of Gandankang Formula in Mice Liver: Involved in Oxidative Stress, Excessive Inflammation, and Intestinal Microflora. Antioxidants (Basel) 2022; 11:2234. [PMID: 36421420 PMCID: PMC9687142 DOI: 10.3390/antiox11112234] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/10/2022] [Accepted: 11/10/2022] [Indexed: 04/25/2025] Open
Abstract
To systematically evaluate the effect of Gandankang (GDK) aqueous extract in alleviating acute and chronic liver injury. Forty-one chemical compounds were identified by ultra-high performance liquid chromatography-linear trap quadrupole-orbitrap-tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS) from GDK. All dosages of GDK and Biphenyl diester (BD) improved CCl4-induced acute and chronic liver injury. GDK curbed liver fibrosis and blocked the NF-κB pathway to effectively inhibit the hepatic inflammatory response. Additionally, GDK treatment reduced the abundance of Phascolarctobacterium, Turicibacter, Clostridium_xlva, Atoprostipes, and Eubacterium, in comparison with those in the CCl4 mice and elevated the abundance of Megamonas and Clostridium_IV as evident from 16S rDNA sequencing. Correlation analysis showed that the abundance of Eubacterium and Phascolarctobacterium was positively correlated with inflammation, fibrosis, and oxidation indexes. This indicates that GDK ameliorates chronic liver injury by mitigating fibrosis and inflammation. Nrf2 pathway is the key target of GDK in inhibiting liver inflammation and ferroptosis. Eubacterium and Phascolarctobacterium played a vital role in attenuating liver fibrosis.
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Affiliation(s)
- Yuanyuan Wei
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Huiru Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Yannan Zhang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Jinhua Gu
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
- China Institute of Veterinary Drug Control, Beijing 100081, China
| | - Xiuying Zhang
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
- China Institute of Veterinary Drug Control, Beijing 100081, China
| | - Xuhao Gong
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
- China Institute of Veterinary Drug Control, Beijing 100081, China
| | - Zhihui Hao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
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32
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Sayed AM, Gohar OM, Abd-Alhameed EK, Hassanein EHM, Ali FEM. The importance of natural chalcones in ischemic organ damage: Comprehensive and bioinformatic analysis review. J Food Biochem 2022; 46:e14320. [PMID: 35857486 DOI: 10.1111/jfbc.14320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 07/01/2022] [Accepted: 07/07/2022] [Indexed: 11/26/2022]
Abstract
Over the last few decades, extensive research has been conducted, yielding a detailed account of thousands of newly discovered compounds of natural origin and their biological activities, all of which have the potential to be used for a wide range of therapeutic purposes. There are multiple research papers denoting the central objective of chalcones, which have been shown to have therapeutic potential against various forms of ischemia. The various aspects of chalcones are discussed in this review regarding molecular mechanisms involved in the promising anti-ischemic potential of these chalcones. The main mechanisms involved in these protective effects are Nrf2/Akt activation and NF-κB/TLR4 suppression. Furthermore, in-silico studies were carried out to discover the probable binding of these chalcones to Keap-1 (an inhibitor of Nrf2), Akt, NF-κB, and TLR4 protein molecules. Besides, network pharmacology analysis was conducted to predict the interacting partners of these signals. The obtained results indicated that Nrf2, Akt, NF-κB, and TLR4 are involved in the beneficial anti-ischemic actions of chalcones. Conclusively, the present findings show that chalcones as anti-ischemic agents have a valid rationale. The discussed studies will provide a comprehensive viewpoint on chalcones and can help to optimize their effects in different ischemia. PRACTICAL APPLICATIONS: Ischemic organ damage is an unavoidable pathological condition with a high worldwide incidence. According to the current research progress, natural chalcones have been proved to treat and/or prevent various types of ischemic organ damage by alleviating oxidative stress, inflammation, and apoptosis by different molecular mechanisms. This article displays the comprehensive research progress and the molecular basis of ischemic organ damage pathophysiology and introduces natural chalcones' mechanism in the ischemic organ condition.
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Affiliation(s)
- Ahmed M Sayed
- Biochemistry Laboratory, Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt
| | - Osama M Gohar
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, Egypt
| | - Esraa K Abd-Alhameed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Emad H M Hassanein
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
| | - Fares E M Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt
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Yang X, Dai J, Yao S, An J, Wen G, Jin H, Zhang L, Zheng L, Chen X, Yi Z, Tuo B. APOBEC3B: Future direction of liver cancer research. Front Oncol 2022; 12:996115. [PMID: 36203448 PMCID: PMC9530283 DOI: 10.3389/fonc.2022.996115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 08/22/2022] [Indexed: 12/03/2022] Open
Abstract
Liver cancer is one of the most common cancers in the world, and the rate of liver cancer is high due to the of its illness. The main risk factor for liver cancer is infection with the hepatitis B virus (HBV), but a considerable number of genetic and epigenetic factors are also directly or indirectly involved in the underlying pathogenesis of liver cancer. In particular, the apolipoprotein B mRNA editing enzyme, catalytic peptide-like protein (APOBEC) family (DNA or mRNA editor family), which has been the focus of virology research for more than a decade, has been found to play a significant role in the occurrence and development of various cancers, providing a new direction for the research of liver cancer. APOBEC3B is a cytosine deaminase that controls a variety of biological processes, such as protein expression, innate immunity, and embryonic development, by participating in the process of cytidine deamination to uridine in DNA and RNA. In humans, APOBEC3B has long been known as a DNA editor for limiting viral replication and transcription. APOBEC3B is widely expressed at low levels in a variety of normal tissues and organs, but it is significantly upregulated in different types of tumor tissues and tumor lines. Thus, APOBEC3B has received increasing attention in various cancers, but the role of APOBEC3B in the occurrence and development of liver cancer due to infection with HBV remains unclear. This review provides a brief introduction to the pathogenesis of hepatocellular carcinoma induced by HBV, and it further explores the latest results of APOBEC3B research in the development of HBV and liver cancer, thereby providing new directions and strategies for the treatment and prevention of liver cancer.
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Affiliation(s)
- Xingyue Yang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jing Dai
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Shun Yao
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jiaxing An
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Guorong Wen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Hai Jin
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Li Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Liming Zheng
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Xingyue Chen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhiqiang Yi
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Biguang Tuo
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- The Collaborative Innovation Center of Tissue Damage Repair and Regenerative Medicine of Zunyi Medical University, Zunyi, China
- *Correspondence: Biguang Tuo,
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The Effect of Mineralized Plasmatic Matrix and Chitosan on the Healing of Critical-Sized Mandibular Bone Defects in a Rabbit Model. Processes (Basel) 2022. [DOI: 10.3390/pr10091890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: In maxillofacial surgery, critical size mandibular defects remain a challenging issue. There have been numerous attempts to improve mandibular defect healing. Recently, bone tissue engineering has provided many benefits in improving bone healing. Herein, we tried to investigate the effect of Mineralized plasmatic matrix (MPM) and Chitosan to enhance tissue healing and regeneration in mandibular bone defect. Methods: A mandibular bone defect of critical size was created in 45 New Zealand rabbits. There were three groups of rabbits: the MPM group, the Chitosan group, and the control group. Radiographical, histological, and immune histochemical evaluations were performed at 4, 8, and 12 post-operative weeks. Results: The MPM group demonstrated the highest degree of bone formation with uniform radio-opacity nearly like that of adjacent healthy parent tissue. While in the chitosan group, most of the defect area was filled with radio-opaque bone with persistent small radiolucent areas. The control group showed less bone formation than the MPM and chitosan group, with more radiolucent areas. Sections stained with (H&E) demonstrated an increase in osseous tissue formation in both the MPM and chitosan groups. Staining with Masson’s trichrome revealed an increase in fibrous connective tissue proliferation in both the MPM and chitosan groups. In both the MPM and chitosan groups, nuclear factor kappa p65 was downregulated, and matrix metalloproteinase-9 was upregulated. Conclusion: According to the current study, MPM and Chitosan may have beneficial effects on the healing of critical-sized mandibular bone defects.
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35
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Natural polysaccharides as potential anti-fibrotic agents: A review of their progress. Life Sci 2022; 308:120953. [PMID: 36103957 DOI: 10.1016/j.lfs.2022.120953] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 11/24/2022]
Abstract
Fibrosis, as a common disease which could be found in nearly all organs, is normally initiated by organic injury and eventually ended in cellular dysfunction and organ failure. Currently, effective and safe therapeutic strategies targeting fibrogenesis still in highly demand. Natural polysaccharides derived from natural resources possess promising anti-fibrosis potential, with no deleterious side effects. Based on the etiology and pathogenesis of fibrosis, this review summarizes the intervention effects and mechanisms of natural polysaccharides in the prevention and treatment of fibrosis. Natural polysaccharides are able to regulate each phase of the fibrogenic response, including primary injury to organs, activation of effector cells, the elaboration of extracellular matrix (ECM) and dynamic deposition. In addition, polysaccharides significantly reduce fibrosis levels in multiple organs including heart, lung, liver and kidney. The investigation of the pathogenesis of fibrosis indicates that mechanisms including the inhibition of TGF-β/Smad, NF-κB, HMGB1/TLR4, cAMP/PKA signaling pathways, MMPs/TIMPs system as well as microRNAs are promising therapeutic targets. Natural polysaccharides can target these mediators or pathways to alleviate fibrosis. The information reviewed here offer new insights into the understanding the protective role of natural polysaccharides against fibrosis, help design further experimental studies related to polysaccharides and fibrotic responses, and shed light on a potential treatment for fibrosis.
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36
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Li WQ, Liu WH, Qian D, Liu J, Zhou SQ, Zhang L, Peng W, Su L, Zhang H. Traditional Chinese medicine: An important source for discovering candidate agents against hepatic fibrosis. Front Pharmacol 2022; 13:962525. [PMID: 36081936 PMCID: PMC9445813 DOI: 10.3389/fphar.2022.962525] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 07/28/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatic fibrosis (HF) refers to the pathophysiological process of connective tissue dysplasia in the liver caused by various pathogenic factors. Nowadays, HF is becoming a severe threat to the health of human being. However, the drugs available for treating HF are limited. Currently, increasing natural agents derived from traditional Chinese medicines (TCMs) have been found to be beneficial for HF. A systemic literature search was conducted from PubMed, GeenMedical, Sci-Hub, CNKI, Google Scholar and Baidu Scholar, with the keywords of "traditional Chinese medicine," "herbal medicine," "natural agents," "liver diseases," and "hepatic fibrosis." So far, more than 76 natural monomers have been isolated and identified from the TCMs with inhibitory effect on HF, including alkaloids, flavones, quinones, terpenoids, saponins, phenylpropanoids, and polysaccharides, etc. The anti-hepatic fibrosis effects of these compounds include hepatoprotection, inhibition of hepatic stellate cells (HSC) activation, regulation of extracellular matrix (ECM) synthesis & secretion, regulation of autophagy, and antioxidant & anti-inflammation, etc. Natural compounds and extracts from TCMs are promising agents for the prevention and treatment of HF, and this review would be of great significance to development of novel drugs for treating HF.
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Affiliation(s)
- Wen-Qing Li
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Hao Liu
- Department of Pharmacy, Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Die Qian
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jia Liu
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shi-Qiong Zhou
- Hospital of Nursing, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Lei Zhang
- Department of Vascular Surgery, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Peng
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Li Su
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Hong Zhang
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Androutsakos T, Bakasis AD, Pouliakis A, Gazouli M, Vallilas C, Hatzis G. Single Nucleotide Polymorphisms of Toll-like Receptor 4 in Hepatocellular Carcinoma-A Single-Center Study. Int J Mol Sci 2022; 23:9430. [PMID: 36012696 PMCID: PMC9409058 DOI: 10.3390/ijms23169430] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver tumor leading to significant morbidity and mortality; its exact genetic background is largely unrecognized. Toll-like receptor-4 (TLR4) reacts with lipopolysaccharides, molecules found in the outer membrane of Gram-negative bacteria. In damaged liver, TLR4 expression is upregulated, leading to hepatic inflammation and injury. We tried to investigate the role of the two most common single-nucleotide polymorphisms (SNPs) of TLR4 in HCC-genesis. Aged > 18 years old, cirrhotic patients were included in this study. Exclusion criteria were non-HCC tumors and HIV co-infection. TLR4 SNPs association with HCC occurrence was the primary endpoint, and associations with all-cause and liver-related mortality, as well as time durations between diagnosis of cirrhosis and HCC development or death and diagnosis of HCC and death were secondary endpoints. A total of 52 out of 260 included patients had or developed HCC. TLR4 SNPs showed no correlation with primary or secondary endpoints, except for the shorter duration between HCC development and death in patients with TLR4 mutations. Overall, TLR4 SNPs showed no correlation with carcinogenesis or deaths in patients with liver cirrhosis; patients with TLR4 SNPs that developed HCC had lower survival rates, a finding that should be further evaluated.
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Affiliation(s)
- Theodoros Androutsakos
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios-Dimitrios Bakasis
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Abraham Pouliakis
- 2nd Department of Pathology, University General Hospital Attikon, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece
| | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Christos Vallilas
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Gregorios Hatzis
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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38
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Alamoudi AJ, Alessi SA, Rizg WY, Jali AM, Safhi AY, Sabei FY, Alshehri S, Hosny KM, Abdel-Naim AB. Cordycepin Attenuates Testosterone-Induced Benign Prostatic Hyperplasia in Rats via Modulation of AMPK and AKT Activation. Pharmaceutics 2022; 14:pharmaceutics14081652. [PMID: 36015278 PMCID: PMC9415290 DOI: 10.3390/pharmaceutics14081652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 12/01/2022] Open
Abstract
Benign prostatic hyperplasia (BPH) is a disease that commonly affects elderly men. Cordycepin is an adenosine analog with a wide range of pharmacological activities including antiproliferative and prostatic smooth muscle relaxant effects. This study was designed to assess the actions of cordycepin in testosterone-induced BPH in rats. Animals were divided into six treatment groups: control, cordycepin-alone (10 mg/kg), testosterone-alone (3 mg/kg), cordycepin (5 mg/kg) + testosterone, cordycepin (10 mg/kg) + testosterone, and finasteride (0.5 mg/kg) + testosterone. Treatments were continued daily, 5 days a week, for 4 weeks. Cordycepin significantly prevented the increase in prostate weight and prostate index induced by testosterone. This was confirmed by histopathological examinations. Cordycepin antiproliferative activity was further defined by its ability to inhibit cyclin-D1 and proliferating cell nuclear antigen (PCNA) expression. In addition, cordycepin exhibited significant antioxidant properties as proven by the prevention of lipid peroxidation, reduced glutathione diminution, and superoxide dismutase exhaustion. This was paralleled by anti-inflammatory activity as shown by the inhibition of interleukin-6, tumor necrosis factor-α, and nuclear factor-κB expression in prostatic tissues. It also enhanced apoptosis as demonstrated by its ability to enhance and inhibit mRNA expression of Bax and Bcl2, respectively. Western blot analysis indicated that cordycepin augmented phospho-AMP-activated protein kinase (p-AMPK) and inhibited p-AKT expression. Collectively, cordycepin has the ability to prevent testosterone-induced BPH in rats. This is mediated, at least partially, by its antiproliferative, antioxidant, anti-inflammatory, and pro-apoptotic actions in addition to its modulation of AMPK and AKT activation.
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Affiliation(s)
- Abdulmohsin J. Alamoudi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Correspondence: ; Tel.: +966-551624044
| | - Sami A. Alessi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department of Pharmaceutical Care, King Abdulaziz Hospital, Jeddah 21589, Saudi Arabia
| | - Waleed Y. Rizg
- Center of Research Excellence for Drug Research and Pharmaceutical Industries, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Abdulmajeed M. Jali
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Awaji Y. Safhi
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Fahad Y. Sabei
- Department of Pharmaceutics, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Sameer Alshehri
- Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Khaled M. Hosny
- Department of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Ashraf B. Abdel-Naim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Fucoidan-Mediated Inhibition of Fibrotic Properties in Oral Submucous Fibrosis via the MEG3/miR-181a/Egr1 Axis. Pharmaceuticals (Basel) 2022; 15:ph15070833. [PMID: 35890132 PMCID: PMC9317791 DOI: 10.3390/ph15070833] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 01/27/2023] Open
Abstract
Oral submucous fibrosis (OSF) is a chronic fibrotic remodeling disease that can progress to oral cancer. However, efficient clinical diagnosis and treatment methods for OSF are still lacking. This study investigated the anti-fibrotic effect of fucoidan on oral fibrosis. To evaluate the fibrotic ability (myofibroblast activities), we performed wound-healing, Transwell migration, and collagen contraction assays by using patient-derived normal and fibrotic buccal submucous fibroblasts (BMFs and fBMFs, respectively). RNA-sequencing and dual-luciferase reporter and RNA immunoprecipitation chip assays were performed to identify the clinical significance and molecular mechanism of non-coding RNAs. Fucoidan suppressed the myofibroblast activities and inhibited the MEG3 in fBMFs. MEG3 was overexpressed in the OSF tissue and was positively associated with myofibroblast markers. Knockdown of MEG3 markedly inhibited myofibroblast activities, which were restored by inhibiting miR-181a and overexpressing Egr1. The results from luciferase reporter and RIP assays confirmed that MEG3 functioned as a competing endogenous RNA (ceRNA) and could directly target miR-181a, thereby preventing the miR-181a-mediated translational repression of Egr1. This study demonstrated that MEG3 exerts a profibrotic effect on OSF by targeting miR-181a/Egr1. Therefore, the administration of fucoidan may serve as a potential therapeutic strategy for OSF by targeting the overexpression of MEG3.
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Association of statin treatment with hepatocellular carcinoma risk in end-stage kidney disease patients with chronic viral hepatitis. Sci Rep 2022; 12:10807. [PMID: 35752695 PMCID: PMC9233705 DOI: 10.1038/s41598-022-14713-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 06/10/2022] [Indexed: 11/12/2022] Open
Abstract
Statin use in end-stage kidney disease (ESKD) patients are not encouraged due to low cardioprotective effects. Although the risk of hepatocellular carcinoma (HCC), a frequently occurring cancer in East Asia, is elevated in ESKD patients, the relationship between statins and HCC is not known despite its possible chemopreventive effect. The relationship between statin use and HCC development in ESKD patients with chronic hepatitis was evaluated. In total, 6165 dialysis patients with chronic hepatitis B or C were selected from a national health insurance database. Patients prescribed with ≥ 28 cumulative defined daily doses of statins during the first 3 months after dialysis commencement were defined as statin users, while those not prescribed with statins were considered as non-users. Primary outcome was the first diagnosis of HCC. Sub-distribution hazard model with inverse probability of treatment weighting was used to estimate HCC risk considering death as competing risk. During a median follow-up of 2.8 years, HCC occurred in 114 (3.2%) statin non-users and 33 (1.2%) statin users. The HCC risk was 41% lower in statin users than in non-users (sub-distribution hazard ratio, 0.59; 95% confidence interval [CI], 0.42-0.81). The weighted incidence rate of HCC was lower in statin users than in statin non-users (incidence rate difference, - 3.7; 95% CI - 5.7 to - 1.7; P < 0.001). Incidence rate ratio (IRR) was also consistent with other analyses (IRR, 0.56; 95% CI, 0.41 to 0.78; P < 0.001). Statin use was associated with a lower risk of incident HCC in dialysis patients with chronic hepatitis B or C infection.
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Ge C, Tan J, Lou D, Zhu L, Zhong Z, Dai X, Sun Y, Kuang Q, Zhao J, Wang L, Liu J, Wang B, Xu M. Mulberrin confers protection against hepatic fibrosis by Trim31/Nrf2 signaling. Redox Biol 2022; 51:102274. [PMID: 35240537 PMCID: PMC8891817 DOI: 10.1016/j.redox.2022.102274] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/14/2022] [Accepted: 02/22/2022] [Indexed: 02/06/2023] Open
Abstract
Mulberrin (Mul) is a key component of the traditional Chinese medicine Romulus Mori with various biological functions. However, the effects of Mul on liver fibrosis have not been addressed, and thus were investigated in our present study, as well as the underlying mechanisms. Here, we found that Mul administration significantly ameliorated carbon tetrachloride (CCl4)-induced liver injury and dysfunction in mice. Furthermore, CCl4-triggerd collagen deposition and liver fibrosis were remarkably attenuated in mice with Mul supplementation through suppressing transforming growth factor β1 (TGF-β1)/SMAD2/3 signaling pathway. Additionally, Mul treatments strongly restrained the hepatic inflammation in CCl4-challenged mice via blocking nuclear factor-κB (NF-κB) signaling. Importantly, we found that Mul markedly increased liver TRIM31 expression in CCl4-treated mice, accompanied with the inactivation of NOD-like receptor protein 3 (NLRP3) inflammasome. CCl4-triggered hepatic oxidative stress was also efficiently mitigated by Mul consumption via improving nuclear factor E2-related factor 2 (Nrf2) activation. Our in vitro studies confirmed that Mul reduced the activation of human and mouse primary hepatic stellate cells (HSCs) stimulated by TGF-β1. Consistently, Mul remarkably retarded the inflammatory response and reactive oxygen species (ROS) accumulation both in human and murine hepatocytes. More importantly, by using hepatocyte-specific TRIM31 knockout mice (TRIM31Hep-cKO) and mouse primary hepatocytes with Nrf2-knockout (Nrf2KO), we identified that the anti-fibrotic and hepatic protective effects of Mul were TRIM31/Nrf2 signaling-dependent, relieving HSCs activation and liver fibrosis. Therefore, Mul-ameliorated hepatocyte injury contributed to the suppression of HSCs activation by improving TRIM31/Nrf2 axis, thus providing a novel therapeutic strategy for hepatic fibrosis treatment.
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Affiliation(s)
- Chenxu Ge
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China
| | - Jun Tan
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China.
| | - Deshuai Lou
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China
| | - Liancai Zhu
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, PR China
| | - Zixuan Zhong
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China
| | - Xianling Dai
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, PR China
| | - Yan Sun
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, PR China
| | - Qin Kuang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, PR China
| | - Junjie Zhao
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China
| | - Longyan Wang
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China
| | - Jin Liu
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China
| | - Bochu Wang
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, PR China.
| | - Minxuan Xu
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China.
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Du S, Sun L, Wang Y, Zhu W, Gao J, Pei W, Zhang Y. ADAM12 is an independent predictor of poor prognosis in liver cancer. Sci Rep 2022; 12:6634. [PMID: 35459884 PMCID: PMC9033838 DOI: 10.1038/s41598-022-10608-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 04/11/2022] [Indexed: 12/12/2022] Open
Abstract
Disintegrin and metalloproteinase 12 (ADAM12) is thought to trigger the occurrence and development of numerous tumours, including colorectal, breast, and pancreatic cancers. On the basis of The Cancer Genome Atlas (TCGA) datasets, in this study, the relationship between ADAM12 gene expression and hepatocellular carcinoma (HCC), the prognostic value of this relationship, and the potential mechanisms influencing HCC development were evaluated. The results showed that the ADAM12 gene was significantly and highly expressed in liver cancer tissue. The high expression of the ADAM12 gene in liver cancer tissue significantly and positively correlated with T stage, pathological stage, and residual tumour. Kaplan–Meier and Cox regression analyses revealed that ADAM12 gene expression is an independent risk factor influencing the prognosis of patients with liver cancer. Pathway analyses of ADAM12 in HCC revealed ADAM12-correlated signalling pathways, and the expression level of ADAM12 was associated with immune cell infiltration. In vitro experiments demonstrated that the expression level of ADAM12 in Huh-7 and Hep3B cells was significantly higher than that in other HCC cells. ShRNA transfection experiments confirmed that the expression levels of TGF-β and Notch pathway-related proteins were significantly decreased. An EdU cell proliferation assay showed that a low level of ADAM12 gene expression significantly inhibited the proliferative activity of HCC cells. Cell cycle experiments showed that low ADAM12 expression blocked the G1/S phase transition. Overall, this research revealed that high ADAM12 gene expression implies a poor prognosis for patients with primary liver cancer. In addition, it is a potential indicator for the diagnosis of liver cancer.
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Affiliation(s)
- Shuangqiu Du
- Anhui Province Key Laboratory of Biological Macromolecules Research, Wannan Medical College, Wuhu, 241002, China
| | - Linlin Sun
- Anhui Province Key Laboratory of Biological Macromolecules Research, Wannan Medical College, Wuhu, 241002, China
| | - Yun Wang
- Anhui Province Key Laboratory of Biological Macromolecules Research, Wannan Medical College, Wuhu, 241002, China
| | - Wenhao Zhu
- Anhui Province Key Laboratory of Biological Macromolecules Research, Wannan Medical College, Wuhu, 241002, China
| | - Jialin Gao
- Department of Endocrinology, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241002, China
| | - Wenjun Pei
- Anhui Province Key Laboratory of Biological Macromolecules Research, Wannan Medical College, Wuhu, 241002, China.
| | - Yao Zhang
- Anhui Province Key Laboratory of Biological Macromolecules Research, Wannan Medical College, Wuhu, 241002, China.
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Huang X, Fan M, Huang W. Pleiotropic roles of FXR in liver and colorectal cancers. Mol Cell Endocrinol 2022; 543:111543. [PMID: 34995680 PMCID: PMC8818033 DOI: 10.1016/j.mce.2021.111543] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 12/01/2022]
Abstract
Nuclear receptor farnesoid X receptor (FXR) is generally considered a cell protector of enterohepatic tissues and a suppressor of liver cancer and colorectal carcinoma (CRC). Loss or reduction of FXR expression occurs during carcinogenesis, and the FXR level is inversely associated with the aggressive behaviors of the malignancy. Global deletion of FXR and tissue-specific deletion of FXR display distinct effects on tumorigenesis. Epigenetic silencing and inflammatory context are two main contributors to impaired FXR expression and activity. FXR exerts its antitumorigenic function via the following mechanisms: 1) FXR regulates multiple metabolic processes, notably bile acid homeostasis; 2) FXR antagonizes hepatic and enteric inflammation; 3) FXR impedes aberrant activation of some cancer-related pathways; and 4) FXR downregulates a number of oncogenes while upregulating some tumor suppressor genes. Restoring FXR functions via its agonists provides a therapeutic approach for patients with liver cancer and CRC. However, an in-depth understanding of the species-specific pharmacological effects is a prerequisite for assessing the clinical safety and efficacy of FXR agonists in human cancer treatment.
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Affiliation(s)
- Xiongfei Huang
- Department of Pathology and Institute of Oncology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350004, PR China; Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian, 350108, PR China.
| | - Mingjie Fan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA, 91010, USA.
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Gad El-Hak HN, Mahmoud HS, Ahmed EA, Elnegris HM, Aldayel TS, Abdelrazek HMA, Soliman MTA, El-Menyawy MAI. Methanolic Phoenix dactylifera L. Extract Ameliorates Cisplatin-Induced Hepatic Injury in Male Rats. Nutrients 2022; 14:1025. [PMID: 35268000 PMCID: PMC8912432 DOI: 10.3390/nu14051025] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 02/20/2022] [Accepted: 02/21/2022] [Indexed: 12/20/2022] Open
Abstract
This study investigated the ameliorative potential of methanolic date flesh extract (MDFE) against cisplatin-induced hepatic injury. Twenty male rats (weighing 180-200 g) were allocated into four groups: control; date flesh (DF) group (oral 600 mg/kg MDFE for 21 days); Cis group (7.5 mg/kg i.p. at day 16); and date flesh/cisplatin (DF/Cis) group (oral 600 mg/kg MDFE for 21 days and 7.5 mg/kg i.p. at day 16). Hepatic biochemical parameters in sera, and inflammatory and oxidant/antioxidant hepatic biomarkers were estimated. Hepatic histological changes and the immunohistochemistry of cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), and alpha smooth muscle actin (α-SMA) were assessed. Pretreatment with MDFE decreased Cis-triggered liver biochemical parameters, oxidative stress, inflammatory biomarkers, and histological damage. Moreover, MDFE treatment reduced Cis-induced hepatic NF-κB, COX-2, and α-SMA protein expression. MDFE exerted a hepatoprotective effect when used concomitantly with Cis. Its effect was mediated via its antioxidant and anti-inflammatory ingredients.
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Affiliation(s)
- Heba Nageh Gad El-Hak
- Zoology Department, Faculty of Sciences, Suez Canal University, Ismailia 41522, Egypt;
| | - Hany Salah Mahmoud
- Center of Scientific Foundation for Experimental Studies and Research, Ismailia 41511, Egypt;
| | - Eman A. Ahmed
- Department of Pharmacology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | - Heba M. Elnegris
- Department of Histology and Cell Biology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt;
- Department of Histology and Cell Biology, Faculty of Medicine, Badr University in Cairo, Cairo 11829, Egypt
| | - Tahany Saleh Aldayel
- Department of Physical Sport Sciences, College of Education, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Heba M. A. Abdelrazek
- Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt;
| | - Mohamed T. A. Soliman
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha 67614, Saudi Arabia;
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Wei Z, Sun X, He Q, Zhao Y, Wu Y, Han X, Wu Z, Chu X, Guan S. Nephroprotective effect of magnesium isoglycyrrhizinate against arsenic trioxide‑induced acute kidney damage in mice. Exp Ther Med 2022; 23:276. [PMID: 35317438 PMCID: PMC8908469 DOI: 10.3892/etm.2022.11202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/17/2022] [Indexed: 11/15/2022] Open
Abstract
Magnesium isoglycyrrhizinate (MgIG) has anti-inflammatory, antioxidative, antiviral and anti-hepatotoxic effects. However, protective effects of MgIG against renal damage caused by arsenic trioxide (ATO) have not been reported. The present study aimed to clarify the protective function of MgIG on kidney damaged induced by ATO. Other than the control group and the group treated with MgIG alone, mice were injected intraperitoneally with ATO (5 mg/kg/day) for 7 days to establish a mouse model of kidney damage. On the 8th day, blood and kidney tissue were collected and the inflammatory factors and antioxidants levels in the kidney tissue and serum were measured. The expression of protein levels of caspase-3, Bcl-2, Bax, Toll-like receptor-4 (TLR4) and nuclear factor-κB (NF-κB) were determined via western blot analysis. In the renal tissue of mice, ATO exposure dramatically elevated markers of oxidative stress, apoptosis and inflammation. However, MgIG could also restore the activities of urea nitrogen and creatinine to normal levels, decrease the malondialdehyde level and reactive oxygen species formation and increase superoxide dismutase, catalase and glutathione activities. MgIG also ameliorated the morphological abnormalities generated by ATO, reduced inflammation and apoptosis and inhibited the TLR4/NF-κB signaling pathway. In conclusion, MgIG may mitigate ATO-induced kidney damage by decreasing apoptosis, oxidative stress and inflammation and its mechanism may be connected to the inhibition of TLR4/NF-κB signaling.
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Affiliation(s)
- Ziheng Wei
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
| | - Xiaoqi Sun
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
| | - Qianqian He
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
| | - Yang Zhao
- Department of Academic Research, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yongchao Wu
- Department of Radiological Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xue Han
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
| | - Zhonglin Wu
- Department of Radiological Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xi Chu
- Department of Pharmacy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Shengjiang Guan
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, P.R. China
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Raj D, Sharma V, Upadhyaya A, Kumar N, Joshi R, Acharya V, Kumar D, Patial V. Swertia purpurascens Wall ethanolic extract mitigates hepatic fibrosis and restores hepatic hepcidin levels via inhibition of TGFβ/SMAD/NFκB signaling in rats. JOURNAL OF ETHNOPHARMACOLOGY 2022; 284:114741. [PMID: 34699946 DOI: 10.1016/j.jep.2021.114741] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/28/2021] [Accepted: 10/09/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Swertia purpurascens Wall belongs to a well-known genus in traditional systems of medicine worldwide. In folklore, it is used to treat various ailments, including hepatic disorders, as an alternative to the endangered species Swertia chirayita. However, the therapeutic potential of Swertia purpurascens Wall against hepatic fibrosis has not been validated yet. AIM OF THE STUDY The present study was planned to evaluate the efficacy of the Swertia purpurascens Wall extract (SPE) against hepatic fibrosis and elucidate the underlying mechanism of action. MATERIALS AND METHODS The metabolite profiling of the SPE was done using UHPLC-QTOF-MS/MS. The acute oral toxicity study of SPE at 2 g/kg BW dose was done in rats. Further, the liver fibrosis was induced by the CCl4 intoxication, and the efficacy of SPE at three doses (100, 200 and 400 mg/kg BW) was evaluated by studying biochemical parameters, histopathology, immunohistochemistry, qRT-PCR, western blotting and in silico analysis. RESULTS UHPLC-QTOF-MS/MS analysis revealed the presence of a total of 23 compounds in SPE. Acute oral toxicity study of SPE at 2 g/kg BW showed no harmful effects in rats. Further, the liver fibrosis was induced by the CCl4 administration, and the efficacy of SPE was evaluated at three doses (100, 200 and 400 mg/kg BW). SPE treatment significantly improved the body weight gain, the relative liver weight, serum liver injury markers and endogenous antioxidant enzyme levels in the CCl4-treated rats. SPE also recovered the altered liver histology and effectively reduced the fibrotic tissue deposition in the hepatic parenchyma. Further, SPE significantly inhibited the fibrotic (TGFβ, αSMA, SMADs and Col1A), proinflammatory markers (NFκB, TNFα and IL1β) and apoptosis in the liver tissue. Interestingly, SPE treatment also restored the altered hepcidin levels in the liver tissue. In silico study revealed the potential of various metabolites as drug candidates and their interaction with target proteins. CONCLUSION Altogether, SPE showed its therapeutic potential against CCl4-induced hepatic fibrosis by restoring the hepatic hepcidin levels and inhibiting TGFβ/SMAD/NFκB signaling in rats.
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Affiliation(s)
- Desh Raj
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; PG Department of Dravyaguna, Rajiv Gandhi Govt. Post Graduate Ayurvedic College and Hospital, Paprola, 176115, H.P, India
| | - Vinesh Sharma
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Ashwani Upadhyaya
- PG Department of Dravyaguna, Rajiv Gandhi Govt. Post Graduate Ayurvedic College and Hospital, Paprola, 176115, H.P, India
| | - Neeraj Kumar
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Robin Joshi
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Vishal Acharya
- Biotechnology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Dinesh Kumar
- Chemical Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India
| | - Vikram Patial
- Pharmacology and Toxicology Laboratory, Dietetics & Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, 176061, H.P, India; Academy of Scientific and Innovative Research AcSIR, Ghaziabad, 201002, U.P, India.
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Ibrahim Fouad G, Ahmed KA. Curcumin Ameliorates Doxorubicin-Induced Cardiotoxicity and Hepatotoxicity Via Suppressing Oxidative Stress and Modulating iNOS, NF-κB, and TNF-α in Rats. Cardiovasc Toxicol 2022; 22:152-166. [PMID: 34837640 DOI: 10.1007/s12012-021-09710-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 11/19/2021] [Indexed: 01/14/2023]
Abstract
Doxorubicin (DOX) is one of the widely used anti-tumor drugs. However, DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) are among the side effects that limited its therapeutic efficiency and clinical applicability. This study aimed to investigate the cardioprotective and hepatoprotective potentials of curcumin (CMN)-a bioactive polyphenolic compound-in alleviating DOX-induced cardiotoxicity (DIC) and hepatotoxicity (DIH) in male rats. A single intraperitoneal (i.p.) dose of DOX (20 mg/kg) was used to induce DIC and DIH. DOX-intoxicated rats were co-treated with CMN (100 mg/kg, oral) for 10 days before and 5 days after a single dose of DOX. We studied the anti-inflammatory and anti-oxidative activities of CMN on biochemical and immunohistochemical aspects. DOX disrupted cardiac and hepatic functions and stimulated oxidative stress and inflammation in both tissues that was confirmed biochemically and immunohistochemically. DOX enhanced inflammatory interferon-gamma (IFN-γ) and upregulated immunoexpression of nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-alpha (TNF-α). DOX induced structural alterations in both cardiac and hepatic tissues. CMN demonstrated cardioprotective potential through reducing cardiac troponin I (cTn1) and aspartate amino transaminase (AST). In addition, CMN significantly ameliorated liver function through decreasing alanine amino transaminase (ALT) and, gamma-glutamyl transferase (GGT), total cholesterol (TC), and triglycerides (TG). CMN demonstrated anti-inflammatory potential through decreasing IFN-γ levels and immunoexpression of iNOS, NF-κB, and TNF-α. Histopathologically, CMN restored DOX-associated cardiac and liver structural alterations. CMN showed anti-oxidative and anti-inflammatory potentials in both the cardiac and hepatic tissues. In addition, cTn1, IFN-γ, and AST could be used as blood-based biomarkers.
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Affiliation(s)
- Ghadha Ibrahim Fouad
- Department of Therapeutic Chemistry, National Research Centre, 33 El-Bohouth St., Dokki, Cairo, 12622, Egypt.
| | - Kawkab A Ahmed
- Pathology Department, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt
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Heme Oxygenase-1 Inhibits the Proliferation of Hepatic Stellate Cells by Activating PPARγ and Suppressing NF-κB. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:8920861. [PMID: 35047060 PMCID: PMC8763483 DOI: 10.1155/2022/8920861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/13/2021] [Accepted: 10/15/2021] [Indexed: 11/22/2022]
Abstract
Background Hepatic stellate cells (HSCs) are reported to play significant roles in the development of liver fibrosis. Heme oxygenase-1 (HO-1) is a key rate-limiting enzyme, which could decrease collagen synthesis and liver damage. Nevertheless, it was yet elusive towards the function and mechanism of HO-1. Methods An HO-1 inducer Hemin or an HO-1 inhibitor ZnPP-IX was used to treat the activated HSC-T6, respectively. MTT assay was adopted to detect cell proliferation. Immunocytochemical staining was employed to test the levels of alpha-smooth muscle actin (α-SMA), peroxisome proliferator-activated receptor-γ (PPARγ), and nuclear factor-kappa B (NF-kappa B) levels in HSC-T6. HO-1, PPARγ, and NF-κB expression levels were measured by qRT-PCR and Western blotting. ELISA was then used to detect the levels of transforming growth factor- (TGF-) beta 1 (TGF-β1), interleukin-6 (IL-6), serum hyaluronic acid (HA), and serum type III procollagen aminopeptide (PIIIP). Results HSC-T6 proliferation was inhibited in Hemin-treated HSCs. The levels of α-SMA, HA, and PIIIP and the production of ECM were lower in Hemin-treated HSCs, whereas those could be rescued by ZnPP-IX. NF-κB activation was decreased, but PPARγ expression was increased after HO-1 upregulation. Furthermore, the levels of TGF-β1 and IL-6, which were downstream of activated NF-κB in HSC-T6, were reduced. The PPAR-specific inhibitor GW9662 could block those mentioned effects. Conclusions Our data demonstrated that HO-1 induction could inhibit HSC proliferation and activation by regulating PPARγ expression and NF-κB activation directly or indirectly, which makes it a promising therapeutic target for liver fibrosis.
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Hazem RM, Ibrahim AZ, Ali DA, Moustafa YM. Dapagliflozin improves steatohepatitis in diabetic rats via inhibition of oxidative stress and inflammation. Int Immunopharmacol 2022; 104:108503. [PMID: 34998036 DOI: 10.1016/j.intimp.2021.108503] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/19/2021] [Accepted: 12/26/2021] [Indexed: 12/11/2022]
Abstract
Type-2 diabetes mellitus and NAFLD are considered as one of the greatest worldwide metabolic disorders with growing incidence. It was found that patients with T2DM have two-fold increase to develop NAFLD. Evidence that some antidiabetic agents improve NAFLD/NASH in patients with T2DM is evolving. However, there are no certain pharmacologic therapies. The current study aimed to investigate the underlying mechanisms for the hepatoprotective effect of dapagliflozin against steatohepatitis in diabetic rats. Type-2 diabetes was induced by HFD followed by a single dose of STZ (30 mg/kg I.P). Fifty rats were randomly divided into 5 groups: Group1; normal control, Group 2; diabetic control, Groups (3-5); diabetic rats received daily dapagliflozin (0.75, 1.5, 3 mg/kg, p.o.) respectively for 6 weeks. At the end of the experiment, blood glucose level and serum insulin were measured. Hepatic tissue homogenization was performed for measuring inflammatory and oxidative stress markers. In addition, histopathological investigation of the hepatic tissue was done. Diabetic rats exhibited remarkable increase in liver weight and liver enzymes, along with histopathological changes, significant elevation in MDA, IL-1 β, TGFβ levels and, NF-κB, alpha-SMA expressions. Dapagliflozin treatment decreased liver weight, liver enzymes, together with marked improvement in histopathological changes. Furthermore, dapagliflozin increased antioxidant enzymes, GSH levels. Interestingly, Dapagliflozin reduced IL-1 β, TGFβ levels and, NF-κB, alpha-SMA expressions. Present data show that dapagliflozin represent a viable approach to protect the liver against diabetes-encouraged steatohepatitis through inhibiting oxidative stress, inflammation and fibrosis progression thus conserving liver function.
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Affiliation(s)
- Reem M Hazem
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed Z Ibrahim
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Dina A Ali
- Department of clinical Pharmacology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.
| | - Yasser M Moustafa
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Badr University, Cairo 11829, Egypt
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Kim MJ, Choi B, Kim JY, Min Y, Kwon DH, Son J, Lee JS, Lee JS, Chun E, Lee KY. USP8 regulates liver cancer progression via the inhibition of TRAF6-mediated signal for NF-κB activation and autophagy induction by TLR4. Transl Oncol 2022; 15:101250. [PMID: 34688043 PMCID: PMC8546492 DOI: 10.1016/j.tranon.2021.101250] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Herein, we aimed to elucidate the molecular and cellular mechanism in which ubiquitin-specific protease 8 (USP8) is implicated in liver cancer progression via TRAF6-mediated signal. USP8 induces the deubiquitination of TRAF6, TAB2, TAK1, p62, and BECN1, which are pivotal roles for NF-κB activation and autophagy induction. Notably, the LIHC patient with low USP8 mRNA expression showed markedly shorter survival time, whereas there was no significant difference in the other 18-human cancers. Importantly, the TCGA data analysis on LIHC and transcriptome analysis on the USP8 knockout (USP8KO) SK-HEP-1 cells revealed a significant correlation between USP8 and TRAF6, TAB2, TAK1, p62, and BECN1, and enhanced NF-κB-dependent and autophagy-related cancer progression/metastasis-related genes in response to LPS stimulation. Furthermore, USP8KO SK-HEP-1 cells showed an increase in cancer migration and invasion by TLR4 stimulation, and a marked increase of tumorigenicity and metastasis in xenografted NSG mice. The results demonstrate that USP8 is negatively implicated in the LIHC progression through the regulation of TRAF6-mediated signal for the activation of NF-κB activation and autophagy induction. Our findings provide useful insight into the LIHC pathogenesis of cancer progression.
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Affiliation(s)
- Mi-Jeong Kim
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Bongkum Choi
- Department of Medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Ji Young Kim
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Yoon Min
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Do Hee Kwon
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Juhee Son
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Ji Su Lee
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea
| | - Joo Sang Lee
- Department of Precision medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea
| | - Eunyoung Chun
- CHA Vaccine Institute, 560 Dunchon-daero, Jungwon-gu, Seongnam-si, Gyeonggi-do 13230, Republic of Korea.
| | - Ki-Young Lee
- Department of Immunology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea; Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Samsung Medical Center, Sungkyunkwan University, Seoul, Republic of Korea.
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