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Feng Y, Shang B, Yang Y, Zhang D, Liu C, Qin Z, Zhou Y, Meng J, Liu X. Impact of DPP-4 Inhibitors on Interleukin Levels in Type 2 Diabetes Mellitus. J Clin Endocrinol Metab 2025; 110:1195-1204. [PMID: 39512193 PMCID: PMC11913085 DOI: 10.1210/clinem/dgae783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/17/2024] [Accepted: 11/07/2024] [Indexed: 11/15/2024]
Abstract
BACKGROUND AND OBJECTIVE Accumulating evidence had implicated pathological involvement of interleukins (ILs) in progression and complications in patients with type 2 diabetes mellitus (T2DM). Dipeptidyl peptidase-4 inhibitors (DPP-4i) produced favorable effects on glucose homeostasis in T2DM. This study aimed to evaluate the impact of DPP-4i on IL concentrations in T2DM. DATA SOURCES PubMed, Embase, and the Cochrane library were systematically searched for relevant articles from inception to May 31, 2024. The search included DPP-4i, T2DM, and randomized controlled trials (RCTs) and related terms. STUDY SELECTION AND DATA EXTRACTION Placebo- or active agents-controlled human studies were screened. All the RCTs were identified if they provided detailed information on changes of ILs during DPP-4i treatment. DATA SYNTHESIS A total of 14 RCTs involving 850 participants were identified. Pooled estimates revealed that DPP-4i significantly lowered IL-6 concentrations (-0.54 pg/mL; 95% CI, -0.82 to -0.25; I2 = 10%, P = .0003) compared to placebo. Similar effects were demonstrated for IL-1β (-16.33 pg/mL; 95% CI, -19.56 to -13.11; I2 = 0%, P < .00001), whereas the effect on IL-18 was not statistically significant (-13.55 pg/mL; 95% CI, -76.95 to 49.85; I2 = 0%, P = .68). Subgroup analysis on IL-6 demonstrated that marked effects were found in groups of basal IL-6 concentrations (< 5 pg/mL), body mass index (≥ 28 kg/m2) and type of DPP-4i (linagliptin). CONCLUSION DPP-4i favorably decreased IL-6 levels in patients with T2DM. The impact of DPP-4i on IL-1β and IL-18 needed to be explored with more studies. Further trials should be performed to elucidate this anti-inflammatory effect of DPP-4i during treatment of T2DM.
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Affiliation(s)
- Yiduo Feng
- Department of Nephrology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Beibei Shang
- Department of Pharmacy, Children's Hospital, Capital Institute of Paediatrics, Beijing 100020, China
| | - Yu Yang
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Donglei Zhang
- Department of Hematology, Zhongnan Hospital, Wuhan University, Hubei 430000, China
| | - Changbin Liu
- Department of Rehabilitation Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Zheng Qin
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Yilun Zhou
- Department of Nephrology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Jie Meng
- Department of Pathology, Beijing TongRen Hospital, Capital Medical University, Beijing 100005, China
| | - Xin Liu
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
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Ma G, Zhang S, Yu B. Impact of Dipeptidyl Peptidase-4 Inhibitors on Aminotransferases Levels in Patients with Type 2 Diabetes Mellitus With Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trial. CURRENT THERAPEUTIC RESEARCH 2024; 102:100768. [PMID: 39831144 PMCID: PMC11741081 DOI: 10.1016/j.curtheres.2024.100768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/26/2024] [Indexed: 01/22/2025]
Abstract
Background Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) are highly prevalent diseases that constitute enormous public health problems. The efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors in blood glucose control in T2DM patients with NAFLD has been established, but little is known about its effect on liver enzyme levels. Objective This meta-analysis aimed to evaluate the influences of DPP-4 inhibitors on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in patients with T2DM and NAFLD. Methods To identify the relevant studies, we searched PubMed, Embase, the Cochrane Library, Wanfang Data, and China National Knowledge Infrastructure. Means differences in liver enzymes and metabolic outcomes were meta-analyzed using a random-effects model, with subgroup analyses by gender, age, area, follow-up duration, and type of DPP-4 inhibitor. Quality assessment of the included studies was conducted using the revised Cochrane risk of bias tool. Results A total of 1323 patients from 16 studies were included in this meta-analysis. The results of analysis of DPP-4 inhibitors showed that the mean difference was -6.19 (95% confidence interval [CI]: -9.45 to -2.92) for ALT and -5.17 (95% CI: -8.10 to -2.23) for AST; this effect was statistically significant from the placebo group which indicates the beneficial effect on liver enzymes. Subgroup analysis revealed that while there were no significant gender differences in enzyme reductions, individuals over 55 years old experienced more pronounced decreases in ALT. Notably, Asian studies showed significant reductions in liver enzymes, contrasting with the minor variations observed in Euramerican regions, and the effectiveness of DPP-4 inhibitors was particularly pronounced during shorter follow-up periods, with effects diminishing over time. Regarding secondary outcomes, there was a notable improvement in gamma-glutamyl transpeptidase, with a mean reduction, and in HbA1c levels, indicating improved glycemic control. Homeostatic model assessment for insulin resistance levels also improved, reflecting better insulin sensitivity. Additionally, adverse event analysis confirmed that DPP-4 inhibitors were well-tolerated with a favorable safety profile. Conclusions DPP-4 inhibitors appear to enhance glycemic control and improve liver enzyme levels, suggesting a potentially effective therapeutic approach for managing T2DM/NAFLD and highlighting their broader metabolic benefits.
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Affiliation(s)
- Gang Ma
- Department of hepatobiliary surgery, The First People's Hospital of Guangyuan, Guangyuan, Sichuan, China
| | - Song Zhang
- Departmant of Pharmacy, The First People's Hospital of Guangyuan, Guangyuan, Sichuan, China
| | - Baozhong Yu
- Clinical trial institutions, The First People's Hospital of Guangyuan, Guangyuan, Sichuan, China
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Amorim R, Soares P, Chavarria D, Benfeito S, Cagide F, Teixeira J, Oliveira PJ, Borges F. Decreasing the burden of non-alcoholic fatty liver disease: From therapeutic targets to drug discovery opportunities. Eur J Med Chem 2024; 277:116723. [PMID: 39163775 DOI: 10.1016/j.ejmech.2024.116723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/22/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) presents a pervasive global pandemic, affecting approximately 25 % of the world's population. This grave health issue not only demands urgent attention but also stands as a significant economic concern on a global scale. The genesis of NAFLD can be primarily attributed to unhealthy dietary habits and a sedentary lifestyle, albeit certain genetic factors have also been recorded to contribute to its occurrence. NAFLD is characterized by fat accumulation in more than 5 % of hepatocytes according to histological analysis, or >5.6 % of lipid volume fraction in total liver weight in patients. The pathophysiology of NAFLD/non-alcoholic steatohepatitis (NASH) is multifactorial and the mechanisms underlying the progression to advanced forms remain unclear, thereby representing a challenge to disease therapy. Despite the substantial efforts from the scientific community and the large number of pre-clinical and clinical trials performed so far, only one drug was approved by the Food and Drug Administration (FDA) to treat NAFLD/NASH specifically. This review provides an overview of available information concerning emerging molecular targets and drug candidates tested in clinical studies for the treatment of NAFLD/NASH. Improving our understanding of NAFLD pathophysiology and pharmacotherapy is crucial not only to explore new molecular targets, but also to potentiate drug discovery programs to develop new therapeutic strategies. This knowledge endeavours scientific efforts to reduce the time for achieving a specific and effective drug for NAFLD or NASH management and improve patients' quality of life.
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Affiliation(s)
- Ricardo Amorim
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Pedro Soares
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Daniel Chavarria
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Sofia Benfeito
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - Fernando Cagide
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal
| | - José Teixeira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal
| | - Paulo J Oliveira
- CNC-UC, Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; CIBB, Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Portugal.
| | - Fernanda Borges
- CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
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Chen S, Suo J, Wang Y, Tang C, Ma B, Li J, Hou Y, Yan B, Shen T, Zhang Q, Ma B. Cordycepin alleviates diabetes mellitus-associated hepatic fibrosis by inhibiting SOX9-mediated Wnt/β-catenin signal axis. Bioorg Chem 2024; 153:107812. [PMID: 39260158 DOI: 10.1016/j.bioorg.2024.107812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 08/28/2024] [Accepted: 09/05/2024] [Indexed: 09/13/2024]
Abstract
Diabetes mellitus can induce liver injury and easily progress to liver fibrosis. However, there is still a lack of effective treatments for diabetes-induced hepatic fibrosis. Cordycepin (COR), a natural nucleoside derived from Cordyceps militaris, has demonstrated remarkable efficacy in treating metabolic diseases and providing hepatoprotective effects. However, its protective effect and underlying mechanism in diabetes-induced liver injury remain unclear. This study utilized a high-fat diet/streptozotocin-induced diabetic mouse model, as well as LX-2 and AML-12 cell models exposed to high glucose and TGF-β1, to explore the protective effects and mechanisms of Cordycepin in liver fibrosis associated with diabetes. The results showed that COR lowered blood glucose levels, enhanced liver function, mitigated fibrosis, and suppressed HSC activation in diabetic mice. Mechanistically, COR attenuated the activation of the Wnt/β-catenin pathway by inhibiting β-catenin nuclear translocation, and β-catenin knockdown further intensified this effect. Meanwhile, COR significantly inhibited SOX9 expression in vivo and in vitro. Knockdown of SOX9 downregulated Wnt3a and β-catenin expression at the protein and gene levels to exacerbate the inhibitory action of COR on HG&TGF-β1-induced HSCs activations. These results indicate SOX9 is involved in the mechanism by which COR deactivates the Wnt/β-catenin pathway in hepatic fibrosis induced by diabetes. Moreover, prolonged half-life time, slower metabolism and higher exposure of COR were observed in diabetes-induced liver injury animal model via pharmacokinetics studies. Altogether, COR holds potential as a therapeutic agent for ameliorating hepatic injury and fibrosis in diabetes by suppressing the activation of the SOX9-mediated Wnt/β-catenin pathway.
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Affiliation(s)
- Shuang Chen
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, PR China
| | - Jialiang Suo
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, PR China
| | - Yu Wang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, PR China; College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, PR China
| | - Chenglun Tang
- Nanjing Sheng Ming Yuan Health Technology Co. Ltd., Nanjing 210000, PR China
| | - Beiting Ma
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, PR China
| | - Jiaqi Li
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, PR China
| | - Yuyang Hou
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, PR China
| | - Bingrong Yan
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, PR China
| | - Tao Shen
- College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing 211816, PR China.
| | - Qi Zhang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, PR China; College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, PR China.
| | - Bo Ma
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, PR China.
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Feng F, Zhou B, Zhou CL, Huang P, Wang G, Yao K. Vitamin D, selenium, and antidiabetic drugs in the treatment of type 2 diabetes mellitus with Hashimoto's thyroiditis. World J Diabetes 2024; 15:209-219. [PMID: 38464371 PMCID: PMC10921160 DOI: 10.4239/wjd.v15.i2.209] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/16/2023] [Accepted: 01/16/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Diabetes and thyroiditis are closely related. They occur in combination and cause significant damage to the body. There is no clear treatment for type-2 diabetes mellitus (T2DM) with Hashimoto's thyroiditis (HT). While single symptomatic drug treatment of the two diseases is less effective, combined drug treatment may improve efficacy. AIM To investigate the effect of a combination of vitamin D, selenium, and hypo-glycemic agents in T2DM with HT. METHODS This retrospective study included 150 patients with T2DM and HT treated at The Central Hospital of Shaoyang from March 2020 to February 2023. Fifty patients were assigned to the control group, test group A, and test group B according to different treatment methods. The control group received low-iodine diet guidance and hypoglycemic drug treatment. Test group A received the control treatment plus vitamin D treatment. Test group B received the group A treatment plus selenium. Blood levels of markers of thyroid function [free T3 (FT3), thyroid stimulating hormone (TSH), free T4 (FT4)], autoantibodies [thyroid peroxidase antibody (TPOAB) and thyroid globulin antibody (TGAB)], blood lipid index [low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triacylglycerol (TG)], blood glucose index [fasting blood glucose (FBG), and hemoglobin A1c (HbA1c)] were measured pre-treatment and 3 and 6 months after treatment. The relationships between serum 25-hydroxyvitamin D3 [25 (OH) D3] level and each of these indices were analyzed. RESULTS The levels of 25 (OH) D3, FT3, FT4, and LDL-C increased in the order of the control group, test group A, and test group B (all P < 0.05). The TPOAB, TGAB, TC, TG, FBG, HbA1c, and TSH levels increased in the order of test groups B, A, and the control group (all P < 0.05). All the above indices were compared after 3 and 6 months of treatment. Pre-treatment, there was no divergence in serum 25 (OH) D3 level, thyroid function-related indexes, autoantibodies level, blood glucose, and blood lipid index between the control group, test groups A and B (all P > 0.05). The 25 (OH) D3 levels in test groups A and B were negatively correlated with FT4 and TGAB (all P < 0.05). CONCLUSION The combination drug treatment for T2DM with HT significantly improved thyroid function, autoantibody, and blood glucose and lipid levels.
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Affiliation(s)
- Fen Feng
- School of Pharmacy, Shaoyang University, Shaoyang 422099, Hunan Province, China
| | - Bin Zhou
- Department of Endocrinology, The Central Hospital of Shaoyang, Shaoyang 422099, Hunan Province, China
| | - Ci-La Zhou
- Department of Endocrinology, The Central Hospital of Shaoyang, Shaoyang 422099, Hunan Province, China
| | - Ping Huang
- Department of Endocrinology, The Central Hospital of Shaoyang, Shaoyang 422099, Hunan Province, China
| | - Gang Wang
- Department of Endocrinology, The Central Hospital of Shaoyang, Shaoyang 422099, Hunan Province, China
| | - Kuang Yao
- Department of Endocrinology, The Central Hospital of Shaoyang, Shaoyang 422099, Hunan Province, China
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Bołdys A, Bułdak Ł, Maligłówka M, Surma S, Okopień B. Potential Therapeutic Strategies in the Treatment of Metabolic-Associated Fatty Liver Disease. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1789. [PMID: 37893507 PMCID: PMC10608225 DOI: 10.3390/medicina59101789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/29/2023] [Accepted: 10/04/2023] [Indexed: 10/29/2023]
Abstract
Metabolic-associated Fatty Liver Disease is one of the outstanding challenges in gastroenterology. The increasing incidence of the disease is undoubtedly connected with the ongoing obesity pandemic. The lack of specific symptoms in the early phases and the grave complications of the disease require an active approach to prompt diagnosis and treatment. Therapeutic lifestyle changes should be introduced in a great majority of patients; but, in many cases, the adherence is not satisfactory. There is a great need for an effective pharmacological therapy for Metabolic-Associated Fatty Liver Disease, especially before the onset of steatohepatitis. Currently, there are no specific recommendations on the selection of drugs to treat liver steatosis and prevent patients from progression toward more advanced stages (steatohepatitis, cirrhosis, and cancer). Therefore, in this Review, we provide data on the clinical efficacy of therapeutic interventions that might improve the course of Metabolic-Associated Fatty Liver Disease. These include the drugs used in the treatment of obesity and hyperlipidemias, as well as affecting the gut microbiota and endocrine system, and other experimental approaches, including functional foods. Finally, we provide advice on the selection of drugs for patients with concomitant Metabolic-Associated Fatty Liver Disease.
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Affiliation(s)
| | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medykow 18, 40-752 Katowice, Poland
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Zou CY, Sun Y, Liang J. Comparative efficacy of diabetes medications on liver enzymes and fat fraction in patients with nonalcoholic fatty liver disease: A network meta-analysis ,. Clin Res Hepatol Gastroenterol 2023; 47:102053. [PMID: 36403941 DOI: 10.1016/j.clinre.2022.102053] [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: 09/18/2022] [Revised: 11/03/2022] [Accepted: 11/16/2022] [Indexed: 11/18/2022]
Abstract
OBJECTIVES This network meta-analysis (NMA) aimed to evaluate the relative rank-order of existing diabetes medications in patients with nonalcoholic fatty liver disease (NAFLD) with or without type 2 diabetes mellitus (T2DM). METHODS A systematic literature search was conducted using the Medline, Embase and Cochrane databases. Clinical trials comparing the efficacy of diabetes medications with other interventions, including lifestyle modification and placebo, in patients with NAFLD were included. The results from the NMA are presented as the weighted mean difference (WMD) of the continuous results and the corresponding 95% confidence intervals (95% CIs). RESULTS The articles presented the results of 49 trials involving 3,836 subjects published between 2013 and 2021. According to our results, thiazolidinedione (TZD) was ranked as the best diabetes medication in the reduction of alanine aminotransferase (ALT) (WMD = -10.10, 95% CI: -15.18, -5.01), followed by dipeptidyl peptidase-4 inhibitor (DPP4i) (WMD = -8.90, 95% CI: -14.41, -3.40). DPP4i also resulted in the greatest reduction in aspartate aminotransferase (AST) (WMD = -6.89, 95% CI: -11.72, -2.07). γ-Glutamyl transferase (γ-GT) reduction was highest in patients treated with glucagon-like peptide 1 receptor agonists (GLP1RAs) (WMD = -15.48, 95% CI: -30.93, -0.02). Ultimately, SGLT2is and GLP1RAs were superior to other diabetes medications or placebo in reducing liver fat fraction (LFF) (WMD = -6.09, 95% CI: -10.50, -1.68; WMD = -5.55, 95% CI: -10.40, -0.69, respectively). CONCLUSION Diabetes medications, including TZD, DPP4i and GLP1RAs, were found to be suitable alternatives for liver enzyme reduction in the treatment of NAFLD patients. SGLT2is are considered the most effective therapies for lipid modulation in these patients.
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Affiliation(s)
- Cai-Yan Zou
- Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China
| | - Yan Sun
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China
| | - Jun Liang
- Medical College, Soochow University, Suzhou, Jiangsu 215123, China; Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, China.
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Koullias ES, Koskinas J. Pharmacotherapy for Non-alcoholic Fatty Liver Disease Associated with Diabetes Mellitus Type 2. J Clin Transl Hepatol 2022; 10:965-971. [PMID: 36304499 PMCID: PMC9547270 DOI: 10.14218/jcth.2021.00564] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 04/14/2022] [Accepted: 04/27/2022] [Indexed: 12/04/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus type 2 commonly coexist as a manifestation of metabolic syndrome. The presence of diabetes promotes the progression of simple fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis, and the presence of NAFLD increases the risk of diabetic complications. This coexistence affects a large part of the population, imposing a great burden on health care systems worldwide. Apart from diet modification and exercise, recent advances in the pharmacotherapy of diabetes offer new prospects regarding liver steatosis and steatohepatitis improvement, enriching the existing algorithm and supporting a multifaceted approach to diabetic patients with fatty liver disease. These agents mainly include members of the families of glucagon-like peptide-1 analogues and the sodium-glucose co-transporter-2 inhibitors. In addition, agents acting on more than one receptor simultaneously are presently under study, in an attempt to further enhance our available options.
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Affiliation(s)
- Emmanouil S. Koullias
- Correspondence to: Emmanouil S. Koullias, 2nd Department of Internal Medicine, National and Kapodistrian University of Athens, Ampelokipoi, Athens, Greece. ORCID: https://orcid.org/0000-0002-4037-7123. Tel: +69-4-5631-395, E-mail:
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Galatou E, Mourelatou E, Hatziantoniou S, Vizirianakis IS. Nonalcoholic Steatohepatitis (NASH) and Atherosclerosis: Explaining Their Pathophysiology, Association and the Role of Incretin-Based Drugs. Antioxidants (Basel) 2022; 11:1060. [PMID: 35739957 PMCID: PMC9220192 DOI: 10.3390/antiox11061060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/23/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the most severe manifestation of nonalcoholic fatty liver disease (NAFLD), a common complication of type 2 diabetes, and may lead to cirrhosis and hepatocellular carcinoma. Oxidative stress and liver cell damage are the major triggers of the severe hepatic inflammation that characterizes NASH, which is highly correlated with atherosclerosis and coronary artery disease. Regarding drug therapy, research on the role of GLP-1 analogues and DPP4 inhibitors, novel classes of antidiabetic drugs, is growing. In this review, we outline the association between NASH and atherosclerosis, the underlying molecular mechanisms, and the effects of incretin-based drugs, especially GLP-1 RAs, for the therapeutic management of these conditions.
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Affiliation(s)
- Eleftheria Galatou
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
| | - Elena Mourelatou
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
| | - Sophia Hatziantoniou
- Laboratory of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, University of Patras, 26504 Patras, Greece;
| | - Ioannis S. Vizirianakis
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417 Nicosia, Cyprus;
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines 2022; 10:274. [PMID: 35203484 PMCID: PMC8869100 DOI: 10.3390/biomedicines10020274] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.
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Affiliation(s)
- Veronika A. Prikhodko
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
| | - Natalia N. Bezborodkina
- Zoological Institute, Russian Academy of Sciences, 1 Universitetskaya emb., 199034 St. Petersburg, Russia;
| | - Sergey V. Okovityi
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia
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Fu ZD, Cai XL, Yang WJ, Zhao MM, Li R, Li YF. Novel glucose-lowering drugs for non-alcoholic fatty liver disease. World J Diabetes 2021; 12:84-97. [PMID: 33520110 PMCID: PMC7807257 DOI: 10.4239/wjd.v12.i1.84] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/22/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The efficacy of novel glucose-lowering drugs in treating non-alcoholic fatty liver disease (NAFLD) is unknown.
AIM To evaluate the efficacy of glucose-lowering drugs dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors in treating NAFLD and to perform a comparison between these treatments.
METHODS Electronic databases were systematically searched. The inclusion criteria were: Randomized controlled trials comparing DPP-4 inhibitors, GLP-1 RAs, or SGLT2 inhibitors against placebo or other active glucose-lowering drugs in NAFLD patients, with outcomes of changes in liver enzyme [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] from baseline.
RESULTS Nineteen studies were finally included in this meta-analysis. Compared with placebo or other active glucose-lowering drug treatment, treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors all led to a significant decrease in ALT change and AST change from baseline. The difference between the DPP-4 inhibitor and SGLT2 inhibitor groups in ALT change was significant in favor of DPP-4 inhibitor treatment (P < 0.05). The trends of reduction in magnetic resonance imaging proton density fat fraction and visceral fat area changes were also observed in all the novel glucose-lowering agent treatment groups.
CONCLUSION Treatment with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors resulted in improvements in serum ALT and AST levels and body fat composition, indicating a beneficial effect in improving liver injury and reducing liver fat in NAFLD patients.
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Affiliation(s)
- Zuo-Di Fu
- Department of Endocrinology, Beijing Friendship Hospital Pinggu Campus, Beijing 101200, China
| | - Xiao-Ling Cai
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Wen-Jia Yang
- Department of Endocrinology and Metabolism, Peking University People’s Hospital, Beijing 100044, China
| | - Ming-Ming Zhao
- The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100079, China
| | - Ran Li
- Sport Science School, Beijing Sport University, Beijing 100078, China
| | - Yu-Feng Li
- Department of Endocrinology, Beijing Friendship Hospital Pinggu Campus, Capital Medical University, Beijing 101200, China
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Hsieh MH, Kao TY, Hsieh TH, Kao CC, Peng CY, Lai HC, Chuang PH, Kao JT. Prognostic roles of diabetes mellitus and hypertension in advanced hepatocellular carcinoma treated with sorafenib. PLoS One 2021; 15:e0244293. [PMID: 33382703 PMCID: PMC7775090 DOI: 10.1371/journal.pone.0244293] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 12/08/2020] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND & AIMS It remains limited whether diabetes mellitus (DM) and hypertension (HTN) affect the prognosis of advanced hepatocellular carcinoma (HCC) treated with sorafenib. Our study attempted to elucidate the roles of DM/HTN and the effects of diabetes medications among advanced HCC patients receiving sorafenib. METHODS From August 2012 to February 2018, 733 advanced HCC patients receiving sorafenib were enrolled at China Medical University, Taichung, Taiwan. According to the presence/absence of DM or HTN, they were divided into four groups: control [DM(-)/HTN(-), n = 353], DM-only [DM(+)/HTN(-), n = 91], HTN-only [DM(-)/HTN(+), n = 184] and DM+HTN groups [DM(+)/HTN(+), n = 105]. Based on the types of diabetes medications, there were three groups among DM patients (the combined cohort of DM-only and DM+HTN groups), including metformin (n = 63), non-metformin oral hypoglycemic agent (OHA) (n = 104) and regular insulin (RI)/neutral protamine hagedorn (NPH) groups (n = 29). We then assessed the survival differences between these groups. RESULTS DM-only and DM+HTN groups significantly presented longer overall survival (OS) than control group (control vs. DM-only, 7.70 vs. 11.83 months, p = 0.003; control vs. DM+HTN, 7.70 vs. 11.43 months, p = 0.008). However, there was no significant OS difference between control and HTN-only group (7.70 vs. 8.80 months, p = 0.111). Besides, all groups of DM patients showed significantly longer OS than control group (control vs. metformin, 7.70 vs. 12.60 months, p = 0.011; control vs. non-metformin OHA, 7.70 vs. 10.80 months, p = 0.016; control vs. RI/NPH, 7.70 vs. 15.20 months, p = 0.026). CONCLUSIONS Rather than HTN, DM predicts better prognosis in advanced HCC treated with sorafenib. Besides, metformin, non-metformin OHA and RI/NPH are associated with longer survival among DM-related advanced HCC patients receiving sorafenib.
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Affiliation(s)
- Ming-Han Hsieh
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Tzu-Yu Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ting-Hui Hsieh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chun-Chi Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Yuan Peng
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Hsueh-Chou Lai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Po-Heng Chuang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jung-Ta Kao
- Department of Medicine, School of Medicine, China Medical University, Taichung, Taiwan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
- * E-mail:
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Vincent RK, Williams DM, Evans M. A look to the future in non-alcoholic fatty liver disease: Are glucagon-like peptide-1 analogues or sodium-glucose co-transporter-2 inhibitors the answer? Diabetes Obes Metab 2020; 22:2227-2240. [PMID: 32945071 DOI: 10.1111/dom.14196] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/19/2020] [Accepted: 09/03/2020] [Indexed: 12/18/2022]
Abstract
The increasing prevalence of diabetes and non-alcoholic fatty liver disease (NAFLD) is a growing public health concern associated with significant morbidity, mortality and economic cost, particularly in those who progress to cirrhosis. Medical treatment is frequently limited, with no specific licensed treatments currently available for people with NAFLD. Its association with diabetes raises the possibility of shared mechanisms of disease progression and treatment. With the ever-growing interest in the non-glycaemic effects of diabetes medications, studies and clinical trials have investigated hepatic outcomes associated with the use of drug classes used for people with type 2 diabetes (T2D), such as glucagon-like peptide-1 (GLP-1) analogues or sodium-glucose co-transporter-2 (SGLT2) inhibitors. Studies exploring the use of GLP-1 analogues or SGLT2 inhibitors in people with NAFLD have observed improved measures of hepatic inflammation, liver enzymes and radiological features over short periods. However, these studies tend to have variable study populations and inconsistent reported outcomes, limiting comparison between drugs and drug classes. As these drugs appear to improve biomarkers of NAFLD, clinicians should consider their use in patients with NAFLD and T2D. However, further evidence with greater participant numbers and longer trial durations is required to support specific licensing for people with NAFLD. Larger trials would allow reporting of major adverse hepatic events, akin to cardiovascular and renal outcome trials, to be determined. This would provide a more meaningful evaluation of the impact of these drugs in NAFLD. Nevertheless, these drugs represent a future potential therapeutic avenue in this difficult-to-treat population and may beget significant health and economic impacts.
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Affiliation(s)
- Rebecca K Vincent
- Department of Gastroenterology, University Hospital Llandough, Cardiff, UK
| | - David M Williams
- Department of Diabetes and Endocrinology, University Hospital Llandough, Cardiff, UK
| | - Marc Evans
- Department of Diabetes and Endocrinology, University Hospital Llandough, Cardiff, UK
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14
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Kim KS, Lee BW. Beneficial effect of anti-diabetic drugs for nonalcoholic fatty liver disease. Clin Mol Hepatol 2020; 26:430-443. [PMID: 32791578 PMCID: PMC7641556 DOI: 10.3350/cmh.2020.0137] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder and is associated with various metabolic diseases, including type 2 diabetes mellitus. There are no approved drugs for NAFLD, and the only approved treatment option is weight reduction. As insulin resistance plays an important role in the development of NAFLD, many anti-diabetic drugs have been evaluated for the treatment of NAFLD. Improvement of liver enzymes has been demonstrated by many anti-diabetic drugs, but histological assessment still remains insufficient. Pioglitazone could become the first-line therapy for T2DM patients with NAFLD, based on evidence of histological improvement in patients with biopsy-proven nonalcoholic steatohepatitis (NASH). Liraglutide, another promising alternative, is not yet recommended in patients with NAFLD/NASH due to limited evidence. Therefore, well-designed randomized controlled trials should be performed in the near future to demonstrate if and how anti-diabetic drugs can play a role in the treatment of NAFLD.
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Affiliation(s)
- Kyung-Soo Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
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15
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Chen L, Zhang X, Zhang L, Zheng D. Effect of Saxagliptin, a Dipeptidyl Peptidase 4 Inhibitor, on Non-Alcoholic Fatty Liver Disease. Diabetes Metab Syndr Obes 2020; 13:3507-3518. [PMID: 33116702 PMCID: PMC7547785 DOI: 10.2147/dmso.s262284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/04/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND AND AIM Non-alcoholic fatty liver disease (NAFLD) represents a broad spectrum of chronic liver disease characterized by aberrant accumulation of triglycerides (TG) in hepatocytes without excessive alcohol consumption. Hepatic lipotoxicity derived from overaccumulation of free fatty acids is considered as one of the typical hallmarks of NAFLD. Insulin resistance (IR) and chronic inflammation are widely recognized as the key etiological factors associated with NAFLD. Dipeptidyl peptidase 4 inhibitor (DPP4i) is a novel pharmacological agent extensively applied in the treatment of Type 2 Diabetes Mellitus (T2DM) for decades which also have a liver protective effect. METHODS In order to invest the therapeutic efficiency and underlying mechanism of DPP4i saxagliptin, we used high-fat diet (HFD) and streptozotocin-induced NAFLD treated with saxagliptin. Biochemical, histomorphological, genetic and protein expression of related pathways were investigated. RESULTS Fasting blood glucose (FBG), TG, total cholesterol (TC), and low-density lipoprotein cholesterin significantly increased in NAFLD group, which also exhibited severe steatosis. Other remarkable findings were hyperinsulinemia, increased DPP4, PTP-1B and TNF-α level and decreased GLP-1, ACOX-1, CPT-1A expression, concomitant with liver DPP4 expression enhancement and serum DPP4 elevation. These undesirable consequences were alleviated by saxagliptin to a certain degree. CONCLUSION DPP4i saxagliptin improves NAFLD by ameliorating IR, inflammation, downregulation of hepatic DPP4 and sDPP4, as well as subsequent steatosis. The elevation of hepatic DPP4 and sDPP4 and succedent post-treatment decrease suggested that DPP4 may involve in the development of NAFLD. The anti-lipotoxic effect of DPP4i may involve the activation of CPT1A and ACOX1 related β-oxidation signaling pathway suppression of TNF-α mediated inflammatory and PTP-1B. The results covered in this article showed that saxagliptin affects many aspects of the pathological characteristics of NAFLD, suggesting that DPP4i saxagliptin may offer a novel therapeutic option for NAFLD.
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Affiliation(s)
- Lin Chen
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China
| | - Xiujuan Zhang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China
| | - Li Zhang
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China
| | - Dongmei Zheng
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China
- Correspondence: Dongmei Zheng Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province250021, People’s Republic of ChinaTel + 86 531 68776375 Email
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Ranjbar G, Mikhailidis DP, Sahebkar A. Effects of newer antidiabetic drugs on nonalcoholic fatty liver and steatohepatitis: Think out of the box! Metabolism 2019; 101:154001. [PMID: 31672448 DOI: 10.1016/j.metabol.2019.154001] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 10/02/2019] [Accepted: 10/15/2019] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western societies and a major cause of hepatic disease worldwide. Its more severe type, namely nonalcoholic steatohepatitis (NASH), may result in the development of cirrhosis and hepatocellular carcinoma. NAFLD, and especially NASH, are also associated with increased cardiovascular morbidity and mortality. Type 2 diabetes mellitus (T2DM) predisposes to NAFLD development and progression via insulin resistance and hyperglycemia. It has also been reported that the majority of T2DM patients have NAFLD/NASH, thus potentially further increasing their cardiometabolic risk. Current guidelines recommend to screen for NAFLD in all T2DM patients and vice-versa. Lifestyle remains the first-line therapeutic option for NAFLD/NASH. Among antidiabetic drugs, pioglitazone was shown to improve histological features of NASH. More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH. The present narrative review considers the up-to-date data on the impact of DPP-4i, SGLT2i, and GLP-1 RAs on biochemical and/or histological markers of NAFLD/NASH. The potential clinical implications of these findings in daily practice are also discussed. Taking into consideration the global increasing prevalence of NAFLD/NASH, therapeutic options that can prevent or treat this disease will exert considerable benefits on human health.
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Affiliation(s)
- Golnaz Ranjbar
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Liu YY, Feng XY, Jia WQ, Jing Z, Xu WR, Cheng XC. Virtual identification of novel PPARα/γ dual agonists by 3D-QSAR, molecule docking and molecular dynamics studies. J Biomol Struct Dyn 2019; 38:2672-2685. [DOI: 10.1080/07391102.2019.1656110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Affiliation(s)
- Ya-Ya Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Xiao-Yan Feng
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Wen-Qing Jia
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Zhi Jing
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
| | - Wei-Ren Xu
- Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, China
| | - Xian-Chao Cheng
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China
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