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Mohamed Abdelgawwad El-Sehrawy AA, Mohammed MH, Salahldin OD, Uthirapathy S, Ballal S, Kalia R, Arya R, Joshi KK, Kadim AS, Kadhim AJ. Crosstalk between microRNA and inflammation; critical regulator of diabetes. Exp Cell Res 2025; 447:114507. [PMID: 40058448 DOI: 10.1016/j.yexcr.2025.114507] [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: 01/13/2025] [Revised: 03/06/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025]
Abstract
A growing body of evidence indicates that microRNAs (miRNAs may be used as biomarkers for the diagnosis, prognosis, and treatment of diabetes, given their changed expression profile as the disease progresses. There is growing interest in using individual miRNAs or whole miRNA clusters linked to diabetes as therapeutic targets because of their abnormal expression and functioning. In diabetes, miRNAs are also involved in inflammatory and immunological responses. Additionally, the inflammatory response controls the generation, processing, and stability of pre- or mature miRNAs and miRNA biogenesis. With a comprehensive grasp of molecular biological activities and the signaling axis, this review emphasizes the critical functions of miRNAs in inflammatory and immunological processes in diabetes. We further emphasized the potential role of these miRNAs in controlling inflammation associated with diabetes. This assessment will direct the shift from many studies to practical applications for tailored diabetes treatment and assist in identifying new therapeutic targets and approaches.
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Affiliation(s)
| | - Mohammed Hashim Mohammed
- Medical Laboratory Techniques Department, College of Health and Medical Technology, Al-maarif University, Anbar, Iraq.
| | | | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq.
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India.
| | - Rishiv Kalia
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Renu Arya
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India.
| | - Kamal Kant Joshi
- Department of Allied Science, Graphic Era Hill University, Dehradun, 248002, Uttarakhand, India; Graphic Era Deemed to Be University, Dehradun, Uttarakhand, India.
| | - Arshed Shakir Kadim
- Radiological Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, Babylon, 51001, Iraq.
| | - Abed J Kadhim
- Department of Medical Engineering, Al-Nisour University College, Baghdad, Iraq.
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Tang M, Wei X, Ma Y, Tan Y, Cao H, Yao S, Wang J, Yang H, Liu F, Peng Y, Fan N. USP13 ameliorates metabolic dysfunction-associated steatohepatitis through targeting PTEN. Life Sci 2025; 360:123264. [PMID: 39571890 DOI: 10.1016/j.lfs.2024.123264] [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: 09/22/2024] [Revised: 11/11/2024] [Accepted: 11/18/2024] [Indexed: 12/01/2024]
Abstract
OBJECTIVE The role of ubiquitin-specific protease 13 (USP13) in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. This study aimed to elucidate the role of USP13 in MASH progression. METHODS THLE-2 cells were subjected to palmitate acid (PA) to generate an in vitro model of lipid accumulation and inflammation. Two in vivo models of MASH were established by feeding mice with a high-fat, high-fructose and high-cholesterol (HFFC) diet for 16 weeks and a methionine/choline-deficient diet (MCD) for 4 weeks, respectively. Usp13 overexpression and knockout (KO) techniques were employed to investigate its role in MASH. RESULTS USP13 expression was significantly downregulated in the livers of MASH mice and in the in vitro model of lipid accumulation and inflammation. Hepatic overexpression of Usp13 markedly alleviated liver steatosis, inflammation and fibrosis, while knockout of Usp13 exacerbated the MASH phenotype. Mechanistically, USP13 directly bound to phosphatase and tensin homolog (PTEN) and deubiquitinated it, thereby elevating the PTEN expression and improving the MASH phenotype. Notably, Pten overexpression in Usp13 knockout mice reversed the exacerbation of MASH brought from Usp13 deficiency. CONCLUSIONS Our findings revealed that USP13 alleviates MASH by directly binding to and deubiquitinating PTEN. The USP13-PTEN axis may represent a promising molecular target for MASH treatment.
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Affiliation(s)
- Min Tang
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Endocrinology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaohui Wei
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yunqin Ma
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yijiong Tan
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Han Cao
- Department of Endocrinology and Metabolism, Shanghai General Hospital of Nanjing Medical University, Shanghai, China; Department of Endocrinology, Songjiang District Central Hospital, Shanghai, China
| | - Shuangshuang Yao
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiaqi Wang
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hua Yang
- Department of Endocrinology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Fang Liu
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongde Peng
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Endocrinology and Metabolism, Shanghai General Hospital of Nanjing Medical University, Shanghai, China.
| | - Nengguang Fan
- Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Zanini BM, de Avila BM, Garcia DN, Hense JD, Veiga GB, Barreto MM, Ashiqueali S, Mason JB, Yadav H, Masternak M, Schneider A. Dynamics of serum exosome microRNA profile altered by chemically induced estropause and rescued by estrogen therapy in female mice. GeroScience 2024; 46:5891-5909. [PMID: 38499957 PMCID: PMC11493931 DOI: 10.1007/s11357-024-01129-9] [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: 01/10/2024] [Accepted: 03/09/2024] [Indexed: 03/20/2024] Open
Abstract
The decline in the ovarian reserve leads to menopause and reduced serum estrogens. MicroRNAs are small non-coding RNAs, which can regulate gene expression and be secreted by cells and trafficked in serum via exosomes. Serum miRNAs regulate tissue function and disease development. Therefore, the aim of this study was to identify miRNA profiles in serum exosomes of mice induced to estropause and treated with 17β-estradiol (E2). Female mice were divided into three groups including control (CTL), injected with 4-Vinylcyclohexene diepoxide (VCD), and injected with VCD plus E2 (VCD + E2). Estropause was confirmed by acyclicity and a significant reduction in the number of ovarian follicles (p < 0.05). Body mass gain during estropause was higher in VCD and VCD + E2 compared to CTL females (p = 0.02). Sequencing of miRNAs was performed from exosomes extracted from serum, and 402 miRNAs were detected. Eight miRNAs were differentially regulated between CTL and VCD groups, seven miRNAs regulated between CTL and VCD + E2 groups, and ten miRNAs regulated between VCD and VCD + E2 groups. Only miR-200a-3p and miR-200b-3p were up-regulated in both serum exosomes and ovarian tissue in both VCD groups, suggesting that these exosomal miRNAs could be associated with ovarian activity. In the hepatic tissue, only miR-370-3p (p = 0.02) was up-regulated in the VCD + E2 group, as observed in serum. Our results suggest that VCD-induced estropause and E2 replacement have an impact on the profile of serum exosomal miRNAs. The miR-200 family was increased in serum exosomes and ovarian tissue and may be a candidate biomarker of ovarian function.
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Affiliation(s)
| | | | | | - Jéssica Damé Hense
- Faculdade de Nutrição, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | | | | | - Sarah Ashiqueali
- College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL, USA
| | - Jeffrey B Mason
- College of Veterinary Medicine, Department of Veterinary Clinical and Life Sciences, Center for Integrated BioSystems, Utah State University, Logan, UT, USA
| | - Hariom Yadav
- USF Center for Microbiome Research, and Department of Neurosurgery and Brain Repair, Microbiomes Institute, University of South Florida, Tampa, FL, USA
| | - Michal Masternak
- Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA
- Department of Head and Neck Surgery, Poznan University of Medical Sciences, Poznan, Poland
| | - Augusto Schneider
- Faculdade de Nutrição, Universidade Federal de Pelotas, Pelotas, RS, Brazil.
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Almohawes ZN, El-Kott A, Morsy K, Shati AA, El-Kenawy AE, Khalifa HS, Elsaid FG, Abd-Lateif AEKM, Abu-Zaiton A, Ebealy ER, Abdel-Daim MM, Ghanem RA, Abd-Ella EM. Salidroside inhibits insulin resistance and hepatic steatosis by downregulating miR-21 and subsequent activation of AMPK and upregulation of PPARα in the liver and muscles of high fat diet-fed rats. Arch Physiol Biochem 2024; 130:257-274. [PMID: 35061559 DOI: 10.1080/13813455.2021.2024578] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/15/2021] [Accepted: 12/27/2021] [Indexed: 02/06/2023]
Abstract
This study evaluated if salidroside (SAL) alleviates high-fat diet (HFD)-induced non-alcoholic fatty liver disease (NAFLD) by downregulating miR-21. Rats (n = 8/group) were treated for 12 weeks as normal diet (control/ND), ND + agmoir negative control (NC) (150 µg/kg), ND + SAL (300 mg/kg), HFD, HFD + SAL, HFD + compound C (an AMPK inhibitor) (200 ng/kg), HFD + SAL + NXT629 (a PPAR-α antagonist) (30 mg/kg), and HFD + SAL + miR-21 agomir (150 µg/kg). SAL improved glucose and insulin tolerance and preserved livers in HFD-fed rats. In ND and HFD-fed rats, SAL reduced levels of serum and hepatic lipids and the hepatic expression of SREBP1, SREBP2, fatty acid (FA) synthase, and HMGCOAR. It also activated hepatic Nrf2 and increased hepatic/muscular activity of AMPK and levels of PPARα. All effects afforded by SAL were prevented by CC, NXT629, and miR-21 agmoir. In conclusion, activation of AMPK and upregulation of PPARα mediate the anti-steatotic effect of SAL.
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Affiliation(s)
- Zakiah N Almohawes
- Biology Department, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Attalla El-Kott
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
- Zoology Department, College of Science, Damanhour University, Damanhour, Egypt
| | - Kareem Morsy
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
- Zoology Department, College of Science, Cairo University, Cairo, Egypt
| | - Ali A Shati
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Ayman E El-Kenawy
- Pathology Department, College of Medicine, Taif University, Taif, Saudi Arabia
| | - Heba S Khalifa
- Zoology Department, College of Science, Damanhour University, Damanhour, Egypt
| | - Fahmy G Elsaid
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | | | | | - Eman R Ebealy
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Mohamed M Abdel-Daim
- Pharmaceutical Sciences Department, Pharmacy Program, Batterjee Medical College, Jeddah, Saudi Arabia
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Reham A Ghanem
- Oral Biology Department, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Gamasa, Egypt
| | - Eman M Abd-Ella
- Zoology Department, College of Science, Fayoum University, Fayoum, Egypt
- Biology Department, College of Science and Art, Al-Baha University, Al-Mandaq, Saudi Arabia
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Tsota M, Giardoglou P, Mentsiou-Nikolaou E, Symianakis P, Kalafati IP, Kyriazopoulou-Korovesi AA, Angelidakis L, Papaioannou M, Konstantaki C, Stamatelopoulos K, Dedoussis GV. Investigation of Antihypertensive Properties of Chios Mastic via Monitoring microRNA-21 Expression Levels in the Plasma of Well-Controlled Hypertensive Patients. Noncoding RNA 2024; 10:33. [PMID: 38921830 PMCID: PMC11207086 DOI: 10.3390/ncrna10030033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 05/27/2024] [Accepted: 05/29/2024] [Indexed: 06/27/2024] Open
Abstract
Hypertension is a chronic, multifactorial disease, leading to high cardiovascular morbidity and mortality globally. Despite the advantages of pharmaceutical treatments, natural products have gained scientific interest due to their emerging phytotherapeutic properties. Chios mastic is a natural Greek product, consisting of bioactive compounds which modify microRNAs' (small, expression-regulating molecules) expression. In this study, we investigated the antihypertensive properties of Chios mastic through the assessment of miR-21 levels. Herein, plasma samples of 57 individuals with hypertension, recruited for the purposes of the HYPER-MASTIC study, were analyzed. This was a clinical trial with Chios mastic supplements in which the patients were divided into groups receiving high and low mastic doses and placebo supplements, respectively. miR-21 was significantly upregulated in patients compared to normotensive individuals. Mean changes in miR-21 levels were statistically significant, after adjusting for sex and age, between the placebo and low-dose group and between the low- and high-dose group. Post-intervention miR-21 levels were positively associated with night-time systolic blood pressure, pulse pressure, and central systolic mean arterial pressure and negatively associated with night-time pulse wave velocity in the low-dose group. Our findings suggest a potential implication of miR-21 in the association of Chios mastic with night-time blood pressure measurements.
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Affiliation(s)
- Maria Tsota
- Department of Nutrition-Dietetics, School of Health Science and Education, Harokopio University, 17676 Athens, Greece; (M.T.); (E.M.-N.)
| | - Panagiota Giardoglou
- Department of Nutrition-Dietetics, School of Health Science and Education, Harokopio University, 17676 Athens, Greece; (M.T.); (E.M.-N.)
| | - Evangelia Mentsiou-Nikolaou
- Department of Nutrition-Dietetics, School of Health Science and Education, Harokopio University, 17676 Athens, Greece; (M.T.); (E.M.-N.)
| | - Panagiotis Symianakis
- Department of Nutrition-Dietetics, School of Health Science and Education, Harokopio University, 17676 Athens, Greece; (M.T.); (E.M.-N.)
| | - Ioanna Panagiota Kalafati
- Department of Nutrition-Dietetics, School of Health Science and Education, Harokopio University, 17676 Athens, Greece; (M.T.); (E.M.-N.)
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.-A.K.-K.); (K.S.)
| | | | - Lasthenis Angelidakis
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.-A.K.-K.); (K.S.)
| | - Maria Papaioannou
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.-A.K.-K.); (K.S.)
| | - Christina Konstantaki
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.-A.K.-K.); (K.S.)
| | - HYPER-MASTIC Consortium
- Department of Nutrition-Dietetics, School of Health Science and Education, Harokopio University, 17676 Athens, Greece; (M.T.); (E.M.-N.)
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.-A.K.-K.); (K.S.)
- Department of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece
- Department of Biology, National and Kapodistrian University of Athens, 15772 Athens, Greece
| | - Kimon Stamatelopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (A.-A.K.-K.); (K.S.)
| | - George V. Dedoussis
- Department of Nutrition-Dietetics, School of Health Science and Education, Harokopio University, 17676 Athens, Greece; (M.T.); (E.M.-N.)
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6
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Tian Y, Zhang M, Liu LX, Wang ZC, Liu B, Huang Y, Wang X, Ling YZ, Wang F, Feng X, Tu Y. Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis. Front Immunol 2024; 15:1400744. [PMID: 38799446 PMCID: PMC11116607 DOI: 10.3389/fimmu.2024.1400744] [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: 03/14/2024] [Accepted: 04/03/2024] [Indexed: 05/29/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.
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Affiliation(s)
- Yu Tian
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
- School of Public Health, Benedictine University, Lisle, IL, United States
| | - Meng Zhang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hebei University, Baoding, China
| | - Li-xia Liu
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Zi-chao Wang
- Department of Ultrasound, Hebei Key Laboratory of Precise Imaging of Inflammation Related Tumors, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Bin Liu
- Central Laboratory, Hebei Key Laboratory of Cancer Radiotherapy and Chemotherapy, Affiliated Hospital of Hebei University, Baoding, Hebei, China
| | - Youcai Huang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoling Wang
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Yun-zhi Ling
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Furong Wang
- Department of Pathology, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People’s Hospital, Gaozhou, Guangdong, China
| | - Yanyang Tu
- Research Center, The Huizhou Central People’s Hospital, Guangdong Medical University, Huizhou, Guangdong, China
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Abdel-Wahab BA, El-Shoura EAM, Habeeb MS, Zaafar D. Dapagliflozin alleviates arsenic trioxide-induced hepatic injury in rats via modulating PI3K/AkT/mTOR, STAT3/SOCS3/p53/MDM2 signaling pathways and miRNA-21, miRNA-122 expression. Int Immunopharmacol 2024; 127:111325. [PMID: 38070468 DOI: 10.1016/j.intimp.2023.111325] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 11/27/2023] [Accepted: 11/27/2023] [Indexed: 01/18/2024]
Abstract
Dapagliflozin (DPG) is a sodium-glucose co-transporter 2 inhibitor that is commonly used in the treatment of type 2 diabetes. However, studies have shown that DPG has a protective effect under a variety of experimental conditions through its antioxidative and anti-inflammatory properties. DPG's effect on experimental hepatotoxicity caused by arsenic trioxide (ATO) has yet to be investigated. The purpose of this study was to investigate the protective effect of DPG in preventing hepatic damage caused by ATO and discover the underlying mechanisms. The effect of DPG (1 mg/kg, orally) on ATO (5 mg/kg, i.p.)-induced hepatic injury was evaluated in rats. Serum liver function parameters, as well as oxidative stress biomarkers and inflammatory cytokine levels were assessed. Histopathological changes in the liver were detected using H&E staining. Using Western blotting and PCR techniques, the molecular mechanisms of DPG in ameliorating hepatic injury were investigated. DPG improved liver function by inhibiting histopathological changes, decreasing levels of hepatic function and toxicity parameters measured in both serum and tissues, and exhibiting antioxidant and anti-inflammatory effects, according to the findings. Consistent with the PCR results, DPG also decreased the expression of LC3-II, micro-RNA-122, and micro-RNA-21 while increased the expression of SOCS3. Furthermore, according to western blotting results, DPG was able to reduce the protein expression of AKT, mTOR, PI3K, and STAT3. Although further clinical research is necessary, this study highlights the potential of DPG in preventing liver damage in a rat model of hepatotoxicity induced by ATO.
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Affiliation(s)
- Basel A Abdel-Wahab
- Department of Pharmacology, College of Pharmacy, Najran University, Najran P.O. Box 1988, Saudi Arabia.
| | - Ehab A M El-Shoura
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
| | - Mohammed S Habeeb
- Department of Pharmacology, College of Pharmacy, Najran University, Najran P.O. Box 1988, Saudi Arabia.
| | - Dalia Zaafar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology, and Information, Cairo, Egypt.
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Zhao Y, Zhang X, An M, Zhang J, Liu Y. Recent advancements in nanomedicine based lipid metabolism for tumour immunotherapy. J Drug Target 2023; 31:1050-1064. [PMID: 37962291 DOI: 10.1080/1061186x.2023.2283829] [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: 07/03/2023] [Accepted: 11/09/2023] [Indexed: 11/15/2023]
Abstract
Therapy on lipid metabolism is emerging as a groundbreaking cancer treatment, offering the unprecedented opportunity to effectively treat and in several cases. Tumorigenesis is inextricably linked to lipid metabolism. In this regard, the features of lipid metabolism include lipid synthesis, decomposition, metabolism and lipid storage and mobilisation from intracellular lipid droplets. Most importantly, the regulation of lipid metabolism is central to the appropriate immune response of tumour cells, and ultimately to exert the immune efforts to realise the perspective of many anti-tumour effects. Different cancers and immune cells have different dependence on lipid metabolism, playing a pivotal role in differentiation and function of immune cells. However, what lies before the immunotherapy targeting lipid metabolism is side effects of systemic toxicity and defects of individual drugs, which strongly highlights that nanodelivery strategy is a magnet for it to enhance drug efficiency, reduce drug toxicity and improve application deficiencies. This review will first focus on emerging research progress of lipid metabolic reprogramming mechanism, and then explore the complex role of lipid metabolism in the tumour cells including the effect on immune cells and their nano-preparations of monotherapy and multiple therapies used in combination, in a shift away from conventional cancer research.HighlightsThe regulation of lipid metabolism is central to the appropriate immune response of tumour cells, and ultimately to exert the immune efforts to realise the perspective of many anti-tumour effects.Preparations of focusing lipid metabolism have side effects of systemic toxicity and defects of individual drugs. It strongly highlights that nanodelivery strategy is a magnet for it to enhance drug efficiency, reduce drug toxicity and improve application deficiencies.This review will first focus on emerging research progress of lipid metabolic reprogramming mechanism, and then explore the complex role of lipid metabolism in the tumour cells including the effect on immune cells as well as their nano-preparations of monotherapy and multiple therapies used in combination, in a shift away from conventional cancer research.
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Affiliation(s)
- Yumeng Zhao
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Xiaojie Zhang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Min An
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Juntao Zhang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
| | - Yanhua Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan, China
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9
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Deng X, Niu L, Xiao J, Guo Q, Liang J, Tang J, Liu X, Xiao C. Involvement of intestinal flora and miRNA into the mechanism of coarse grains improving type 2 diabetes: an overview. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2023; 103:4257-4267. [PMID: 36224106 DOI: 10.1002/jsfa.12270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/09/2022] [Accepted: 10/12/2022] [Indexed: 06/06/2023]
Abstract
The prevalence of type 2 diabetes has been growing at an increasing rate worldwide. Dietary therapy is probably the easiest and least expensive method to prevent and treat diabetes. Previous studies have reported that coarse grains have anti-diabetic effects. Although considerable efforts have been made on the anti-diabetic function of different grains, the mechanisms of coarse grains on type 2 diabetes have not been systematically compared and summarized so far. Intestinal flora, reported as the main 'organ' of action underlying coarse grains, is an important factor in the alleviation of type 2 diabetes by coarse grains. Furthermore, microRNA (miRNA), as a new disease marker and 'dark nutrient', plays a likely influential role in cross-border communication among coarse grains, intestinal flora, and hosts. Given this context, this article reviews several possible mechanisms for the role of coarse grains on diabetes, incorporating resistance to inflammation and oxidative stress, repair of insulin signaling and β-cell dysfunction, and highlights the regulation of intestinal flora disorders and miRNAs expression, along with some novel insights. © 2022 Society of Chemical Industry.
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Affiliation(s)
- Xu Deng
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Li Niu
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Jing Xiao
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Qianqian Guo
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Jiayi Liang
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Jiayu Tang
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Xuebo Liu
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
| | - Chunxia Xiao
- College of Food Science and Engineering, Northwest A&F University, Yangling, China
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Sundrani D, Karkhanis A, Randhir K, Panchanadikar T, Joshi S. MicroRNAs targeting peroxisome proliferator-activated receptor (PPAR) gene are differentially expressed in low birth weight placentae. Placenta 2023; 139:51-60. [PMID: 37311266 DOI: 10.1016/j.placenta.2023.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 05/23/2023] [Accepted: 06/07/2023] [Indexed: 06/15/2023]
Abstract
INTRODUCTION Peroxisome proliferator-activated receptors (PPARs) are activated by natural ligands like fatty acids and influence placental angiogenesis and pregnancy outcome. However, the underlying molecular mechanisms are not clear. This study aims to investigate the association of maternal and placental fatty acid levels with DNA methylation and microRNA regulation of PPARs in the placentae of women delivering low birth weight (LBW) babies. METHODS This study includes 100 women delivering normal birth weight (NBW) baby and 70 women delivering LBW baby. Maternal and placental fatty acids levels were estimated by gas chromatograph. Gene promoter methylation and mRNA expression of PPARs was analyzed using Epitect Methyl-II PCR assay kit and RT-PCR respectively. Expression of miRNAs targeting PPAR mRNA were analyzed using a Qiagen miRCURY LNA PCR Array on RT-PCR. RESULTS Placental docosahexaenoic acid (DHA) levels and placental mRNA expression of PPARα and PPARγ were lower (p < 0.05 for all) in the LBW group. Differential expression of miRNAs (upregulated miR-33a-5p and miR-22-5p; downregulated miR-301a-5p, miR-518d-5p, miR-27b-5p, miR-106a-5p, miR-21-5p, miR-548d-5p, miR-17-5p and miR-20a-5p) (p < 0.05 for all) was observed in the LBW group. Maternal and placental polyunsaturated fatty acids and total omega-3 fatty acids were positively associated while saturated fatty acids were negatively associated with expression of miRNAs (p < 0.05 for all). Placental expression of miRNAs were positively associated with birth weight (p < 0.05 for all). DISCUSSION Our data suggests that maternal fatty acid status is associated with changes in the placental expression of miRNAs targeting PPAR gene in women delivering LBW babies.
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Affiliation(s)
- Deepali Sundrani
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune, 411043, India.
| | - Aishwarya Karkhanis
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune, 411043, India
| | - Karuna Randhir
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune, 411043, India
| | - Tushar Panchanadikar
- Department of Obstetrics and Gynecology, Bharati Medical College and Hospital, Bharati Vidyapeeth (Deemed to be University), Pune, 411043, India
| | - Sadhana Joshi
- Mother and Child Health, Interactive Research School for Health Affairs, Bharati Vidyapeeth (Deemed to be University), Pune, 411043, India
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Ye M, Fan S, Li X, Yang S, Ji C, Ji F, Zhou B. Four flavonoids from propolis ameliorate free fatty acids-induced non-alcoholic steatohepatitis in HepG2 cells: Involvement of enhanced AMPK activation, mTOR-NF-κBp65 interaction, and PTEN expression. J Funct Foods 2023. [DOI: 10.1016/j.jff.2023.105460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023] Open
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12
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Nguyen Huu T, Park J, Zhang Y, Duong Thanh H, Park I, Choi JM, Yoon HJ, Park SC, Woo HA, Lee SR. The Role of Oxidative Inactivation of Phosphatase PTEN and TCPTP in Fatty Liver Disease. Antioxidants (Basel) 2023; 12:antiox12010120. [PMID: 36670982 PMCID: PMC9854873 DOI: 10.3390/antiox12010120] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/05/2023] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are becoming increasingly prevalent worldwide. Despite the different etiologies, their spectra and histological feature are similar, from simple steatosis to more advanced stages such as steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Studies including peroxiredoxin knockout models revealed that oxidative stress is crucial in these diseases, which present as consequences of redox imbalance. Protein tyrosine phosphatases (PTPs) are a superfamily of enzymes that are major targets of reactive oxygen species (ROS) because of an oxidation-susceptible nucleophilic cysteine in their active site. Herein, we review the oxidative inactivation of two tumor suppressor PTPs, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and T-cell protein tyrosine phosphatase (TCPTP), and their contribution to the pathogenicity of ALD and NAFLD, respectively. This review might provide a better understanding of the pathogenic mechanisms of these diseases and help develop new therapeutic strategies to treat fatty liver disease.
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Affiliation(s)
- Thang Nguyen Huu
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun 58 128, Republic of Korea
| | - Jiyoung Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Ying Zhang
- Department of Cell Biology, School of Medicine, Jiangsu University, Zhenjiang 212013, China
| | - Hien Duong Thanh
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University Medical School, Hwasun 58 128, Republic of Korea
- Department of Anatomy, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Iha Park
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Jin Myung Choi
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Hyun Joong Yoon
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
| | - Sang Chul Park
- The Future Life and Society Research Center, Advanced Institute of Aging Science, Chonnam National University, Gwangju 61469, Republic of Korea
| | - Hyun Ae Woo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea
| | - Seung-Rock Lee
- Department of Biochemistry, Department of Biomedical Sciences, Research Center for Aging and Geriatrics, Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju 61469, Republic of Korea
- Correspondence: ; Tel.: +82-61-379-2775; Fax: +82-61-379-2782
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13
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Ngum JA, Tatang FJ, Toumeni MH, Nguengo SN, Simo USF, Mezajou CF, Kameni C, Ngongang NN, Tchinda MF, Dongho Dongmo FF, Akami M, Ngane Ngono AR, Tamgue O. An overview of natural products that modulate the expression of non-coding RNAs involved in oxidative stress and inflammation-associated disorders. Front Pharmacol 2023; 14:1144836. [PMID: 37168992 PMCID: PMC10165025 DOI: 10.3389/fphar.2023.1144836] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 03/24/2023] [Indexed: 05/13/2023] Open
Abstract
Oxidative stress is a state in which oxidants are produced in excess in the body's tissues and cells, resulting in a biological imbalance amid the generation of reactive oxygen and nitrogen species (RONS) from redox reactions. In case of insufficient antioxidants to balance, the immune system triggers signaling cascades to mount inflammatory responses. Oxidative stress can have deleterious effects on major macromolecules such as lipids, proteins, and nucleic acids, hence, Oxidative stress and inflammation are among the multiple factors contributing to the etiology of several disorders such as diabetes, cancers, and cardiovascular diseases. Non-coding RNAs (ncRNAs) which were once referred to as dark matter have been found to function as key regulators of gene expression through different mechanisms. They have dynamic roles in the onset and development of inflammatory and oxidative stress-related diseases, therefore, are potential targets for the control of those diseases. One way of controlling those diseases is through the use of natural products, a rich source of antioxidants that have drawn attention with several studies showing their involvement in combating chronic diseases given their enormous gains, low side effects, and toxicity. In this review, we highlighted the natural products that have been reported to target ncRNAs as mediators of their biological effects on oxidative stress and several inflammation-associated disorders. Those natural products include Baicalein, Tanshinone IIA, Geniposide, Carvacrol/Thymol, Triptolide, Oleacein, Curcumin, Resveratrol, Solarmargine, Allicin, aqueous extract or pulp of Açai, Quercetin, and Genistein. We also draw attention to some other compounds including Zanthoxylum bungeanum, Canna genus rhizome, Fuzi-ganjiang herb pair, Aronia melanocarpa, Peppermint, and Gingerol that are effective against oxidative stress and inflammation-related disorders, however, have no known effect on ncRNAs. Lastly, we touched on the many ncRNAs that were found to play a role in oxidative stress and inflammation-related disorders but have not yet been investigated as targets of a natural product. Shedding more light into these two last points of shadow will be of great interest in the valorization of natural compounds in the control and therapy of oxidative stress- and inflammation-associated disorders.
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14
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Abdel Halim AS, Rudayni HA, Chaudhary AA, Ali MAM. MicroRNAs: Small molecules with big impacts in liver injury. J Cell Physiol 2023; 238:32-69. [PMID: 36317692 DOI: 10.1002/jcp.30908] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/30/2022] [Accepted: 10/14/2022] [Indexed: 11/07/2022]
Abstract
A type of small noncoding RNAs known as microRNAs (miRNAs) fine-tune gene expression posttranscriptionally by binding to certain messenger RNA targets. Numerous physiological processes in the liver, such as differentiation, proliferation, and apoptosis, are regulated by miRNAs. Additionally, there is growing evidence that miRNAs contribute to liver pathology. Extracellular vesicles like exosomes, which contain secreted miRNAs, may facilitate paracrine and endocrine communication between various tissues by changing the gene expression and function of distal cells. The use of stable miRNAs as noninvasive biomarkers was made possible by the discovery of these molecules in body fluids. Circulating miRNAs reflect the conditions of the liver that are abnormal and may serve as new biomarkers for the early detection, prognosis, and evaluation of liver pathological states. miRNAs are appealing therapeutic targets for a range of liver disease states because altered miRNA expression is associated with deregulation of the liver's metabolism, liver damage, liver fibrosis, and tumor formation. This review provides a comprehensive review and update on miRNAs biogenesis pathways and mechanisms of miRNA-mediated gene silencing. It also outlines how miRNAs affect hepatic cell proliferation, death, and regeneration as well as hepatic detoxification. Additionally, it highlights the diverse functions that miRNAs play in the onset and progression of various liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, fibrosis, hepatitis C virus infection, and hepatocellular carcinoma. Further, it summarizes the diverse liver-specific miRNAs, illustrating the potential merits and possible caveats of their utilization as noninvasive biomarkers and appealing therapeutic targets for liver illnesses.
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Affiliation(s)
- Alyaa S Abdel Halim
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hassan Ahmed Rudayni
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Anis Ahmad Chaudhary
- Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.,Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
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15
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Pervez MA, Khan DA, Gilani STA, Fatima S, Ijaz A, Nida S. Hepato-Protective Effects of Delta-Tocotrienol and Alpha-Tocopherol in Patients with Non-Alcoholic Fatty Liver Disease: Regulation of Circulating MicroRNA Expression. Int J Mol Sci 2022; 24:ijms24010079. [PMID: 36613525 PMCID: PMC9820400 DOI: 10.3390/ijms24010079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 12/01/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
MicroRNAs (miRNAs) play a key role in the regulation of genes for normal metabolism in the liver. Dysregulation of miRNAs is involved in the development and progression of non-alcoholic fatty liver disease (NAFLD). We aimed to explore changes in circulating miRNA expression in response to delta-tocotrienol (δT3) and alpha-tocopherol (αTF) supplementation and correlate them with relevant biochemical markers in patients with NAFLD. In total, 100 patients with NAFLD were randomized to either receive δT3 (n = 50) 300 mg or αTF (n = 50) 268 mg twice/day for 48 weeks. Plasma expression of miRNA-122, -21, -103a-2, -421, -375 and -34a were determined at baseline, 24 and 48 weeks of intervention using RT-qPCR. Both δT3 and αTF significantly downregulated expression of miRNA-122, -21, -103a-2, -421, -375 and -34a. Moreover, δT3 was more effective than αTF in reducing expression of miRNA-375 and -34a. A significant correlation was observed between miRNA expression and biochemical markers of hepatic steatosis, insulin resistance (IR), oxidative stress (OS), inflammation and apoptosis. δT3 and αTF exert hepato-protective effects by downregulating miRNAs involved in hepatic steatosis, IR, OS, inflammation and apoptosis in patients with NAFLD. Furthermore, δT3 has more pronounced effects than αTF in reducing miR-375 and miR-34a, which are linked to regulation of inflammation and apoptosis.
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16
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Stearoyl-CoA desaturase 1 as a therapeutic target for cancer: a focus on hepatocellular carcinoma. Mol Biol Rep 2022; 49:8871-8882. [PMID: 35906508 DOI: 10.1007/s11033-021-07094-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 12/16/2021] [Indexed: 01/14/2023]
Abstract
One of the main characteristics of cancer cells is the alteration in lipid composition, which is associated with a significant monounsaturated fatty acids (MUFAs) enrichment. In addition to their structural functions in newly synthesized membranes in proliferating cancer cells, these fatty acids are involved in tumorigenic signaling. Increased expression and activity of stearoyl CoA desaturase (SCD1), i.e., an enzyme converting saturated fatty acids to Δ9-monounsaturated fatty acids, has been observed in various cancer cells. This increase in expression and activity has also been associated with cancer aggressiveness and poor patient outcome. Previous studies have also indicated the SCD1 involvement in increased cancer cells proliferation, growth, migration, epithelial to mesenchymal transition, metastasis, chemoresistance, and maintenance of cancer stem cells properties. Hence, SCD1 seems to be a player in malignancy development and may be considered a novel therapeutic target in cancers, including hepatocellular carcinoma (HCC). This review study aims to discuss the impact of SCD1 as a major component in lipid signaling in HCC.
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17
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Leslie J, Geh D, Elsharkawy AM, Mann DA, Vacca M. Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions. J Hepatol 2022; 77:219-236. [PMID: 35157957 DOI: 10.1016/j.jhep.2022.01.029] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/12/2022] [Accepted: 01/31/2022] [Indexed: 12/16/2022]
Abstract
HCV hijacks many host metabolic processes in an effort to aid viral replication. The resulting hepatic metabolic dysfunction underpins many of the hepatic and extrahepatic manifestations of chronic hepatitis C (CHC). However, the natural history of CHC is also substantially influenced by the host metabolic status: obesity, insulin resistance and hepatic steatosis are major determinants of CHC progression toward hepatocellular carcinoma (HCC). Direct-acting antivirals (DAAs) have transformed the treatment and natural history of CHC. While DAA therapy effectively eradicates the virus, the long-lasting overlapping metabolic disease can persist, especially in the presence of obesity, increasing the risk of liver disease progression. This review covers the mechanisms by which HCV tunes hepatic and systemic metabolism, highlighting how systemic metabolic disturbance, lipotoxicity and chronic inflammation favour disease progression and a precancerous niche. We also highlight the therapeutic implications of sustained metabolic dysfunction following sustained virologic response as well as considerations for patients who develop HCC on the background of metabolic dysfunction.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel Geh
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmed M Elsharkawy
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Queen Elizabeth Medical Centre, Birmingham, B15 2TH UK; National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey.
| | - Michele Vacca
- Interdisciplinary Department of Medicine, Università degli Studi di Bari "Aldo Moro", Bari, Italy.
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18
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Du K, Zou J, Wang B, Liu C, Khan M, Xie T, Huang X, Shen P, Tian Y, Yuan Y. A Metabolism-Related Gene Prognostic Index Bridging Metabolic Signatures and Antitumor Immune Cycling in Head and Neck Squamous Cell Carcinoma. Front Immunol 2022; 13:857934. [PMID: 35844514 PMCID: PMC9282908 DOI: 10.3389/fimmu.2022.857934] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 05/18/2022] [Indexed: 12/26/2022] Open
Abstract
Background In the era of immunotherapy, predictive or prognostic biomarkers for head and neck squamous cell carcinoma (HNSCC) are urgently needed. Metabolic reprogramming in the tumor microenvironment (TME) is a non-negligible reason for the low therapeutic response to immune checkpoint inhibitor (ICI) therapy. We aimed to construct a metabolism-related gene prognostic index (MRGPI) for HNSCC bridging metabolic characteristics and antitumor immune cycling and identified the immunophenotype, genetic alternations, potential targeted inhibitors, and the benefit of immunotherapy in MRGPI-defined subgroups of HNSCC. Methods Based on The Cancer Genome Atlas (TCGA) HNSCC dataset (n = 502), metabolism-related hub genes were identified by the weighted gene co-expression network analysis (WGCNA). Seven genes were identified to construct the MRGPI by using the Cox regression method and validated with an HNSCC dataset (n = 270) from the Gene Expression Omnibus (GEO) database. Afterward, the prognostic value, metabolic activities, genetic alternations, gene set enrichment analysis (GSEA), immunophenotype, Connectivity map (cMAP), and benefit of immunotherapy in MRGPI-defined subgroups were analyzed. Results The MRGPI was constructed based on HPRT1, AGPAT4, AMY2B, ACADL, CKM, PLA2G2D, and ADA. Patients in the low-MRGPI group had better overall survival than those in the high-MRGPI group, consistent with the results in the GEO cohort (cutoff value = 1.01). Patients with a low MRGPI score display lower metabolic activities and an active antitumor immunity status and more benefit from immunotherapy. In contrast, a higher MRGPI score was correlated with higher metabolic activities, more TP53 mutation rate, lower antitumor immunity ability, an immunosuppressive TME, and less benefit from immunotherapy. Conclusion The MRGPI is a promising indicator to distinguish the prognosis, the metabolic, molecular, and immune phenotype, and the benefit from immunotherapy in HNSCC.
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Affiliation(s)
- Kunpeng Du
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Jingwen Zou
- Department of Liver Surgery of the Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Baiyao Wang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Chunshan Liu
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Muhammad Khan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Tao Xie
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Xiaoting Huang
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Piao Shen
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Yunhong Tian
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- *Correspondence: Yunhong Tian, ; Yawei Yuan,
| | - Yawei Yuan
- Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- *Correspondence: Yunhong Tian, ; Yawei Yuan,
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Pandita D, Pandita A. Omics Technology for the Promotion of Nutraceuticals and Functional Foods. Front Physiol 2022; 13:817247. [PMID: 35634143 PMCID: PMC9136416 DOI: 10.3389/fphys.2022.817247] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 03/23/2022] [Indexed: 12/24/2022] Open
Abstract
The influence of nutrition and environment on human health has been known for ages. Phytonutrients (7,000 flavonoids and phenolic compounds; 600 carotenoids) and pro-health nutrients—nutraceuticals positively add to human health and may prevent disorders such as cancer, diabetes, obesity, cardiovascular diseases, and dementia. Plant-derived bioactive metabolites have acquired an imperative function in human diet and nutrition. Natural phytochemicals affect genome expression (nutrigenomics and transcriptomics) and signaling pathways and act as epigenetic modulators of the epigenome (nutri epigenomics). Transcriptomics, proteomics, epigenomics, miRNomics, and metabolomics are some of the main platforms of complete omics analyses, finding use in functional food and nutraceuticals. Now the recent advancement in the integrated omics approach, which is an amalgamation of multiple omics platforms, is practiced comprehensively to comprehend food functionality in food science.
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Affiliation(s)
- Deepu Pandita
- Government Department of School Education, Jammu, India
- *Correspondence: Deepu Pandita,
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Zhao Y, Gao L, Jiang C, Chen J, Qin Z, Zhong F, Yan Y, Tong R, Zhou M, Yuan A, Pu J. The transcription factor zinc fingers and homeoboxes 2 alleviates NASH by transcriptional activation of phosphatase and tensin homolog. Hepatology 2022; 75:939-954. [PMID: 34545586 DOI: 10.1002/hep.32165] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/25/2021] [Accepted: 08/08/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS NASH, which is a common clinical condition predisposing to advanced liver diseases, has become a worldwide epidemic. A large and growing unmet therapeutic need for this condition reflects incomplete understanding of its pathogenesis. In the current study, we identified a transcription factor, zinc fingers and homeoboxes 2 (ZHX2), in hepatocytes as a protective factor against steatohepatitis. APPROACH AND RESULTS We found that hepatic ZHX2 was significantly suppressed in NASH models and steatotic hepatic cells. Hepatocyte-specific ablation of ZHX2 exacerbated NASH-related phenotypes in mice, including lipid accumulation, enhanced inflammation, and hepatic fibrosis. Conversely, hepatocyte-specific overexpression of ZHX2 significantly alleviated the progression of NASH in an experimental setting. Integrated analysis of transcriptomic profiling and chromatin immunoprecipitation sequencing data demonstrated that the phosphatase and tensin homolog (PTEN) was a target gene of ZHX2 in hepatocyte. ZHX2 bound to the promoter of PTEN gene and subsequently promoted the transcription of PTEN, which mediated the beneficial role of ZHX2 against NASH. CONCLUSIONS The current findings demonstrate a protective role of ZHX2 against NASH progression by transcriptionally activating PTEN. These findings shed light on the therapeutic potential of targeting ZHX2 for treating NASH and related metabolic disorders.
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Affiliation(s)
- Yichao Zhao
- State Key Laboratory for Oncogenes and Related GenesDivision of CardiologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Cancer InstituteShanghaiChina
| | - Lingchen Gao
- State Key Laboratory for Oncogenes and Related GenesDivision of CardiologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Cancer InstituteShanghaiChina
| | - Chenglin Jiang
- Graduate School of Bengbu Medical CollegeBengbuAnhuiChina
| | - Jianqing Chen
- Graduate School of Bengbu Medical CollegeBengbuAnhuiChina
| | - Zihan Qin
- State Key Laboratory for Oncogenes and Related GenesDivision of CardiologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Cancer InstituteShanghaiChina
| | - Fangyuan Zhong
- State Key Laboratory for Oncogenes and Related GenesDivision of CardiologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Cancer InstituteShanghaiChina
| | - Yang Yan
- State Key Laboratory for Oncogenes and Related GenesDivision of CardiologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Cancer InstituteShanghaiChina
| | - Renyang Tong
- State Key Laboratory for Oncogenes and Related GenesDivision of CardiologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Cancer InstituteShanghaiChina
| | - Meng Zhou
- State Key Laboratory for Oncogenes and Related GenesDivision of CardiologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Cancer InstituteShanghaiChina
| | - Ancai Yuan
- State Key Laboratory for Oncogenes and Related GenesDivision of CardiologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Cancer InstituteShanghaiChina
| | - Jun Pu
- State Key Laboratory for Oncogenes and Related GenesDivision of CardiologyRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai Cancer InstituteShanghaiChina
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Wang Q, Tan Y, Jiang T, Wang X, Li Q, Li Y, Dong L, Liu X, Xu G. Metabolic Reprogramming and Its Relationship to Survival in Hepatocellular Carcinoma. Cells 2022; 11:cells11071066. [PMID: 35406630 PMCID: PMC8997969 DOI: 10.3390/cells11071066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 01/15/2023] Open
Abstract
Hepatocarcinogenesis is frequently accompanied by substantial metabolic reprogramming to maximize the growth and proliferation of cancer cells. In this study, we carried out a comprehensive study of metabolomics and lipidomics profiles combined with gene expression analysis to characterize the metabolic reprogramming in hepatocellular carcinoma (HCC). Compared with adjacent noncancerous liver tissue, the enhanced aerobic glycolysis and de novo lipogenesis (DNL) and the repressed urea cycle were underscored in HCC tissue. Furthermore, multiscale embedded correlation analysis was performed to construct differential correlation networks and reveal pathologically relevant molecule modules. The obtained hub nodes were further screened according to the maximum biochemical diversity and the least intraclass correlation. Finally, a panel of ornithine, FFA 18:1, PC O-32:1 and TG (18:1_17:1_18:2) was generated to achieve the prognostic risk stratification of HCC patients (p < 0.001 by log-rank test). Altogether, our findings suggest that the metabolic dysfunctions of HCC detected via metabolomics and lipidomics would contribute to a better understanding of clinical relevance of hepatic metabolic reprogramming and provide potential sources for the identification of therapeutic targets and the discovery of biomarkers.
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Affiliation(s)
- Qingqing Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Q.W.); (X.W.); (Q.L.); (Y.L.); (G.X.)
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yexiong Tan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China; (Y.T.); (T.J.)
| | - Tianyi Jiang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China; (Y.T.); (T.J.)
| | - Xiaolin Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Q.W.); (X.W.); (Q.L.); (Y.L.); (G.X.)
| | - Qi Li
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Q.W.); (X.W.); (Q.L.); (Y.L.); (G.X.)
| | - Yanli Li
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Q.W.); (X.W.); (Q.L.); (Y.L.); (G.X.)
| | - Liwei Dong
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, The Second Military Medical University, Shanghai 200438, China; (Y.T.); (T.J.)
- Correspondence: (L.D.); (X.L.); Tel.: +86-411-84379532 (X.L.)
| | - Xinyu Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Q.W.); (X.W.); (Q.L.); (Y.L.); (G.X.)
- Correspondence: (L.D.); (X.L.); Tel.: +86-411-84379532 (X.L.)
| | - Guowang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; (Q.W.); (X.W.); (Q.L.); (Y.L.); (G.X.)
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Differential effects of single fatty acids and fatty acid mixtures on the phosphoinositide 3-kinase/Akt/eNOS pathway in endothelial cells. Eur J Nutr 2022; 61:2463-2473. [PMID: 35157107 PMCID: PMC9279250 DOI: 10.1007/s00394-022-02821-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/25/2022] [Indexed: 12/30/2022]
Abstract
SCOPE Dietary fat composition is an important modulator of vascular function. Non-esterified fatty acids (NEFA) enriched in saturated fatty acids (SFA) are thought to reduce vascular reactivity by attenuating insulin signalling via vasodilator pathways (phosphoinositide 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS)) and enhancing signalling via pro-inflammatory pathways. METHODS To examine the effects of fatty acids on these pathways, human aortic endothelial cells were incubated with single fatty acids, and mixtures of these fatty acids to mimic typical NEFA composition and concentrations achieved in our previous human study. RNA was extracted to determine gene expression using real-time RT-PCR and cell lysates prepared to assess protein phosphorylation by Western blotting. RESULTS Oleic acid (OA, 100 µM) was shown to down regulate expression of the insulin receptor, PTEN and a PI3K catalytic (p110β) and regulatory (p85α) subunit compared to palmitic, linoleic and stearic acids (P < 0.04), and promote greater eNOS phosphorylation at Ser1177. Both concentration and composition of the SFA and SFA plus n-3 polyunsaturated fatty acids (PUFA) mixtures had significant effects on genes involved in the PI3K/Akt pathway. Greater up-regulation was found with 800 than 400 µM concentration (respective of concentrations in insulin resistant and normal individuals), whereas greater down-regulation was evident with SFA plus n-3 PUFA than SFA mixture alone. CONCLUSION Our findings provide novel insights into the modulation of the PI3K/Akt/eNOS pathway by single fatty acids and fatty acid mixtures. In particular, OA appears to promote signalling via this pathway, with further work required to determine the primary molecular site(s) of action.
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Pérez-García A, Torrecilla-Parra M, Fernández-de Frutos M, Martín-Martín Y, Pardo-Marqués V, Ramírez CM. Posttranscriptional Regulation of Insulin Resistance: Implications for Metabolic Diseases. Biomolecules 2022; 12:biom12020208. [PMID: 35204710 PMCID: PMC8961590 DOI: 10.3390/biom12020208] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 12/14/2022] Open
Abstract
Insulin resistance defines an impairment in the biologic response to insulin action in target tissues, primarily the liver, muscle, adipose tissue, and brain. Insulin resistance affects physiology in many ways, causing hyperglycemia, hypertension, dyslipidemia, visceral adiposity, hyperinsulinemia, elevated inflammatory markers, and endothelial dysfunction, and its persistence leads to the development metabolic disease, including diabetes, obesity, cardiovascular disease, or nonalcoholic fatty liver disease (NAFLD), as well as neurological disorders such as Alzheimer’s disease. In addition to classical transcriptional factors, posttranscriptional control of gene expression exerted by microRNAs and RNA-binding proteins constitutes a new level of regulation with important implications in metabolic homeostasis. In this review, we describe miRNAs and RBPs that control key genes involved in the insulin signaling pathway and related regulatory networks, and their impact on human metabolic diseases at the molecular level, as well as their potential use for diagnosis and future therapeutics.
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MacDonald-Ramos K, Martínez-Ibarra A, Monroy A, Miranda-Ríos J, Cerbón M. Effect of Dietary Fatty Acids on MicroRNA Expression Related to Metabolic Disorders and Inflammation in Human and Animal Trials. Nutrients 2021; 13:1830. [PMID: 34072137 PMCID: PMC8226960 DOI: 10.3390/nu13061830] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/02/2021] [Accepted: 04/06/2021] [Indexed: 12/18/2022] Open
Abstract
Dietary fatty acids (DFAs) play key roles in different metabolic processes in humans and other mammals. DFAs have been considered beneficial for health, particularly polyunsaturated (PUFAs) and monounsaturated fatty acids (MUFAs). Additionally, microRNAs (miRNAs) exert their function on DFA metabolism by modulating gene expression, and have drawn great attention for their potential as biomarkers and therapeutic targets. This review explicitly examined the effects of DFAs on miRNA expression associated with metabolic diseases, such as obesity, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease (CVD), as well as inflammation, published in the last ten years. DFAs have been shown to induce and repress miRNA expression associated with metabolic disease and inflammation in different cell types and organisms, both in vivo and in vitro, depending on varying combinations of DFAs, doses, and the duration of treatment. However, studies are limited and heterogeneous in methodology. Additionally, recent studies demonstrated that high fat ketogenic diets, many enriched with saturated fats, do not increase serum saturated fat content in humans, and are not associated with increased inflammation. Thus, these findings shed light on the complexity of novel treatment and DFA interventions for metabolic disease and to maintain health. Further studies are needed to advance molecular therapeutic approaches, including miRNA-based strategies in human health and disease.
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Affiliation(s)
- Karla MacDonald-Ramos
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología “Isidro Espinosa de los Reyes”-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico; (K.M.-R.); (A.M.-I.)
| | - Alejandra Martínez-Ibarra
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología “Isidro Espinosa de los Reyes”-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico; (K.M.-R.); (A.M.-I.)
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México 04960, Mexico
| | - Adriana Monroy
- Servicio de Oncología, Hospital General de México Dr. Eduardo Liceaga, Ciudad de México 06720, Mexico;
| | - Juan Miranda-Ríos
- Unidad de Genética de la Nutrición, Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México, Ciudad de México 04530, Mexico;
- Instituto Nacional de Pediatría, Ciudad de México 04530, Mexico
| | - Marco Cerbón
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología “Isidro Espinosa de los Reyes”-Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 11000, Mexico; (K.M.-R.); (A.M.-I.)
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Amorim R, Simões ICM, Veloso C, Carvalho A, Simões RF, Pereira FB, Thiel T, Normann A, Morais C, Jurado AS, Wieckowski MR, Teixeira J, Oliveira PJ. Exploratory Data Analysis of Cell and Mitochondrial High-Fat, High-Sugar Toxicity on Human HepG2 Cells. Nutrients 2021; 13:nu13051723. [PMID: 34069635 PMCID: PMC8161147 DOI: 10.3390/nu13051723] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/06/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH), one of the deleterious stages of non-alcoholic fatty liver disease, remains a significant cause of liver-related morbidity and mortality worldwide. In the current work, we used an exploratory data analysis to investigate time-dependent cellular and mitochondrial effects of different supra-physiological fatty acids (FA) overload strategies, in the presence or absence of fructose (F), on human hepatoma-derived HepG2 cells. We measured intracellular neutral lipid content and reactive oxygen species (ROS) levels, mitochondrial respiration and morphology, and caspases activity and cell death. FA-treatments induced a time-dependent increase in neutral lipid content, which was paralleled by an increase in ROS. Fructose, by itself, did not increase intracellular lipid content nor aggravated the effects of palmitic acid (PA) or free fatty acids mixture (FFA), although it led to an up-expression of hepatic fructokinase. Instead, F decreased mitochondrial phospholipid content, as well as OXPHOS subunits levels. Increased lipid accumulation and ROS in FA-treatments preceded mitochondrial dysfunction, comprising altered mitochondrial membrane potential (ΔΨm) and morphology, and decreased oxygen consumption rates, especially with PA. Consequently, supra-physiological PA alone or combined with F prompted the activation of caspase pathways leading to a time-dependent decrease in cell viability. Exploratory data analysis methods support this conclusion by clearly identifying the effects of FA treatments. In fact, unsupervised learning algorithms created homogeneous and cohesive clusters, with a clear separation between PA and FFA treated samples to identify a minimal subset of critical mitochondrial markers in order to attain a feasible model to predict cell death in NAFLD or for high throughput screening of possible therapeutic agents, with particular focus in measuring mitochondrial function.
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Affiliation(s)
- Ricardo Amorim
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
- CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Inês C. M. Simões
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland; (I.C.M.S.); (M.R.W.)
| | - Caroline Veloso
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
| | - Adriana Carvalho
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Rui F. Simões
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Francisco B. Pereira
- Center for Informatics and Systems, University of Coimbra, Polo II, Pinhal de Marrocos, 3030-290 Coimbra, Portugal;
- Coimbra Polytechnic-ISEC, 3030-190 Coimbra, Portugal
| | - Theresa Thiel
- Mediagnostic, D-72770 Reutlingen, Germany; (T.T.); (A.N.)
| | - Andrea Normann
- Mediagnostic, D-72770 Reutlingen, Germany; (T.T.); (A.N.)
| | - Catarina Morais
- Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal; (C.M.); (A.S.J.)
| | - Amália S. Jurado
- Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal; (C.M.); (A.S.J.)
| | - Mariusz R. Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland; (I.C.M.S.); (M.R.W.)
| | - José Teixeira
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
- CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Paulo J. Oliveira
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
- Correspondence:
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Wang X, He Y, Mackowiak B, Gao B. MicroRNAs as regulators, biomarkers and therapeutic targets in liver diseases. Gut 2021; 70:784-795. [PMID: 33127832 DOI: 10.1136/gutjnl-2020-322526] [Citation(s) in RCA: 277] [Impact Index Per Article: 69.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/01/2020] [Accepted: 10/09/2020] [Indexed: 12/11/2022]
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding to specific mRNA targets and promoting their degradation and/or translational inhibition. miRNAs regulate both physiological and pathological liver functions. Altered expression of miRNAs is associated with liver metabolism dysregulation, liver injury, liver fibrosis and tumour development, making miRNAs attractive therapeutic strategies for the diagnosis and treatment of liver diseases. Here, we review recent advances regarding the regulation and function of miRNAs in liver diseases with a major focus on miRNAs that are specifically expressed or enriched in hepatocytes (miR-122, miR-194/192), neutrophils (miR-223), hepatic stellate cells (miR-29), immune cells (miR-155) and in circulation (miR-21). The functions and target genes of these miRNAs are emphasised in alcohol-associated liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, viral hepatitis and hepatocellular carcinoma, as well liver fibrosis and liver failure. We touch on the roles of miRNAs in intercellular communication between hepatocytes and other types of cells via extracellular vesicles in the pathogenesis of liver diseases. We provide perspective on the application of miRNAs as biomarkers for early diagnosis, prognosis and assessment of liver diseases and discuss the challenges in miRNA-based therapy for liver diseases. Further investigation of miRNAs in the liver will help us better understand the pathogeneses of liver diseases and may identify biomarkers and therapeutic targets for liver diseases in the future.
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Affiliation(s)
- Xiaolin Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bryan Mackowiak
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
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Porcine circovirus type 2 infection activates NF-κB pathway and cellular inflammatory responses through circPDCD4/miR-21/PDCD4 axis in porcine kidney 15 cell. Virus Res 2021; 298:198385. [PMID: 33713752 DOI: 10.1016/j.virusres.2021.198385] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/03/2021] [Accepted: 03/05/2021] [Indexed: 12/12/2022]
Abstract
Porcine circovirus type 2 (PCV2) causes postweaning multisystemic wasting syndrome (PMWS) as well as other PCV-associated diseases (PCVADs), which seriously affect the development of the swine industry. The association between aberrant expression of microRNA-21 (miR-21) and the pathogenesis of inflammatory diseases is already known. Also, our previous study showed elevated ssc-miR-21-5p (miR-21) levels in PCV2-infected porcine kidney 15 (PK-15) cells. However, the functional expression of miR-21 in PCV2 infection is unknown. Here, we found that the miR-21 levels were substantially upregulated in PCV2-infected cells, while the expression of PDCD4 and a PDCD4-derived circRNA (circPDCD4) were downregulated compared with the noninfected cells. The results of RNA immunoprecipitation and dual-luciferase reporter (DLR) assay revealed that circPDCD4 acted as a miR-21 sponge and PDCD4 was a miR-21 target. Functionally, we found that miR-21 overexpression induced the NF-κB pathway along with inflammation in cells exposed to PCV2. Further, the overexpression of PDCD4 or circPDCD4 downregulated miR-21 levels and subsequently, attenuated the miR-21-induced activation of inflammation and the NF-κB pathway. Thus, PCV2 activated the NF-κB pathway and cellular inflammatory responses through regulating circPDCD4, miR-21, and PDCD4 in PK-15 cells.
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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Hwang S, Yun H, Moon S, Cho YE, Gao B. Role of Neutrophils in the Pathogenesis of Nonalcoholic Steatohepatitis. Front Endocrinol (Lausanne) 2021; 12:751802. [PMID: 34707573 PMCID: PMC8542869 DOI: 10.3389/fendo.2021.751802] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/23/2021] [Indexed: 12/18/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of liver disorders, from fatty liver to nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. Compared with fatty liver, NASH is characterized by increased liver injury and inflammation, in which liver-infiltrating immune cells, with neutrophil infiltration as a hallmark of NASH, play a critical role in promoting the progression of fatty liver to NASH. Neutrophils are the first responders to injury and infection in various tissues, establishing the first line of defense through multiple mechanisms such as phagocytosis, cytokine secretion, reactive oxygen species production, and neutrophil extracellular trap formation; however, their roles in the pathogenesis of NASH remain obscure. The current review summarizes the roles of neutrophils that facilitate the progression of fatty liver to NASH and their involvement in inflammation resolution during NASH pathogenesis. The notion that neutrophils are potential therapeutic targets for the treatment of NASH is also discussed.
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Affiliation(s)
- Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea
| | - Hwayoung Yun
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea
| | - Sungwon Moon
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea
| | - Ye Eun Cho
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, South Korea
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
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Belisario DC, Kopecka J, Pasino M, Akman M, De Smaele E, Donadelli M, Riganti C. Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance. Cells 2020; 9:cells9122598. [PMID: 33291643 PMCID: PMC7761956 DOI: 10.3390/cells9122598] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 02/07/2023] Open
Abstract
Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells.
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Affiliation(s)
- Dimas Carolina Belisario
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy; (D.C.B.); (J.K.); (M.P.); (M.A.)
| | - Joanna Kopecka
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy; (D.C.B.); (J.K.); (M.P.); (M.A.)
| | - Martina Pasino
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy; (D.C.B.); (J.K.); (M.P.); (M.A.)
| | - Muhlis Akman
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy; (D.C.B.); (J.K.); (M.P.); (M.A.)
| | - Enrico De Smaele
- Department of Experimental Medicine, Sapienza University of Roma, 00185 Roma, Italy;
| | - Massimo Donadelli
- Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134 Verona, Italy;
| | - Chiara Riganti
- Department of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy; (D.C.B.); (J.K.); (M.P.); (M.A.)
- Correspondence: ; Tel.: +39-011-670-5857
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Rehman K, Haider K, Jabeen K, Akash MSH. Current perspectives of oleic acid: Regulation of molecular pathways in mitochondrial and endothelial functioning against insulin resistance and diabetes. Rev Endocr Metab Disord 2020; 21:631-643. [PMID: 32125563 DOI: 10.1007/s11154-020-09549-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Insulin resistance (IR) and type 2 diabetes mellitus (T2DM) is a leading cause of deaths due to metabolic disorders in recent years. Molecular mechanisms involved in the initiation and development of IR and T2DM are multiples. The major factors include mitochondrial dysfunction which may cause incomplete fatty acid oxidation (FAO). Oleic acid upregulates the expression of genes causing FAO by deacetylation of PGC1α by PKA-dependent activation of SIRT1-PGC1α complex. Another potent factor for the development of IR and T2DM is endothelial dysfunction as damaged endothelium causes increased release of inflammatory mediators such as TNF-α, IL-6, IL-1β, sVCAM, sICAM, E-selectin and other proinflammatory cytokines. While, on the other hand, oleic acid has the ability to regulate E-selectin, and sICAM expression. Rest of the risk factors may include inflammation, β-cell dysfunction, oxidative stress, hormonal imbalance, apoptosis, and enzyme dysregulation. Here, we have highlighted how oleic acid regulates underlying causatives factors and hence, keeps surpassing effect in prevention and treatment of IR and T2DM. However, the percentage contribution of these factors in combating IR and ultimately averting T2DM is still debatable. Thus, because of its exceptional protective effect, it can be considered as an improved therapeutic agent in prophylaxis and/or treatment of IR and T2DM.
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Affiliation(s)
- Kanwal Rehman
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan.
| | - Kamran Haider
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Komal Jabeen
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
- Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
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A Lipidomic Signature Complements Stemness Features Acquisition in Liver Cancer Cells. Int J Mol Sci 2020; 21:ijms21228452. [PMID: 33182805 PMCID: PMC7709039 DOI: 10.3390/ijms21228452] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/06/2020] [Accepted: 11/09/2020] [Indexed: 12/16/2022] Open
Abstract
Lipid catabolism and anabolism changes play a role in stemness acquisition by cancer cells, and cancer stem cells (CSCs) are particularly dependent on the activity of the enzymes involved in these processes. Lipidomic changes could play a role in CSCs’ ability to cause disease relapse and chemoresistance. The exploration of lipid composition and metabolism changes in CSCs in the context of hepatocellular cancer (HCC) is still incomplete and their lipidomic scenario continues to be elusive. We aimed to evaluate through high-throughput mass spectrometry (MS)-based lipidomics the levels of the members of the six major classes of sphingolipids and phospholipids in two HCC cell lines (HepG2 and Huh-7) silenced for the expression of histone variant macroH2A1 (favoring stemness acquisition), or silenced for the expression of focal adhesion tyrosine kinase (FAK) (hindering aggressiveness and stemness). Transcriptomic changes were evaluated by RNA sequencing as well. We found definite lipidomic and transcriptomic changes in the HCC lines upon knockdown (KD) of macroH2A1 or FAK, in line with the acquisition or loss of stemness features. In particular, macroH2A1 KD increased total sphingomyelin (SM) levels and decreased total lysophosphatidylcholine (LPC) levels, while FAK KD decreased total phosphatidylcholine (PC) levels. In conclusion, in HCC cell lines knocked down for specific signaling/epigenetic processes driving opposite stemness potential, we defined a lipidomic signature that hallmarks hepatic CSCs to be exploited for therapeutic strategies.
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Bai D, Wu Y, Deol P, Nobumori Y, Zhou Q, Sladek FM, Liu X. Palmitic acid negatively regulates tumor suppressor PTEN through T366 phosphorylation and protein degradation. Cancer Lett 2020; 496:127-133. [PMID: 33039560 DOI: 10.1016/j.canlet.2020.10.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 09/19/2020] [Accepted: 10/06/2020] [Indexed: 01/22/2023]
Abstract
Chronic elevated free fatty (FFA) levels are linked to metabolic disorders and tumorigenesis. However, the molecular mechanism by which FFAs induce cancer remains poorly understood. Here, we show that the tumor suppressor PTEN protein levels were decreased in high fat diet (HFD) fed mice. As palmitic acid (PA, C16:0) showed a significant increase in the HFD fed mice, we further investigated its role in PTEN down regulation. Our studies revealed that exposure of cells to high doses of PA induced mTOR/S6K-mediated phosphorylation of PTEN at T366. The phosphorylation subsequently enhanced the interaction of PTEN with the E3 ubiquitin ligase WW domain-containing protein 2 (WWP2), which promoted polyubiquitination of PTEN and protein degradation. Consistent with PTEN degradation, exposure of cells to increased concentrations of PA also promoted PTEN-mediated AKT activation and cell proliferation. Significantly, a higher level of S6K activation, PTEN T366 phosphorylation, and AKT activation were also observed in the livers of the HFD fed mice. These results provide a molecular mechanism by which a HFD and elevated PA regulate cell proliferation through inactivation of tumor suppressor PTEN.
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Affiliation(s)
- Dongmei Bai
- Department of Biochemistry, University of California, Riverside, CA, 92521, USA
| | - Yong Wu
- Department of Biochemistry, University of California, Riverside, CA, 92521, USA
| | - Poonamjot Deol
- Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, 92521, USA
| | - Yumiko Nobumori
- Department of Biochemistry, University of California, Riverside, CA, 92521, USA
| | - Qi Zhou
- Department of Biochemistry, University of California, Riverside, CA, 92521, USA
| | - Frances M Sladek
- Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA, 92521, USA
| | - Xuan Liu
- Department of Biochemistry, University of California, Riverside, CA, 92521, USA.
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Sobolewski C, Abegg D, Berthou F, Dolicka D, Calo N, Sempoux C, Fournier M, Maeder C, Ay AS, Clavien PA, Humar B, Dufour JF, Adibekian A, Foti M. S100A11/ANXA2 belongs to a tumour suppressor/oncogene network deregulated early with steatosis and involved in inflammation and hepatocellular carcinoma development. Gut 2020; 69:1841-1854. [PMID: 31919231 DOI: 10.1136/gutjnl-2019-319019] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 12/19/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) development occurs with non-alcoholic fatty liver disease (NAFLD) in the absence of cirrhosis and with an increasing incidence due to the obesity pandemic. Mutations of tumour suppressor (TS) genes and oncogenes (ONC) have been widely characterised in HCC. However, mounting evidence indicates that non-genomic alterations of TS/ONC occur early with NAFLD, thereby potentially promoting hepatocarcinogenesis in an inflammatory/fibrotic context. The aim of this study was to identify and characterise these alterations. DESIGN The proteome of steatotic liver tissues from mice spontaneously developing HCC was analysed. Alterations of TSs/ONCs were further investigated in various mouse models of NAFLD/HCC and in human samples. The inflammatory, fibrogenic and oncogenic functions of S100A11 were assessed through in vivo, in vitro and ex-vivo analyses. RESULTS A whole set of TSs/ONCs, respectively, downregulated or upregulated was uncovered in mice and human with NAFLD. Alterations of these TSs/ONCs were preserved or even exacerbated in HCC. Among them, overexpression of S100A11 was associated with high-grade HCC and poor prognosis. S100A11 downregulation in vivo significantly restrains the development of inflammation and fibrosis in mice fed a choline/methionine-deficient diet. Finally, in vitro and ex-vivo analyses revealed that S100A11 is a marker of hepatocyte de-differentiation, secreted by cancer cells, and promoting cell proliferation and migration. CONCLUSION Cellular stress associated with NAFLD triggers non-genomic alterations of a whole network of TSs/ONCs fostering hepatocarcinogenesis. Among those, overexpression of the oncogenic factor S100A11 promotes inflammation/fibrosis in vivo and is significantly associated with high-grade HCC with poor prognosis.
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Affiliation(s)
- Cyril Sobolewski
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Daniel Abegg
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida, USA
| | - Flavien Berthou
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Dobrochna Dolicka
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Nicolas Calo
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Christine Sempoux
- Department of Clinical Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Margot Fournier
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Christine Maeder
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Anne-Sophie Ay
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
| | - Pierre-Alain Clavien
- Visceral and Transplantation Surgery, University Hospital of Zurich, Zurich, Switzerland
| | - Bostjan Humar
- Department of Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Jean-François Dufour
- Department of Hepatology and Clinical Research, University of Bern, Bern, Switzerland
| | - Alexander Adibekian
- Department of Chemistry, The Scripps Research Institute, Jupiter, Florida, USA
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, University of Geneva Faculty of Medicine, Geneve, GE, Switzerland
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Botello-Manilla AE, Chávez-Tapia NC, Uribe M, Nuño-Lámbarri N. Genetics and epigenetics purpose in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2020; 14:733-748. [PMID: 32552211 DOI: 10.1080/17474124.2020.1780915] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION nonalcoholic fatty liver disease (NAFLD) comprises a broad spectrum of diseases, which can progress from benign steatosis to nonalcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma. NAFLD is the most common chronic liver disease in developed countries, affecting approximately 25% of the general population. Insulin resistance, adipose tissue dysfunction, mitochondrial and endoplasmic reticulum stress, chronic inflammation, genetic and epigenetic factors are NAFLD triggers that control the disease susceptibility and progression. AREAS COVERED In recent years a large number of investigations have been carried out to elucidate genetic and epigenetic factors in the disease pathogenesis, as well as the search for diagnostic markers and therapeutic targets. This paper objective is to report the most studied genetic and epigenetic variants around NAFLD. EXPERT OPINION NAFLD lead to various comorbidities, which have a considerable impact on the patient wellness and life quality, as well as on the costs they generate for the country's health services. It is essential to continue with molecular research, since it could be used as a clinical tool for prognosis and disease severity. Specifically, in the field of hepatology, plasma miRNAs could provide a novel tool in liver diseases diagnosis and monitoring, representing an alternative to invasive diagnostic procedures.
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Affiliation(s)
| | - Norberto Carlos Chávez-Tapia
- Traslational Research Unit, Médica Sur Clinic & Foundation , Mexico City, Mexico.,Obesity and Digestive Diseases Unit, Médica Sur Clinic & Foundation , Mexico City, Mexico
| | - Misael Uribe
- Obesity and Digestive Diseases Unit, Médica Sur Clinic & Foundation , Mexico City, Mexico
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Venniyoor A. PTEN: A Thrifty Gene That Causes Disease in Times of Plenty? Front Nutr 2020; 7:81. [PMID: 32582754 PMCID: PMC7290048 DOI: 10.3389/fnut.2020.00081] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 05/06/2020] [Indexed: 12/15/2022] Open
Abstract
The modern obesity epidemic with associated disorders of metabolism and cancer has been attributed to the presence of "thrifty genes". In the distant past, these genes helped the organism to improve energy efficiency and store excess energy safely as fat to survive periods of famine, but in the present day obesogenic environment, have turned detrimental. I propose PTEN as the likely gene as it has functions that span metabolism, cancer and reproduction, all of which are deranged in obesity and insulin resistance. The activity of PTEN can be calibrated in utero by availability of nutrients by the methylation arm of the epigenetic pathway. Deficiency of protein and choline has been shown to upregulate DNA methyltransferases (DNMT), especially 1 and 3a; these can then methylate promoter region of PTEN and suppress its expression. Thus, the gene is tuned like a metabolic rheostat proportional to the availability of specific nutrients, and the resultant "dose" of the protein, which sits astride and negatively regulates the insulin-PI3K/AKT/mTOR pathway, decides energy usage and proliferation. This "fixes" the metabolic capacity of the organism periconceptionally to a specific postnatal level of nutrition, but when faced with a discordant environment, leads to obesity related diseases.
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Affiliation(s)
- Ajit Venniyoor
- Department of Medical Oncology, National Oncology Centre, The Royal Hospital, Muscat, Oman
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Molecular Mechanisms Regulating Obesity-Associated Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12051290. [PMID: 32443737 PMCID: PMC7281233 DOI: 10.3390/cancers12051290] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 05/14/2020] [Accepted: 05/17/2020] [Indexed: 02/07/2023] Open
Abstract
Obesity is a global, intractable issue, altering inflammatory and stress response pathways, and promoting tissue adiposity and tumorigenesis. Visceral fat accumulation is correlated with primary tumor recurrence, poor prognosis and chemotherapeutic resistance. Accumulating evidence highlights a close association between obesity and an increased incidence of hepatocellular carcinoma (HCC). Obesity drives HCC, and obesity-associated tumorigenesis develops via nonalcoholic fatty liver (NAFL), progressing to nonalcoholic steatohepatitis (NASH) and ultimately to HCC. The better molecular elucidation and proteogenomic characterization of obesity-associated HCC might eventually open up potential therapeutic avenues. The mechanisms relating obesity and HCC are correlated with adipose tissue remodeling, alteration in the gut microbiome, genetic factors, ER stress, oxidative stress and epigenetic changes. During obesity-related hepatocarcinogenesis, adipokine secretion is dysregulated and the nuclear factor erythroid 2 related factor 1 (Nrf-1), nuclear factor kappa B (NF-κB), mammalian target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways are activated. This review captures the present trends allied with the molecular mechanisms involved in obesity-associated hepatic tumorigenesis, showcasing next generation molecular therapeutic strategies and their mechanisms for the successful treatment of HCC.
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38
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Orlistat delays hepatocarcinogenesis in mice with hepatic co-activation of AKT and c-Met. Toxicol Appl Pharmacol 2020; 392:114918. [DOI: 10.1016/j.taap.2020.114918] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 02/06/2020] [Accepted: 02/07/2020] [Indexed: 12/15/2022]
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Zhang J, Lin S, Jiang D, Li M, Chen Y, Li J, Fan J. Chronic hepatitis B and non-alcoholic fatty liver disease: Conspirators or competitors? Liver Int 2020; 40:496-508. [PMID: 31903714 DOI: 10.1111/liv.14369] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 12/16/2019] [Accepted: 01/02/2020] [Indexed: 02/06/2023]
Abstract
Despite the widespread use of vaccines and antiviral drugs, approximately 350-400 million patients with chronic hepatitis B (CHB) remain worldwide, who carry high risk of cirrhosis and liver carcinoma. Moreover, owing to improvements in global living standards and lifestyle changes, non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease. Coexistence of NAFLD and CHB is commonly observed, especially in Asian CHB populations; however, little is known regarding the relationship between these two diseases as comorbidities. In this review, we summarize recent advances in clinical and basic researches related to the underlying mutual interactions, as well as potential animal models to facilitate further investigation.
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Affiliation(s)
- Jianbin Zhang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Shuangzhe Lin
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Daixi Jiang
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Mengting Li
- Department of Gastroenterology, Yinzhou People's Hospital, Zhejiang, China
| | - Yuanwen Chen
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jun Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jiangao Fan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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40
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Klieser E, Mayr C, Kiesslich T, Wissniowski T, Fazio PD, Neureiter D, Ocker M. The Crosstalk of miRNA and Oxidative Stress in the Liver: From Physiology to Pathology and Clinical Implications. Int J Mol Sci 2019; 20:ijms20215266. [PMID: 31652839 PMCID: PMC6862076 DOI: 10.3390/ijms20215266] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 10/14/2019] [Accepted: 10/21/2019] [Indexed: 02/07/2023] Open
Abstract
The liver is the central metabolic organ of mammals. In humans, most diseases of the liver are primarily caused by an unhealthy lifestyle-high fat diet, drug and alcohol consumption- or due to infections and exposure to toxic substances like aflatoxin or other environmental factors. All these noxae cause changes in the metabolism of functional cells in the liver. In this literature review we focus on the changes at the miRNA level, the formation and impact of reactive oxygen species and the crosstalk between those factors. Both, miRNAs and oxidative stress are involved in the multifactorial development and progression of acute and chronic liver diseases, as well as in viral hepatitis and carcinogenesis, by influencing numerous signaling and metabolic pathways. Furthermore, expression patterns of miRNAs and antioxidants can be used for biomonitoring the course of disease and show potential to serve as possible therapeutic targets.
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Affiliation(s)
- Eckhard Klieser
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Christian Mayr
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Tobias Kiesslich
- Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Institute of Physiology and Pathophysiology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
| | - Till Wissniowski
- Department of Gastroenterology and Endocrinology, Philipps University Marburg, 35043 Marburg, Germany.
| | - Pietro Di Fazio
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany.
| | - Daniel Neureiter
- Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria.
- Cancer Cluster Salzburg, 5020 Salzburg, Austria.
| | - Matthias Ocker
- Translational Medicine Oncology, Bayer AG, 13353 Berlin, Germany.
- Department of Gastroenterology CBF, Charité University Medicine Berlin, 12200 Berlin, Germany.
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Kocic H, Damiani G, Stamenkovic B, Tirant M, Jovic A, Tiodorovic D, Peris K. Dietary compounds as potential modulators of microRNA expression in psoriasis. Ther Adv Chronic Dis 2019; 10:2040622319864805. [PMID: 31431821 PMCID: PMC6686315 DOI: 10.1177/2040622319864805] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 06/28/2019] [Indexed: 12/11/2022] Open
Abstract
Nutrigenomic DNA reprogramming in different chronic diseases and cancer has been assessed through the stimulation of gene expression and mRNA synthesis versus DNA silencing by CpG DNA modification (methylation); histone modification (acetylation, methylation) and expression of small noncoding RNAs, known as microRNAs (miRNAs). With regard to the specific nutrigenomic effects in psoriasis, the influence of specific diets on inflammatory cell signaling transcriptional factors such as nuclear factor (NF)-κB and Wnt signaling pathways, on disease-related specific cytokine expression, pro/antioxidant balance, keratinocyte proliferation/apoptosis and on proliferation/differentiation ratio have been documented; however, the influence of dietary compounds on the balance between 'good and bad' miRNA expression has not been considered. This review aims to summarize knowledge about aberrant microRNAs expression in psoriasis and to emphasize the potential impact of some dietary compounds on endogenous miRNA synthesis in experimental conditions in vivo and in vitro. Among the aberrantly expressed miRNAs in psoriasis, one of the most prominently upregulated seems to be miR-21. The beneficial effects of phenolic compounds (curcumin and resveratrol), vitamin D, methyl donors, and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) are discussed. Highly expressed miR-155 has been downregulated by flavonoids (through a quercetin-rich diet) and by vitamin D. Quercetin has been effective in modulating miR-146a. On the other hand, downregulated miR-125b expression was restored by vitamin D, Coenzyme Q10 and by microelement selenium. In conclusion, the miRNA profile, together with other 'omics', may constitute a multifaceted approach to explore the impact of diet on psoriasis prevention and treatment.
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Affiliation(s)
- Hristina Kocic
- Clinic for Dermatology Clinical Center University Nis, Klinicki Centar Nis, Bul Dr Zorana Djindjica 48, Nis, 18000, Serbia
| | - Giovanni Damiani
- Unita Operativa di Dermatologia, IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico, Milano, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Universita degli Studi di Milano, Milano, Italy
| | - Bojana Stamenkovic
- Department of Rheumatology, Institut za Kardiovaskularne Bolesti Niska Banja University Nis, Nis, Serbia
| | | | - Andrija Jovic
- Dermatology, Clinic for Dermatology University Clinical Center Nis, Nis, Serbia
| | - Danica Tiodorovic
- Dermatology, Clinic for Dermatology, Medical Faculty University Nis, Nis, Serbia
| | - Ketty Peris
- Dermatology, Institute of Dermatology, Catholic University, Roma, Italy
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Clément S, Sobolewski C, Gomes D, Rojas A, Goossens N, Conzelmann S, Calo N, Negro F, Foti M. Activation of the oncogenic miR-21-5p promotes HCV replication and steatosis induced by the viral core 3a protein. Liver Int 2019; 39:1226-1236. [PMID: 30938910 DOI: 10.1111/liv.14112] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 03/11/2019] [Accepted: 03/28/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS miR-21-5p is a potent oncogenic microRNA targeting many key tumour suppressors including phosphatase and tensin homolog (PTEN). We recently identified PTEN as a key factor modulated by hepatitis C virus (HCV) to promote virion egress. In hepatocytes, expression of HCV-3a core protein was sufficient to downregulate PTEN and to trigger lipid droplet accumulation. Here, we investigated whether HCV controls PTEN expression through miR-21-5p-dependent mechanisms to trigger steatosis in hepatocytes and to promote HCV life cycle. METHODS MiR-21-5p expression in HCV-infected patients was evaluated by transcriptome meta-analysis. HCV replication and viral particle production were investigated in Jc1-infected Huh-7 cells after miR-21-5p inhibition. PTEN expression and steatosis were assessed in HCV-3a core protein-expressing Huh-7 cells and in mouse primary hepatocytes having miR-21-5p inhibited or genetically deleted respectively. HCV-3a core-induced steatosis was assessed in vivo in Mir21a knockout mice. RESULTS MiR-21-5p expression was significantly increased in hepatic tissues from HCV-infected patients. Infection by HCV-Jc1, or transduction with HCV-3a core, upregulated miR-21-5p expression and/or activity in Huh-7 cells. miR-21-5p inhibition decreased HCV replication and release of infectious virions by Huh-7 cells. HCV-3a core-induced PTEN downregulation and steatosis were further prevented in Huh-7 cells following miR-21-5p inhibition or in Mir21a knockout mouse primary hepatocytes. Finally, steatosis induction by AAV8-mediated HCV-3a core expression was reduced in vivo in Mir21a knockout mice. CONCLUSION MiR-21-5p activation by HCV is a key molecular step, promoting both HCV life cycle and HCV-3a core-induced steatosis and may be among the molecular changes induced by HCV-3a to promote carcinogenesis.
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Affiliation(s)
- Sophie Clément
- Division of Clinical Pathology, University Hospital, Geneva, Switzerland
| | - Cyril Sobolewski
- Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Diana Gomes
- Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Angela Rojas
- Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Nicolas Goossens
- Division of Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland
| | - Stéphanie Conzelmann
- Faculty of Medicine, Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Nicolas Calo
- Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Francesco Negro
- Division of Clinical Pathology, University Hospital, Geneva, Switzerland.,Division of Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland.,Faculty of Medicine, Diabetes Center, University of Geneva, Geneva, Switzerland
| | - Michelangelo Foti
- Faculty of Medicine, Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.,Faculty of Medicine, Diabetes Center, University of Geneva, Geneva, Switzerland
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Role of Noncoding RNA in Development of Nonalcoholic Fatty Liver Disease. BIOMED RESEARCH INTERNATIONAL 2019; 2019:8690592. [PMID: 30931332 PMCID: PMC6413411 DOI: 10.1155/2019/8690592] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 02/13/2019] [Indexed: 12/13/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence globally, but little is known about its specific molecular mechanisms. During the past decade, noncoding RNAs (ncRNAs) have been linked to NAFLD initiation and progression. They are a class of RNAs that play an important role in regulating gene expression despite not encoding proteins. This review summarizes recent research on the relationship between ncRNAs and NAFLD. We discussed the potential applicability of ncRNAs as a biomarker for early NAFLD diagnosis and assessment of disease severity. With further study, ncRNAs should prove to be valuable new targets for NAFLD treatment and benefit the development of noninvasive diagnostic methods.
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Interplay between early-life malnutrition, epigenetic modulation of the immune function and liver diseases. Nutr Res Rev 2019; 32:128-145. [PMID: 30707092 DOI: 10.1017/s0954422418000239] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Early-life nutrition plays a critical role in fetal growth and development. Food intake absence and excess are the two main types of energy malnutrition that predispose to the appearance of diseases in adulthood, according to the hypothesis of 'developmental origins of health and disease'. Epidemiological data have shown an association between early-life malnutrition and the metabolic syndrome in later life. Evidence has also demonstrated that nutrition during this period of life can affect the development of the immune system through epigenetic mechanisms. Thus, epigenetics has an essential role in the complex interplay between environmental factors and genetics. Altogether, this leads to the inflammatory response that is commonly seen in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. In conjunction, DNA methylation, covalent modification of histones and the expression of non-coding RNA are the epigenetic phenomena that affect inflammatory processes in the context of NAFLD. Here, we highlight current understanding of the mechanisms underlying developmental programming of NAFLD linked to epigenetic modulation of the immune system and environmental factors, such as malnutrition.
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45
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Zhou K, Yao P, He J, Zhao H. Lipophagy in nonliver tissues and some related diseases: Pathogenic and therapeutic implications. J Cell Physiol 2018; 234:7938-7947. [PMID: 30537019 DOI: 10.1002/jcp.27988] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 11/21/2018] [Indexed: 12/24/2022]
Abstract
Lipid autophagy (lipophagy) is defined as a selective autophagy process in which some intracellular lipid droplets are selectively degraded by autophagic lysosomes pathway. The occurrence of lipophagy was first discovered in liver tissues. Additionally, abundant evidence indicated that the occurrence of hepatic lipophagy has been implicated in many liver diseases including fatty liver diseases, nonalcoholic fatty liver diseases, liver fibrosis, and liver cirrhosis. However, recent studies suggested that hepatic lipophagy occurs not only in liver tissue but also in other nonliver tissues and cells. Furthermore, the occurrence of lipophagy plays a crucial role in nonliver tissues and some related diseases. For instance, lipophagy relieves insulin resistance in adipose tissue from obesity patient with type 2 diabetes. Additionally, lipophagy has the ability to remit neurodegenerative diseases by reducing activity-dependent neurodegeneration in nervous tissue. Lipophagy decreases muscle lipid accumulation and accordingly improves lipid storage myopathy in muscle tissue. Moreover, lipophagy alleviates the malignancy and metastasis of cancer in clear renal cell carcinoma tissue. Lipophagy is also involved in other processes, such as spermatogenesis, osteoblastogenesis, and mucosal ulceration. In conclusion, targeting lipophagy may be a critical regulator and a new therapeutic strategy for nonliver tissues and some related diseases.
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Affiliation(s)
- Kebing Zhou
- Department of Emergency Medicine, Affiliated Nanhua Hospital, University of South China, Hengyang, China
| | - Pingbo Yao
- Department of Emergency Medicine, Affiliated Nanhua Hospital, University of South China, Hengyang, China
| | - Jun He
- Department of Emergency Medicine, Affiliated Nanhua Hospital, University of South China, Hengyang, China
| | - Hong Zhao
- Department of Basic nursing, Nursing College, University of South China, Hengyang, China
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46
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MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes. Int J Mol Sci 2018; 19:ijms19123705. [PMID: 30469501 PMCID: PMC6321520 DOI: 10.3390/ijms19123705] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/08/2018] [Accepted: 11/17/2018] [Indexed: 12/21/2022] Open
Abstract
The insulin signaling pathway is composed of a large number of molecules that positively or negatively modulate insulin specific signal transduction following its binding to the cognate receptor. Given the importance of the final effects of insulin signal transduction, it is conceivable that many regulators are needed in order to tightly control the metabolic or proliferative functional outputs. MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively modulate gene expression through their specific binding within the 3′UTR sequence of messenger RNA (mRNA), thus causing mRNA decoy or translational inhibition. In the last decade, miRNAs have been addressed as pivotal cellular rheostats which control many fundamental signaling pathways, including insulin signal transduction. Several studies demonstrated that multiple alterations of miRNAs expression or function are relevant for the development of insulin resistance in type 2 diabetes (T2D); such alterations have been highlighted in multiple insulin target organs including liver, muscles, and adipose tissue. Indirectly, miRNAs have been identified as modulators of inflammation-derived insulin resistance, by controlling/tuning the activity of innate immune cells in insulin target tissues. Here, we review main findings on miRNA functions as modulators of insulin signaling in physiologic- or in T2D insulin resistance- status. Additionally, we report the latest hypotheses of prospective therapies involving miRNAs as potential targets for future drugs in T2D.
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Nakagawa H, Hayata Y, Kawamura S, Yamada T, Fujiwara N, Koike K. Lipid Metabolic Reprogramming in Hepatocellular Carcinoma. Cancers (Basel) 2018; 10:cancers10110447. [PMID: 30445800 PMCID: PMC6265967 DOI: 10.3390/cancers10110447] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 11/10/2018] [Accepted: 11/13/2018] [Indexed: 12/23/2022] Open
Abstract
Metabolic reprogramming for adaptation to the local environment has been recognized as a hallmark of cancer. Although alterations in fatty acid (FA) metabolism in cancer cells have received less attention compared to other metabolic alterations such as glucose or glutamine metabolism, recent studies have uncovered the importance of lipid metabolic reprogramming in carcinogenesis. Obesity and nonalcoholic steatohepatitis (NASH) are well-known risk factors of hepatocellular carcinoma (HCC), and individuals with these conditions exhibit an increased intake of dietary FAs accompanied by enhanced lipolysis of visceral adipose tissue due to insulin resistance, resulting in enormous exogenous FA supplies to hepatocytes via the portal vein and lymph vessels. This “lipid-rich condition” is highly characteristic of obesity- and NASH-driven HCC. Although the way in which HCC cells adapt to such a condition and exploit it to aid their progression is not understood, we recently obtained new insights into this mechanism through lipid metabolic reprogramming. In addition, accumulating evidence supports the importance of lipid metabolic reprogramming in various situations of hepatocarcinogenesis. Thus, in this review, we discuss the latest findings regarding the role of FA metabolism pathways in hepatocarcinogenesis, focusing on obesity- and NASH-driven lipid metabolic reprogramming.
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Affiliation(s)
- Hayato Nakagawa
- Department of Gastroenterology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| | - Yuki Hayata
- Department of Gastroenterology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| | - Satoshi Kawamura
- Department of Gastroenterology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| | - Tomoharu Yamada
- Department of Gastroenterology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| | - Naoto Fujiwara
- Department of Gastroenterology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
| | - Kazuhiko Koike
- Department of Gastroenterology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
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Kovacovicova K, Skolnaja M, Heinmaa M, Mistrik M, Pata P, Pata I, Bartek J, Vinciguerra M. Senolytic Cocktail Dasatinib+Quercetin (D+Q) Does Not Enhance the Efficacy of Senescence-Inducing Chemotherapy in Liver Cancer. Front Oncol 2018; 8:459. [PMID: 30425964 PMCID: PMC6218402 DOI: 10.3389/fonc.2018.00459] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 10/01/2018] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, which develops in the context of fibrosis and cirrhosis caused by chronic inflammation, in turn due to non-alcoholic fatty liver disease (NAFLD), alcohol consumption and/or hepatitis viral infection. An increased number of senescent cells are associated with age-related tissue degeneration during NAFLD-induced HCC, or during chemotherapeutic treatment. Senolytic agents target selectively senescent cells. A combination of the senolytic drugs dasatinib and quercetin (D+Q) reduced hepatic lipid accumulation and alleviated age-associated physical dysfunction in mice. However, whether D+Q can impact the treatment of HCC, at the end-stage of the NAFLD inflammatory spectrum, is unknown. Here, using two well-established HCC cell lines (HepG2, Huh-7), we demonstrate that the maximal cytostatic doses for D and/or Q (1 + 1 μM) lacked efficacy in removing doxorubicin-induced β-gal-positive senescent cells. Moreover, D+Q did not affect doxorubicin-dependent induction of flattened morphology, activation of p16, expression of SASP-associated genes or formation of γH2AX foci. We then investigated the antitumor efficacy of doxorubicin, D+Q, or the combination, in xenograft studies conducted with HCC cells inoculated in athymic nude mice. Doxorubicin reduced tumor growth by 30% compared to control mice, while D+Q was ineffective in synergizing with doxorubicin and in clearing doxorubicin-induced HCC senescent cells. Unexpectedly, D+Q alone appeared to have acute pro-tumorigenic effects in control mice. While our data need to be confirmed in animal models that fully recapitulate NAFLD, we demonstrate that these compounds are ineffective, alone or in synergy with senescence-inducing chemotherapy, against experimental HCC.
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Affiliation(s)
| | - Marianna Skolnaja
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia.,IVEX Lab, Tallinn, Estonia
| | - Mihkel Heinmaa
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia
| | - Martin Mistrik
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University, Olomouc, Czechia
| | - Pille Pata
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Tallinn, Estonia.,IVEX Lab, Tallinn, Estonia
| | | | - Jiri Bartek
- Faculty of Medicine and Dentistry, Institute of Molecular and Translational Medicine, Palacky University, Olomouc, Czechia.,Genome Integrity Unit, Danish Cancer Society Research Center, Copenhagen, Denmark.,Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Solna, Sweden
| | - Manlio Vinciguerra
- International Clinical Research Center (FNUSA-ICRC), Brno, Czechia.,Division of Medicine, Institute for Liver and Digestive Health, University College London, London, United Kingdom
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Lo Re O, Douet J, Buschbeck M, Fusilli C, Pazienza V, Panebianco C, Castracani CC, Mazza T, Li Volti G, Vinciguerra M. Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells. Epigenetics 2018; 13:829-845. [PMID: 30165787 DOI: 10.1080/15592294.2018.1514239] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinomas (HCCs) contain a sub-population of cancer stem cells (CSCs) that are responsible for tumor relapse, metastasis, and chemoresistance. We recently showed that loss of macroH2A1, a variant of the histone H2A and an epigenetic regulator of stem-cell function, in HCC leads to CSC-like features such as resistance to chemotherapeutic agents and growth of large and relatively undifferentiated tumors in xenograft models. These HCC cells silenced for macroH2A1 also exhibited stem-like metabolic changes consistent with enhanced glycolysis. However, there is no consensus as to the metabolic characteristics of CSCs that render them adaptable to microenvironmental changes by conveniently shifting energy production source or by acquiring intermediate metabolic phenotypes. Here, we assessed long-term proliferation, energy metabolism, and central carbon metabolism in human hepatoma HepG2 cells depleted in macroH2A1. MacroH2A1-depleted HepG2 cells were insensitive to serum exhaustion and showed two distinct, but interdependent changes in glucose and lipid metabolism in CSCs: (1) massive upregulation of acetyl-coA that is transformed into enhanced lipid content and (2) increased activation of the pentose phosphate pathway, diverting glycolytic intermediates to provide precursors for nucleotide synthesis. Integration of metabolomic analyses with RNA-Seq data revealed a critical role for the Liver X Receptor pathway, whose inhibition resulted in attenuated CSCs-like features. These findings shed light on the metabolic phenotype of epigenetically modified CSC-like hepatic cells, and highlight a potential approach for selective therapeutic targeting.
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Affiliation(s)
- Oriana Lo Re
- a Center for Translational Medicine, International Clinical Research Center , St'Anne University Hospital , Brno , Czech Republic.,b Department of Biology, Faculty of Medicine , Masaryk University , Brno , Czech Republic
| | - Julien Douet
- d Josep Carreras Leukemia Research Institute (IJC), Campus ICO-Germans Trias I Pujol , Universitat Autònoma de Barcelona , Badalona , Spain.,e Programme of Predictive and Personalized Medicine of Cancer , Germans Trias i Pujol Research Institute (PMPPC-IGTP) , Badalona , Spain
| | - Marcus Buschbeck
- d Josep Carreras Leukemia Research Institute (IJC), Campus ICO-Germans Trias I Pujol , Universitat Autònoma de Barcelona , Badalona , Spain.,e Programme of Predictive and Personalized Medicine of Cancer , Germans Trias i Pujol Research Institute (PMPPC-IGTP) , Badalona , Spain
| | - Caterina Fusilli
- c IRCCS Casa Sollievo della Sofferenza , UO of Bioinformatics , San Giovanni Rotondo , Italy
| | - Valerio Pazienza
- f Gastroenterology unit , IRCCS Casa Sollievo della Sofferenza , San Giovanni Rotondo , Italy
| | - Concetta Panebianco
- f Gastroenterology unit , IRCCS Casa Sollievo della Sofferenza , San Giovanni Rotondo , Italy
| | | | - Tommaso Mazza
- c IRCCS Casa Sollievo della Sofferenza , UO of Bioinformatics , San Giovanni Rotondo , Italy
| | - Giovanni Li Volti
- g Department of Biomedical and Biotechnological Sciences , University of Catania , Catania , Italy
| | - Manlio Vinciguerra
- a Center for Translational Medicine, International Clinical Research Center , St'Anne University Hospital , Brno , Czech Republic.,h Institute for Liver and Digestive Health, Division of Medicine , University College London (UCL) , London , UK
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50
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Park S, Park JH, Jung HJ, Jang JH, Ahn S, Kim Y, Suh PG, Chae S, Yoon JH, Ryu SH, Hwang D. A secretome profile indicative of oleate-induced proliferation of HepG2 hepatocellular carcinoma cells. Exp Mol Med 2018; 50:1-14. [PMID: 30076294 PMCID: PMC6076227 DOI: 10.1038/s12276-018-0120-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 03/18/2018] [Accepted: 04/13/2018] [Indexed: 12/13/2022] Open
Abstract
Increased fatty acid (FA) is often observed in highly proliferative tumors. FAs have been shown to modulate the secretion of proteins from tumor cells, contributing to tumor survival. However, the secreted factors affected by FA have not been systematically explored. Here, we found that treatment of oleate, a monounsaturated omega-9 FA, promoted the proliferation of HepG2 cells. To examine the secreted factors associated with oleate-induced cell proliferation, we performed a comprehensive secretome profiling of oleate-treated and untreated HepG2 cells. A comparison of the secretomes identified 349 differentially secreted proteins (DSPs; 145 upregulated and 192 downregulated) in oleate-treated samples, compared to untreated samples. The functional enrichment and network analyses of the DSPs revealed that the 145 upregulated secreted proteins by oleate treatment were mainly associated with cell proliferation-related processes, such as lipid metabolism, inflammatory response, and ER stress. Based on the network models of the DSPs, we selected six DSPs (MIF, THBS1, PDIA3, APOA1, FASN, and EEF2) that can represent such processes related to cell proliferation. Thus, our results provided a secretome profile indicative of an oleate-induced proliferation of HepG2 cells. By exposing liver cancer cells to oleate, an unsaturated fatty acid, researchers have discovered a group of secreted proteins that may help explain why fatty acids increase proliferative capacity in tumors. Soyeon Park from Pohang University of Science and Technology in South Korea and coworkers treated liver cancer cells with oleate and then measured all the proteins released from the cells. Comparison with untreated cells revealed 145 proteins secreted at elevated levels—most of which were involved in metabolism, stress responses and other proliferation-related processes—and another 192 proteins secreted at reduced levels. The researchers ran additional biochemical analyses on six secreted proteins to validate the changes following exposure to oleate. The authors suggest that these validated proteins could now serve as biomarkers of tumor aggressiveness or as future drug targets.
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Affiliation(s)
- Soyeon Park
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, 37673, Republic of Korea
| | - Ji-Hwan Park
- Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 42988, Republic of Korea
| | - Hee-Jung Jung
- Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 42988, Republic of Korea
| | - Jin-Hyeok Jang
- Department of Brain and Cognitive Sciences, Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, Republic of Korea
| | - Sanghyun Ahn
- Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 42988, Republic of Korea
| | - Younah Kim
- Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 42988, Republic of Korea
| | - Pann-Ghill Suh
- School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, 44919, Republic of Korea
| | - Sehyun Chae
- Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 42988, Republic of Korea
| | - Jong Hyuk Yoon
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, 37673, Republic of Korea. .,Department of Neural Development and Disease, Korea Brain Research Institute, Daegu, 41068, Republic of Korea.
| | - Sung Ho Ryu
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, 37673, Republic of Korea.
| | - Daehee Hwang
- Center for Plant Aging Research, Institute for Basic Science (IBS), Daegu, 42988, Republic of Korea. .,Department of New Biology, DGIST, Daegu, 42988, Republic of Korea.
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