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Li WY, Chen H, Lin D, Zhang T, Chen YL, Jin T, Cao MJ. Purification, crystal structural characterization of porcine kidney dipeptidyl peptidase IV (PkDPP-IV) and its interaction with oyster derived inhibitory peptide ILAPPER. Int J Biol Macromol 2025; 298:140047. [PMID: 39828169 DOI: 10.1016/j.ijbiomac.2025.140047] [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: 07/11/2024] [Revised: 01/01/2025] [Accepted: 01/16/2025] [Indexed: 01/22/2025]
Abstract
Dipeptidyl peptidase IV (DPP-IV) is an important target enzyme for the treatment of type 2 diabetes mellitus (T2DM). Increasing researchers try to screen DPP-IV inhibitory peptides while the cost of DPP-IV is high. In this study, PkDPP-IV was efficiently purified by acid precipitation, ammonium sulfate salting out and gel filtration chromatography with a purification of 283.5 folds and 16.5 % yield. PkDPP-IV is a glycoprotein with molecular weight of 110 kDa and optimal activity at pH 7.0 and 40 °C. Crystal structure indicated that PkDPP-IV is composed of an α/β hydrolase domain and a β-propeller domain, which is highly similar to that of human DPP-IV. A peptide ILAPPER derived from oyster exhibited high inhibitory activity with Ki value of 0.131 μM against PkDPP-IV. The crystal structure of the PkDPP-IV + ILAPPER complex revealed that ILAPPER stably occupy the S1 and S2 catalytic pockets of PkDPP-IV by forming three hydrogen bonds with Tyr-547, Ser-630, and Tyr-662, thereby inhibiting enzyme activity. Analysis of transmembrane transport pathway suggested that ILAPPER is transported by the Caco-2 cell monolayer via the paracellular pathway. All the results provide a new approach for rapid preparation of natural PkDPP-IV, and the potential application of ILAPPER as an antihyperglycemic peptide in functional foods.
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Affiliation(s)
- Wan-Yu Li
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
| | - Hong Chen
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
| | - Duanquan Lin
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
| | - Tuo Zhang
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China
| | - Yu-Lei Chen
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
| | - Tengchuan Jin
- CAS Key Laboratory of innate immunity and chronic disease, CAS Center for Excellence in Molecular Cell Science, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui 230007, China
| | - Min-Jie Cao
- College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China.
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Ali S, Shaikh S, Ahmad K, Choi I. Identification of active compounds as novel dipeptidyl peptidase-4 inhibitors through machine learning and structure-based molecular docking simulations. J Biomol Struct Dyn 2025; 43:1611-1620. [PMID: 38100571 DOI: 10.1080/07391102.2023.2292299] [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: 07/25/2023] [Accepted: 11/23/2023] [Indexed: 12/17/2023]
Abstract
The enzyme dipeptidyl peptidase 4 (DPP4) is a potential therapeutic target for type 2 diabetes (T2DM). Many synthetic anti-DPP4 medications are available to treat T2DM. The need for secure and efficient medicines has been unmet due to the adverse side effects of existing DPP4 medications. The present study implemented a combined approach to machine learning and structure-based virtual screening to identify DPP4 inhibitors. Two ML models were trained based on DPP4 IC50 datasets. The ML models random forest (RF) and multilayer perceptron (MLP) neural network showed good accuracy, with the area under the curve being 0.93 and 0.91, respectively. The natural compound library was screened through ML models, and 1% (217) of compounds were selected for further screening. Structure-based virtual screening was performed along with positive control sitagliptin to obtain more specific and selective leads for DPP4. Based on binding affinity, drug-likeness properties, and interaction with DPP4, Z-614 and Z-997 compounds showed high binding affinity and specificity in the catalytic pocket of DPP4. Finally, the stability conformation of the DPP4 enzyme complex was checked by a molecular dynamics (MD) simulation. The MD simulation showed that both compounds bind better in the catalytic pocket, but the Z-614 compound altered the DPP4 native conformation. Therefore, Z-614 showed a high deviation in the backbone. This combined approach (ML and structure-based) study reported that Z-997 binds most stably to DPP4 in their catalytic pocket with a binding free energy of -70.3 kJ/mol, suggesting its therapeutic potential as a treatment option for T2DM disease.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Shahid Ali
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, South Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan, South Korea
| | - Sibhghatulla Shaikh
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, South Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan, South Korea
| | - Khurshid Ahmad
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, South Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan, South Korea
| | - Inho Choi
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan, South Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan, South Korea
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Duță C, Muscurel C, Dogaru CB, Stoian I. Targeting Ferroptosis in Parkinson's: Repurposing Diabetes Drugs as a Promising Treatment. Int J Mol Sci 2025; 26:1516. [PMID: 40003982 PMCID: PMC11855881 DOI: 10.3390/ijms26041516] [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: 12/31/2024] [Revised: 02/02/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
This review explores the promising potential of repurposing type 2 diabetes (T2D) medications for the treatment of Parkinson's disease (PD), highlighting the shared pathophysiological mechanisms between these two age-related conditions, such as oxidative stress, mitochondrial dysfunction, and ferroptosis. The overlap suggests that existing diabetes drugs could target the common pathways involved in both conditions. Specifically, the review discusses how T2D medications, including metformin (Met), peroxisome-proliferator-activated receptor gamma (PPAR-γ) agonists, sodium-glucose cotransporter-2 (SGLT2) inhibitors, incretins, and dipeptidyl-peptidase 4 (DPP-4) inhibitors, can improve mitochondrial function, reduce neuroinflammation and oxidative stress, and potentially inhibit ferroptosis. The connection between ferroptosis and existing treatments, including diabetes medication, are only beginning to be explored. The limited data can be attributed also to the complexity of mechanisms involved in ferroptosis and Parkinson's disease and to the fact that the specific role of ferroptosis in Parkinson's disease pathogenesis has not been a primary focus until recent. Despite the promising preclinical evidence, clinical findings are mixed, underscoring the need for further research to elucidate these drugs' roles in neurodegeneration. Repurposing existing diabetes medications that have well-established safety profiles for Parkinson's disease treatment could significantly reduce the time and cost associated with drug development and could offer a more comprehensive approach to managing Parkinson's disease compared to treatments targeting a single mechanism.
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Affiliation(s)
| | | | - Carmen Beatrice Dogaru
- Department of Biochemistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.D.); (C.M.); (I.S.)
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Liao HW, Cheng CY, Chen HY, Chen JY, Pan HC, Huang TM, Wu VC. Dipeptidyl peptidase 4 inhibitors reduce the risk of adverse outcomes after acute kidney injury in diabetic patients. Clin Kidney J 2025; 18:sfae385. [PMID: 39927258 PMCID: PMC11806628 DOI: 10.1093/ckj/sfae385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Indexed: 02/11/2025] Open
Abstract
Background Dipeptidyl peptidase 4 inhibitors (DPP4is) are considered safe for use in patients with diabetes mellitus and kidney dysfunction. We explored whether usage of DPP4is in patients who recovered from dialysis-requiring acute kidney injury (AKI) could reduce the risk of future cardiac and kidney events. Methods We used the TriNetX platform to investigate whether the use of DPP4is in diabetes mellitus patients within 90 days of discharge from acute kidney disease could reduce the risk of all-cause mortality, major adverse kidney events (MAKEs), major adverse cardiovascular events (MACEs), and re-dialysis. The patients were followed for 5 years or until the occurrence of significant outcomes, with cohort data collected from 1 January 2016 to 30 September 2022. Results The cohort utilizing DPP4is comprised 7348 patients with acute kidney disease, while the control group encompassed 229 417 individuals. After applying propensity score matching, 7343 patients (age 66.2 ± 13.4 years; male, 49.9%) who used DPP4is showed a significant reduction in the risk of all-cause mortality [adjusted hazard ratio (aHR) 0.89; E-value 1.50 , MAKEs (aHR 0.86; E-value 1.59), MACEs (aHR 0.91; E-value 1.44), and re-dialysis (aHR 0.73; E-value 2.10) after a median follow-up of 2.4 years. Conclusions We demonstrated that in diabetes mellitus patients concurrently experiencing acute kidney disease, DPP4i usage could decrease the risk of mortality, MAKEs, MACEs, and re-dialysis. These findings emphasize the pivotal role of tailored treatment strategies involving DPP4i for acute kidney disease patients.
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Affiliation(s)
- Hung-Wei Liao
- Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chung-Yi Cheng
- Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Taipei Medical University-Research Center of Urology and Kidney (RCUK), School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Hsing-Yu Chen
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jui-Yi Chen
- Division of Nephrology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
- Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Heng-Chih Pan
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
- Chang Gung University College of Medicine, Taoyuan, Taiwan
- Division of Nephrology, Department of Internal Medicine, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- Community Medicine Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Tao-Min Huang
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Vin-Cent Wu
- Primary Aldosteronism Center of Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- NSARF (National Taiwan University Hospital Study Group of ARF), TAIPAI (Taiwan Primary Aldosteronism Investigators), and CAKS (Taiwan Consortium for Acute Kidney Injury and Renal Diseases), Taipei, Taiwan
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Khan F, Hussain T, Chaudhry TZ, Payal F, Shehryar A, Rehman A, Ramadhan A, Hayat MT, Dabas MM, Khan M. Comparing the Efficacy and Long-Term Outcomes of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors, Dipeptidyl Peptidase-4 (DPP-4) Inhibitors, Metformin, and Insulin in the Management of Type 2 Diabetes Mellitus. Cureus 2024; 16:e74400. [PMID: 39723311 PMCID: PMC11669386 DOI: 10.7759/cureus.74400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2024] [Indexed: 12/28/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia, insulin resistance, and decreased insulin secretion. With its rising global prevalence, effective management strategies are critical to reducing morbidity and mortality. This systematic review compares the efficacy, safety, and long-term outcomes of four major pharmacological treatments for T2DM: sodium-glucose cotransporter-2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, and insulin. We focused on randomized controlled trials (RCTs) published within the last five years (2019-2024) to provide an up-to-date assessment of glycemic control, cardiovascular and renal benefits, weight effects, and the risk of hypoglycemia. The review highlights that while all four medication classes effectively reduce HbA1c levels, SGLT2 inhibitors stand out for their additional cardiovascular and renal benefits, including significant reductions in major adverse cardiovascular events and chronic kidney disease progression. Metformin remains a cornerstone first-line therapy due to its safety, efficacy, and affordability. DPP-4 inhibitors are a weight-neutral, well-tolerated option, although their efficacy may diminish over time. Insulin, while the most potent glucose-lowering agent, carries a higher risk of hypoglycemia and weight gain. Our findings emphasize the importance of personalized, patient-centered approaches that account for the distinct therapeutic profiles of these treatments. Future research should prioritize head-to-head comparisons and optimal therapy sequencing to refine treatment guidelines for diverse patient populations.
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Affiliation(s)
- Farhan Khan
- Internal Medicine, Rehman Medical Institute, Peshawar, PAK
| | - Tanjil Hussain
- Internal Medicine, London North West Hospitals NHS Trust, London, GBR
| | | | - Fnu Payal
- Internal Medicine, Ghulam Muhammad Mahar Medical College, Karachi, PAK
| | | | | | - Afif Ramadhan
- Internal Medicine, Gadjah Mada University, Yogyakarta, IDN
| | - Muhammad Tassaduq Hayat
- Internal Medicine, Chandka Medical College, Larkana, PAK
- Internal Medicine, Shaheed Mohtarma Benazir Bhutto Medical University, Larkana, PAK
| | | | - Mustafa Khan
- General Surgery, Nishtar Medical University, Multan, PAK
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Zakaria EM, El-Gamal SF, Mahmoud SM, El-Nahas HM, El-Bassossy HM. Sustained linagliptin administration: superior glycemic control and less pancreatic injury in diabetic rats. Pharm Dev Technol 2024; 29:874-885. [PMID: 39311002 DOI: 10.1080/10837450.2024.2407852] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 09/19/2024] [Indexed: 10/01/2024]
Abstract
While linagliptin is the most potent dipeptidyl peptidase 4 inhibitor, its use is limited due to poor bioavailability and the potential risk of pancreatic injury. Here, we investigated whether the sustained weekly administration of linagliptin could provide better effect compared to frequent daily oral administration. Type 2 diabetes was induced by feeding rats a high fructose/fat/salt diet followed by STZ injection. Compared to the partial glycemic control achieved with daily oral linagliptin, a weekly subcutaneous injection containing about one-fourth of the oral dose produced superior glycemic control, as evidenced by the 4-week postprandial glucose follow-up and oral glucose tolerance test. This was confirmed by the significant increase in serum insulin in the case of the sustained linagliptin administration. Higher levels of the anti-inflammatory cytokine adiponectin and lower triglyceride levels were observed after sustained linagliptin administration compared with daily oral linagliptin. In addition, sustained linagliptin displayed a significant increase in β-cells' insulin immunoreactivity when compared with daily linagliptin. More reduction in collagen deposition and caspase-3 immunoreactivity in pancreatic tissue were observed in sustained linagliptin compared with oral linagliptin. In conclusion, sustained linagliptin administration provided superior glycemic control, which seems to be mediated by more reduction in pancreatic injury.
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Affiliation(s)
- Esraa M Zakaria
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Shrouk Fayrouz El-Gamal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Samar Mortada Mahmoud
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Hanan M El-Nahas
- Department of Pharmaceutics, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Hany M El-Bassossy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
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Pradhan SP, Behera A, Sahu PK. Effect of selenium nanoparticles conjugated Vildagliptin on cognitive dysfunction associated with Diabetes mellitus. J Drug Deliv Sci Technol 2024; 98:105907. [DOI: 10.1016/j.jddst.2024.105907] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Chamberlin ML, Peach JT, Wilson SM, Miller ZT, Bothner B, Walk ST, Yeoman CJ, Miles MP. Polyphenol-Rich Aronia melanocarpa Fruit Beneficially Impact Cholesterol, Glucose, and Serum and Gut Metabolites: A Randomized Clinical Trial. Foods 2024; 13:2768. [PMID: 39272533 PMCID: PMC11395532 DOI: 10.3390/foods13172768] [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: 07/19/2024] [Revised: 08/23/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
Polyphenol-rich Aronia fruits have great potential as a functional food with anti-inflammatory, hypolipidemic, and hypoglycemic biologic activities. However, clinical intervention trials investigating the impact of Aronia fruit consumption on human health are limited. A randomized, controlled, double-blinded, parallel intervention trial was conducted using 14 human subjects who ingested either 0 mL or 100 mL of Aronia juice daily for 30 days. Anthropometric measurements, fasting, and postprandial measures of glucose and lipid metabolism and inflammation, 16S rRNA fecal microbial composition data, and mass spectrometry-acquired serum and fecal metabolomic data were collected before and after the intervention period. Data were analyzed using general linear models, ANOVA, and t-tests. Daily consumption of Aronia prevented a rise in cholesterol levels (β = -0.50, p = 0.03) and reduced postprandial glucose (β = -3.03, p < 0.01). No difference in microbial community composition by condition was identified at any taxonomic level, but a decrease (β = -18.2, p = 0.04) in microbial richness with Aronia was detected. Serum and fecal metabolomic profiles indicated shifts associated with central carbon and lipid metabolism and decreases in pro-inflammatory metabolites. Our study further informs the development of polyphenol-based dietary strategies to lower metabolic disease risk.
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Affiliation(s)
- Morgan L. Chamberlin
- Department of Food Systems, Nutrition, and Kinesiology, Montana State University, Bozeman, MT 59717, USA; (M.L.C.)
| | - Jesse T. Peach
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
- Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Stephanie M.G. Wilson
- Department of Food Systems, Nutrition, and Kinesiology, Montana State University, Bozeman, MT 59717, USA; (M.L.C.)
- United States Department of Agriculture, Agricultural Research Service Western Human Nutrition Research Center, Davis, CA 95616, USA
- Institute for Advancing Health through Agriculture, Texas A&M, College Station, TX 77845, USA
| | - Zachary T. Miller
- Department of Research Centers, Montana State University, Bozeman, MT 59717, USA
| | - Brian Bothner
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA
| | - Seth T. Walk
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA
| | - Carl J. Yeoman
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA
- Department of Animal and Range Sciences, Montana State University, Bozeman, MT 59717, USA
| | - Mary P. Miles
- Department of Food Systems, Nutrition, and Kinesiology, Montana State University, Bozeman, MT 59717, USA; (M.L.C.)
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Huang KH, Yang Y, Gau SY, Tsai TH, Lee CY. Association between dipeptidyl peptidase-4 inhibitor use and risk of Parkinson's disease among patients with diabetes mellitus: a retrospective cohort study. Aging (Albany NY) 2024; 16:11994-12007. [PMID: 39177655 PMCID: PMC11386917 DOI: 10.18632/aging.206074] [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: 09/27/2023] [Accepted: 07/11/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND How a person's Parkinson disease (PD) risk is affected by dipeptidyl peptidase-4 (DPP-4) inhibitors remains unclear. We evaluated the association of PD risk with use of these inhibitors in individuals diagnosed as having diabetes mellitus (DM). METHODS Individuals diagnosed as having new-onset DM were enrolled into the case group and comparison group, comprising patients who received a DPP-4 inhibitor and a sulfonylurea, respectively. These groups were matched through propensity score matching on the basis of income level, gender, urbanization level, enrollment year, age, and diabetes complications severity index score. The case group was divided into subgroups on the basis of whether they had a cumulative defined daily dose (cDDD) of <75, 75-150, or >150. The DPP-4 inhibitor-PD risk association was evaluated through a Cox proportional hazards model. The Bonferroni adjustment test was employed to adjust P-values and reduce the false positive rate. RESULTS Compared with those in the comparison group (treatment with a sulfonylurea), patients with a DPP-4 inhibitor cDDD of >150 had a hazard ratio (HR) of 1.30 for PD development (95% confidence interval [CI]: 0.97-1.73; adjusted P = .263); the HRs for patients with a cDDD of <75 or 75-150 were 0.95 (95% CI: 0.71-1.27; adjusted P = .886) and 1.06 (95% CI: 0.75-1.50; adjusted P = .886), respectively. We noted nonsignificant differences regarding the associations between the use of the various DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) and PD risk after adjustment for any individual inhibitor (adjusted P > .05). CONCLUSIONS DPP-4 inhibitors were discovered in this study to not be associated with increased PD risk. This result was confirmed when the analysis was conducted individually for the 4 investigated DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and vildagliptin).
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Affiliation(s)
- Kuang-Hua Huang
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan
| | - Yih Yang
- Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan
| | - Shuo-Yan Gau
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Tung-Han Tsai
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan
| | - Chien-Ying Lee
- Department of Pharmacology, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
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Al Madhoun A. Teneligliptin: A potential therapeutic approach for diabetic cardiomyopathy. World J Diabetes 2024; 15:1654-1658. [PMID: 39192857 PMCID: PMC11346098 DOI: 10.4239/wjd.v15.i8.1654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/14/2024] [Accepted: 06/12/2024] [Indexed: 07/25/2024] Open
Abstract
In this editorial, we comment on the article by Zhang et al. Diabetes mellitus is a chronic disorder associated with several complications like cardiomyopathy, neuropathy, and retinopathy. Diabetes prevalence is increasing worldwide. Multiple diabetes medications are prescribed based on individual patients' needs. However, the exact mechanisms by which many of these drugs exert their pro-tective effects remain unclear. Zhang et al elucidates molecular mechanisms undelaying cardioprotective effect of the dipeptidyl peptidase-IV inhibitor, teneligliptin. Briefly, teneligliptin alleviates the activation of NOD-like receptor protein 3 inflammasome, a multiprotein complex that plays a pivotal role in regulating the innate immune system and inflammatory signaling. Suppression of NOD-like receptor protein 3 inflammasome activity reduces the expression of cytokines, oxygen radicals and inflammation. These findings highlight teneligliptin as an anti-diabetic cardioprotective reagent.
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Affiliation(s)
- Ashraf Al Madhoun
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15400, Kuwait
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Nakatani E, Ohno H, Satoh T, Funaki D, Ueki C, Matsunaga T, Nagahama T, Tonoike T, Yui H, Miyakoshi A, Tanaka Y, Igarashi A, Kumamaru H, Kuriyama N, Sugawara A. Comparing the effects of biguanides and dipeptidyl peptidase-4 inhibitors on cardio-cerebrovascular outcomes, nephropathy, retinopathy, neuropathy, and treatment costs in diabetic patients. PLoS One 2024; 19:e0308734. [PMID: 39121166 PMCID: PMC11315305 DOI: 10.1371/journal.pone.0308734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 07/30/2024] [Indexed: 08/11/2024] Open
Abstract
BACKGROUND Western guidelines often recommend biguanides as the first-line treatment for diabetes. However, dipeptidyl peptidase-4 (DPP-4) inhibitors, alongside biguanides, are increasingly used as the first-line therapy for type 2 diabetes (T2DM) in Japan. However, there have been few studies comparing the effectiveness of biguanides and DPP-4 inhibitors with respect to diabetes-related complications and cardio-cerebrovascular events over the long term, as well as the costs associated. OBJECTIVE We aimed to compare the outcomes of patients with T2DM who initiate treatment with a biguanide versus a DPP-4 inhibitor and the long-term costs associated. METHODS We performed a cohort study between 2012 and 2021 using a new-user design and the Shizuoka Kokuho database. Patients were included if they were diagnosed with T2DM. The primary outcome was the incidence of cardio-cerebrovascular events or mortality from the initial month of treatment; and the secondary outcomes were the incidences of related complications (nephropathy, renal failure, retinopathy, and peripheral neuropathy) and the daily cost of the drugs used. Individuals who had experienced prior events during the preceding year were excluded, and events within 6 months of the start of the study period were censored. Propensity score matching was performed to compare between two groups. RESULTS The matched 1:5 cohort comprised 529 and 2,116 patients who were initially treated with a biguanide or a DPP-4 inhibitor, respectively. Although there were no significant differences in the incidence of cardio-cerebrovascular events or mortality and T2DM-related complications between the two groups (p = 0.139 and p = 0.595), daily biguanide administration was significantly cheaper (mean daily cost for biguanides, 61.1 JPY; for DPP-4 inhibitors, 122.7 JPY; p<0.001). CONCLUSION In patients with T2DM who initiate pharmacotherapy, there were no differences in the long-term incidences of cardio-cerebrovascular events or complications associated with biguanide or DPP-4 use, but the former was less costly.
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Affiliation(s)
- Eiji Nakatani
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
- Shizuoka General Hospital, Shizuoka, Japan
- Allied Medical K.K., Tokyo, Japan
| | | | - Tatsunori Satoh
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
- Shizuoka General Hospital, Shizuoka, Japan
| | - Daito Funaki
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
| | - Chikara Ueki
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
| | - Taku Matsunaga
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
| | - Takayoshi Nagahama
- Allied Medical K.K., Tokyo, Japan
- Institute of Humanistic Social Medicine, Tokyo, Japan
| | | | | | - Akinori Miyakoshi
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
- Shizuoka General Hospital, Shizuoka, Japan
| | - Yoshihiro Tanaka
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
| | - Ataru Igarashi
- Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
- Graduate School of Data Sciences, Yokohama City University School of Medicine, Yokohama, Japan
| | - Hiraku Kumamaru
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
- Department of Healthcare Quality Assessment, The University of Tokyo, Tokyo, Japan
| | - Nagato Kuriyama
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
- Shizuoka General Hospital, Shizuoka, Japan
| | - Akira Sugawara
- Graduate School of Public Health, Shizuoka Graduate University of Public Health, Shizuoka, Japan
- Shizuoka General Hospital, Shizuoka, Japan
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12
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Sandireddy R, Sakthivel S, Gupta P, Behari J, Tripathi M, Singh BK. Systemic impacts of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) on heart, muscle, and kidney related diseases. Front Cell Dev Biol 2024; 12:1433857. [PMID: 39086662 PMCID: PMC11289778 DOI: 10.3389/fcell.2024.1433857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 07/01/2024] [Indexed: 08/02/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is the most common liver disorder worldwide, with an estimated global prevalence of more than 31%. Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as non-alcoholic steatohepatitis (NASH), is a progressive form of MASLD characterized by hepatic steatosis, inflammation, and fibrosis. This review aims to provide a comprehensive analysis of the extrahepatic manifestations of MASH, focusing on chronic diseases related to the cardiovascular, muscular, and renal systems. A systematic review of published studies and literature was conducted to summarize the findings related to the systemic impacts of MASLD and MASH. The review focused on the association of MASLD and MASH with metabolic comorbidities, cardiovascular mortality, sarcopenia, and chronic kidney disease. Mechanistic insights into the concept of lipotoxic inflammatory "spill over" from the MASH-affected liver were also explored. MASLD and MASH are highly associated (50%-80%) with other metabolic comorbidities such as impaired insulin response, type 2 diabetes, dyslipidemia, hypertriglyceridemia, and hypertension. Furthermore, more than 90% of obese patients with type 2 diabetes have MASH. Data suggest that in middle-aged individuals (especially those aged 45-54), MASLD is an independent risk factor for cardiovascular mortality, sarcopenia, and chronic kidney disease. The concept of lipotoxic inflammatory "spill over" from the MASH-affected liver plays a crucial role in mediating the systemic pathological effects observed. Understanding the multifaceted impact of MASH on the heart, muscle, and kidney is crucial for early detection and risk stratification. This knowledge is also timely for implementing comprehensive disease management strategies addressing multi-organ involvement in MASH pathogenesis.
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Affiliation(s)
| | | | | | | | - Madhulika Tripathi
- Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Medical School, Singapore, Singapore
| | - Brijesh Kumar Singh
- Cardiovascular and Metabolic Disorders Research Program, Duke-NUS Medical School, Singapore, Singapore
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13
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Carpio LE, Olivares M, Benítez-Paez A, Serrano-Candelas E, Barigye SJ, Sanz Y, Gozalbes R. Comparative Binding Study of Gliptins to Bacterial DPP4-like Enzymes for the Treatment of Type 2 Diabetes Mellitus (T2DM). Int J Mol Sci 2024; 25:5744. [PMID: 38891933 PMCID: PMC11171585 DOI: 10.3390/ijms25115744] [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: 04/30/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/21/2024] Open
Abstract
The role of the gut microbiota and its interplay with host metabolic health, particularly in the context of type 2 diabetes mellitus (T2DM) management, is garnering increasing attention. Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, constitute a class of drugs extensively used in T2DM treatment. However, their potential interactions with gut microbiota remain poorly understood. In this study, we employed computational methodologies to investigate the binding affinities of various gliptins to DPP4-like homologs produced by intestinal bacteria. The 3D structures of DPP4 homologs from gut microbiota species, including Segatella copri, Phocaeicola vulgatus, Bacteroides uniformis, Parabacteroides merdae, and Alistipes sp., were predicted using computational modeling techniques. Subsequently, molecular dynamics simulations were conducted for 200 ns to ensure the stability of the predicted structures. Stable structures were then utilized to predict the binding interactions with known gliptins through molecular docking algorithms. Our results revealed binding similarities of gliptins toward bacterial DPP4 homologs compared to human DPP4. Specifically, certain gliptins exhibited similar binding scores to bacterial DPP4 homologs as they did with human DPP4, suggesting a potential interaction of these drugs with gut microbiota. These findings could help in understanding the interplay between gliptins and gut microbiota DPP4 homologs, considering the intricate relationship between the host metabolism and microbial communities in the gut.
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Affiliation(s)
- Laureano E. Carpio
- ProtoQSAR SL, CEEI (Centro Europeo de Empresas Innovadoras), Parque Tecnológico de Valencia, 46980 Valencia, Spain; (L.E.C.); (E.S.-C.)
- MolDrug AI Systems SL, 46018 Valencia, Spain
| | - Marta Olivares
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), 46980 Valencia, Spain; (M.O.); (A.B.-P.); (Y.S.)
| | - Alfonso Benítez-Paez
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), 46980 Valencia, Spain; (M.O.); (A.B.-P.); (Y.S.)
| | - Eva Serrano-Candelas
- ProtoQSAR SL, CEEI (Centro Europeo de Empresas Innovadoras), Parque Tecnológico de Valencia, 46980 Valencia, Spain; (L.E.C.); (E.S.-C.)
| | | | - Yolanda Sanz
- Microbial Ecology, Nutrition and Health Research Unit, Institute of Agrochemistry and Food Technology, Spanish National Research Council (IATA-CSIC), 46980 Valencia, Spain; (M.O.); (A.B.-P.); (Y.S.)
| | - Rafael Gozalbes
- ProtoQSAR SL, CEEI (Centro Europeo de Empresas Innovadoras), Parque Tecnológico de Valencia, 46980 Valencia, Spain; (L.E.C.); (E.S.-C.)
- MolDrug AI Systems SL, 46018 Valencia, Spain
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14
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Hayes MJ. Non-insulin Medications for the Management of Type 2 Diabetes. Home Healthc Now 2024; 42:72-77. [PMID: 38437039 DOI: 10.1097/nhh.0000000000001232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2024]
Abstract
Type 2 diabetes (T2D) is predicted to affect 366 million people over the age of 65 years by the year 2030. As the understanding of the core defects associated with T2D advanced, researchers recognized management should target multiple defects in glucose metabolism. As a result, efforts to manage T2D focus on developing new drug therapies aimed at addressing each of the identified metabolic defects. Optimal treatment of T2D is necessary to decrease the risk for coronary heart disease, stroke, and vascular diseases. This article discusses non-insulin pharmacologic treatments for T2D that are guided by glycemic efficacy, safety profiles, effects on weight and hypoglycemia risk, tolerability, patient comorbidities, route of administration, patient preference, and cost.
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Affiliation(s)
- Marla J Hayes
- Marla J. Hayes, MS, RPh, BCPS, BCGP, CDCES , is the Director, Pharmacy, Winner Regional Health, Winner, South Dakota
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15
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Dash JR, Kar B, Pattnaik G. In-silico, in-vitro and in-vivo Biological Activities of Flavonoids for the Management of Type 2 Diabetes. Curr Drug Discov Technol 2024; 21:e120124225551. [PMID: 38243931 DOI: 10.2174/0115701638290819231228081120] [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: 11/19/2023] [Revised: 12/06/2023] [Accepted: 12/18/2023] [Indexed: 01/22/2024]
Abstract
In spite of the fact that many medicinal plants have been truly utilized for the management of diabetes all through the world, very few of them have been reported scientifically. Recently, a diverse variety of animal models have been established to better understand the pathophysiology of diabetes mellitus, and new medications to treat the condition have been introduced in the market. Flavonoids are naturally occurring substances that can be found in plants and various foods and may have health benefits in the treatment of neuropathic pain. Flavonoids have also been shown to have an anti-inflammatory impact that is significant to neuropathic pain, as indicated by a decrease in several pro-inflammatory mediators such TNF-, NF-B IL-6, and IL-1. Flavonoids appear to be a viable novel therapy option for macrovasular complications in preclinical models; however, human clinical data is still inadequate. Recently, several in silico, in-vitro and in-vivo aproaches were made to evaluate mechanisms associated with the pathogenesis of diabetes in a better way. Screening of natural antidiabetic agents from plant sources can be analysed by utilizing advanced in-vitro techniques and animal models. Natural compounds, mostly derived from plants, have been studied in diabetes models generated by chemical agents in the majority of research. The aim of this work was to review the available in silico, in-vitro and animal models of diabetes for screening of natural antidiabetic agents. This review contributes to the scientist's design of new methodologies for the development of novel therapeutic agents having potential antihyperglycemic activity.
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Affiliation(s)
- Jyoshna Rani Dash
- Department of Pharmacy, Centurion University of Technology and Management, Bhubaneswar, Odisha, 751050, India
| | - Biswakanth Kar
- School of Pharmaceutical Sciences, Siksha O Anusandhan Deemed to be University, Bhubaneswar, Odisha, 751003, India
| | - Gurudutta Pattnaik
- Department of Pharmacy, Centurion University of Technology and Management, Bhubaneswar, Odisha, 751050, India
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16
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Abubakar M, Nama L, Ansari MA, Ansari MM, Bhardwaj S, Daksh R, Syamala KLV, Jamadade MS, Chhabra V, Kumar D, Kumar N. GLP-1/GIP Agonist as an Intriguing and Ultimate Remedy for Combating Alzheimer's Disease through its Supporting DPP4 Inhibitors: A Review. Curr Top Med Chem 2024; 24:1635-1664. [PMID: 38803170 DOI: 10.2174/0115680266293416240515075450] [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: 11/17/2023] [Revised: 04/14/2024] [Accepted: 04/22/2024] [Indexed: 05/29/2024]
Abstract
BACKGROUND Alzheimer's disease (AD) is a widespread neurological illness in the elderly, which impacted about 50 million people globally in 2020. Type 2 diabetes has been identified as a risk factor. Insulin and incretins are substances that have various impacts on neurodegenerative processes. Preclinical research has shown that GLP-1 receptor agonists decrease neuroinflammation, tau phosphorylation, amyloid deposition, synaptic function, and memory formation. Phase 2 and 3 studies are now occurring in Alzheimer's disease populations. In this article, we present a detailed assessment of the therapeutic potential of GLP-1 analogues and DPP4 inhibitors in Alzheimer's disease. AIM This study aimed to gain insight into how GLP-1 analogues and associated antagonists of DPP4 safeguard against AD. METHODS This study uses terms from search engines, such as Scopus, PubMed, and Google Scholar, to explore the role, function, and treatment options of the GLP-1 analogue for AD. RESULTS The review suggested that GLP-1 analogues may be useful for treating AD because they have been linked to anti-inflammatory, neurotrophic, and neuroprotective characteristics. Throughout this review, we discuss the underlying causes of AD and how GLP signaling functions. CONCLUSION With a focus on AD, the molecular and pharmacological effects of a few GLP-1/GIP analogs, both synthetic and natural, as well as DPP4 inhibitors, have been mentioned, which are in the preclinical and clinical studies. This has been demonstrated to improve cognitive function in Alzheimer's patients.
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Affiliation(s)
- Mohammad Abubakar
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Lokesh Nama
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Mohammad Arif Ansari
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Mohammad Mazharuddin Ansari
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Shivani Bhardwaj
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Rajni Daksh
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Katta Leela Venkata Syamala
- Department of Regulatory and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Mohini Santosh Jamadade
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Vishal Chhabra
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
| | - Dileep Kumar
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra, 411038, India
- Department of Entomology, University of California, Davis, One Shields Ave, Davis, CA, 95616, USA
| | - Nitesh Kumar
- Department of Pharmacology and Toxicology, National Institution of Pharmaceutical Education and Research, Hajipur, Vaishali, 844102, Bihar, India
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17
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Xu M, Zhang P, Lv W, Chen Y, Chen M, Leng Y, Hu T, Wang K, Zhao Y, Shen J, You X, Gu D, Zhao W, Tan S. A bifunctional anti-PCSK9 scFv/Exendin-4 fusion protein exhibits enhanced lipid-lowering effects via targeting multiple signaling pathways in HFD-fed mice. Int J Biol Macromol 2023; 253:127003. [PMID: 37739280 DOI: 10.1016/j.ijbiomac.2023.127003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 05/14/2023] [Accepted: 09/17/2023] [Indexed: 09/24/2023]
Abstract
Fusion protein which encompasses more than one functional component, has become one of the most important representatives of macromolecular drugs for disease treatment since that monotherapy itself might not be effective enough to eradicate the disease. In this study, we sought to construct a bifunctional antibody fusion protein by fusing anti-PCSK9 scFv with Exendin-4 for simultaneously lowering both LDL-C and TG. Firstly, three Ex4-anti-PCSK9 scFv fusion proteins were constructed by genetically connecting the C-terminal of Exendin-4 to the N-terminal of anti-PCSK9 scFv through various flexible linker peptides (G4S)n (n = 2, 3, 4). After soluble expression in E. coli, the most potent Ex4-(G4S)4-anti-PCSK9 scFv fusion protein was selected based on in vitro activity assays. Then, we investigated the in vivo therapeutic effects of Ex4-(G4S)4-anti-PCSK9 scFv on the serum lipid profile and bodyweight changes as well as underlying molecular mechanism in HFD-fed C57BL/6 mice. The data showed that Ex4-(G4S)4-anti-PCSK9 scFv exhibits enhanced effects of lowering both LDL-C and TG in serum, reducing food intake and body weight via blocking PCSK9/LDLR, activating AMPK/SREBP-1 pathways, and up-regulating sirt6. Conclusively, Ex4-(G4S)4-anti-PCSK9 has the potential to serve as a promising therapeutic agent for effectively treating dyslipidemia with high levels of both LDL-C and TG.
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Affiliation(s)
- Menglong Xu
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Panpan Zhang
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Wenxiu Lv
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yuting Chen
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Manman Chen
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yeqing Leng
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Tuo Hu
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Ke Wang
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Yaqiang Zhao
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Jiaqi Shen
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Xiangyan You
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Dian Gu
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Wenfeng Zhao
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China
| | - Shuhua Tan
- Department of Cell and Molecular Biology, School of Life Science and Technology, State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, PR China.
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18
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Keller LJ, Nguyen TH, Liu LJ, Hurysz BM, Lakemeyer M, Guerra M, Gelsinger DJ, Chanin R, Ngo N, Lum KM, Faucher F, Ipock P, Niphakis MJ, Bhatt AS, O'Donoghue AJ, Huang KC, Bogyo M. Chemoproteomic identification of a DPP4 homolog in Bacteroides thetaiotaomicron. Nat Chem Biol 2023; 19:1469-1479. [PMID: 37349583 DOI: 10.1038/s41589-023-01357-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 05/08/2023] [Indexed: 06/24/2023]
Abstract
Serine hydrolases have important roles in signaling and human metabolism, yet little is known about their functions in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Our functional studies reveal that BT4193 is a true homolog of hDPP4 that can be inhibited by FDA-approved type 2 diabetes medications targeting hDPP4, while the other is a misannotated proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and that loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. However, neither function is dependent on BT4193 proteolytic activity, suggesting a scaffolding or signaling function for this bacterial protease.
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Affiliation(s)
- Laura J Keller
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA
| | - Taylor H Nguyen
- Department of Bioengineering, Stanford University, Stanford, CA, USA
| | - Lawrence J Liu
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Brianna M Hurysz
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Markus Lakemeyer
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Institute of Organic Chemistry and Macromolecular Chemistry, Friedrich-Schiller-University, Jena, Germany
| | - Matteo Guerra
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- Department of Biochemical and Cellular Pharmacology, Genentech, San Francisco, CA, USA
| | - Danielle J Gelsinger
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Rachael Chanin
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Divisions of Hematology and Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Nhi Ngo
- Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA
| | - Kenneth M Lum
- Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA
| | - Franco Faucher
- Department of Chemistry, Stanford University, Stanford, CA, USA
| | - Phillip Ipock
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Ami S Bhatt
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
- Divisions of Hematology and Blood and Marrow Transplantation, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Anthony J O'Donoghue
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Kerwyn Casey Huang
- Department of Bioengineering, Stanford University, Stanford, CA, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
- Chan Zuckerberg Biohub, San Francisco, CA, USA
| | - Matthew Bogyo
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
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19
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Pasha M, Zamir A, Ashraf W, Imran I, Saeed H, Rehman AU, Aziz M, Alqahtani F, Rasool MF. A systematic review on the clinical pharmacokinetics of vildagliptin in healthy and disease populations. Expert Opin Drug Metab Toxicol 2023; 19:991-1003. [PMID: 38008954 DOI: 10.1080/17425255.2023.2288252] [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: 07/24/2023] [Accepted: 11/22/2023] [Indexed: 11/28/2023]
Abstract
INTRODUCTION Vildagliptin, a dipeptidyl peptidase-4 inhibitor, is indicated to cure type 2 diabetes mellitus (T2DM). This systematic literature search aims to assess the current knowledge about the clinical pharmacokinetics (PK) of vildagliptin to provide recommendations for clinical use to prevent the harmful effects of this drug. METHODS The PubMed, Science Direct, EBSCO, Cochrane Central Register of Controlled Trials, and Google Scholar databases were screened for articles related to the clinical PK of vildagliptin using systematic search strategies. RESULTS The literature search identified 2118 records, among which 28 were subsumed in this systematic review that fulfilled the inclusion standards. CONCLUSIONS This systematic review can help dose optimization among critically ill patients (e.g. renal impairment) without exposing them to the drug's toxic effects.
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Affiliation(s)
- Mahnoor Pasha
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Ammara Zamir
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Waseem Ashraf
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Imran Imran
- Department of Pharmacology, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Hamid Saeed
- Allama Iqbal Campus, University College of Pharmacy, Lahore, Pakistan
| | - Anees Ur Rehman
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Majid Aziz
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Faleh Alqahtani
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Muhammad Fawad Rasool
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
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20
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Lagunas-Rangel FA, Liao S, Williams MJ, Trukhan V, Fredriksson R, Schiöth HB. Drosophila as a Rapid Screening Model to Evaluate the Hypoglycemic Effects of Dipeptidyl Peptidase 4 (DPP4) Inhibitors: High Evolutionary Conservation of DPP4. Biomedicines 2023; 11:3032. [PMID: 38002032 PMCID: PMC10669173 DOI: 10.3390/biomedicines11113032] [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: 10/11/2023] [Revised: 11/09/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, have been an integral part of the treatment of type 2 diabetes mellitus (T2DM) for several years. Despite their remarkable efficacy in lowering glucose levels and their compatibility with other hypoglycemic drugs, recent studies have revealed adverse effects, prompting the search for improved drugs within this category, which has required the use of animal models to verify the hypoglycemic effects of these compounds. Currently, in many countries the use of mammals is being significantly restricted, as well as cost prohibitive, and alternative in vivo approaches have been encouraged. In this sense, Drosophila has emerged as a promising alternative for several compelling reasons: it is cost-effective, offers high experimental throughput, is genetically manipulable, and allows the assessment of multigenerational effects, among other advantages. In this study, we present evidence that diprotin A, a DPP4 inhibitor, effectively reduces glucose levels in Drosophila hemolymph. This discovery underscores the potential of Drosophila as an initial screening tool for novel compounds directed against DPP4 enzymatic activity.
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Affiliation(s)
- Francisco Alejandro Lagunas-Rangel
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, 751 24 Uppsala, Sweden; (F.A.L.-R.); (S.L.); (M.J.W.)
| | - Sifang Liao
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, 751 24 Uppsala, Sweden; (F.A.L.-R.); (S.L.); (M.J.W.)
| | - Michael J. Williams
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, 751 24 Uppsala, Sweden; (F.A.L.-R.); (S.L.); (M.J.W.)
| | | | - Robert Fredriksson
- Department of Pharmaceutical Biosciences, Uppsala University, 751 24 Uppsala, Sweden;
| | - Helgi B. Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, 751 24 Uppsala, Sweden; (F.A.L.-R.); (S.L.); (M.J.W.)
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21
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Abstract
Incretin hormones (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) play a role in the pathophysiology of type 2 diabetes. Along with their derivatives they have shown therapeutic success in type 2 diabetes, with the potential for further improvements in glycaemic, cardiorenal and body weight-related outcomes. In type 2 diabetes, the incretin effect (greater insulin secretory response after oral glucose than with 'isoglycaemic' i.v. glucose, i.e. with an identical glycaemic stimulus) is markedly reduced or absent. This appears to be because of a reduced ability of GIP to stimulate insulin secretion, related either to an overall impairment of beta cell function or to specific defects in the GIP signalling pathway. It is likely that a reduced incretin effect impacts on postprandial glycaemic excursions and, thus, may play a role in the deterioration of glycaemic control. In contrast, the insulinotropic potency of GLP-1 appears to be much less impaired, such that exogenous GLP-1 can stimulate insulin secretion, suppress glucagon secretion and reduce plasma glucose concentrations in the fasting and postprandial states. This has led to the development of incretin-based glucose-lowering medications (selective GLP-1 receptor agonists or, more recently, co-agonists, e.g. that stimulate GIP and GLP-1 receptors). Tirzepatide (a GIP/GLP-1 receptor co-agonist), for example, reduces HbA1c and body weight in individuals with type 2 diabetes more effectively than selective GLP-1 receptor agonists (e.g. semaglutide). The mechanisms by which GIP receptor agonism may contribute to better glycaemic control and weight loss after long-term exposure to tirzepatide are a matter of active research and may change the pessimistic view that developed after the disappointing lack of insulinotropic activity in people with type 2 diabetes when exposed to GIP in short-term experiments. Future medications that stimulate incretin hormone and other receptors simultaneously may have the potential to further increase the ability to control plasma glucose concentrations and induce weight loss.
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Affiliation(s)
- Michael A Nauck
- Diabetes, Endocrinology, Metabolism Section, Medical Department I, Katholisches Klinikum Bochum, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany.
- Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz München, Neuherberg, Germany
- German Center for Diabetes Research (DZD), München Neuherberg, Germany
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22
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Ribeiro-Silva JC, Marques VB, Dos Santos L. Effects of dipeptidyl peptidase 4 inhibition on the endothelial control of the vascular tone. Am J Physiol Cell Physiol 2023; 325:C972-C980. [PMID: 37642237 PMCID: PMC11932530 DOI: 10.1152/ajpcell.00246.2023] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 08/24/2023] [Accepted: 08/24/2023] [Indexed: 08/31/2023]
Abstract
Dipeptidyl peptidase 4 (DPP4) is a serine protease known to cleave incretin hormones, which stimulate insulin secretion after food intake, a fact that supported the development of its inhibitors (DPP4i or gliptins) for the treatment of type 2 diabetes mellitus. In addition to their glucose-lowering effects, DPP4i show benefits for the cardiovascular system that could be related, at least in part, to their protective action on vascular endothelium. DPP4i have been associated with the reversal of endothelial dysfunction, an important predictor of cardiovascular events and a hallmark of diseases such as atherosclerosis, diabetes mellitus, hypertension, and heart failure. In animal models of these diseases, DPP4i increase nitric oxide bioavailability and limits oxidative stress, thereby improving the endothelium-dependent relaxation. Similar effects on flow-mediated dilation and attenuation of endothelial dysfunction have also been noted in human studies, suggesting a value for gliptins in the clinical scenario, despite the variability of the results regarding the DPP4i used, treatment duration, and presence of comorbidities. In this mini-review, we discuss the advances in our comprehension of the DPP4i effects on endothelial regulation of vascular tone. Understanding the role of DPP4 and its involvement in the signaling mechanisms leading to endothelial dysfunction will pave the way for a broader use of DPP4i in conditions that endothelial dysfunction is a pivotal pathophysiological player.
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Affiliation(s)
- Joao Carlos Ribeiro-Silva
- Department of Ophthalmology and Visual Sciences, State University of New York Upstate Medical University, Syracuse, New York, United States
| | | | - Leonardo Dos Santos
- Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil
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23
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Li Q, Deng X, Xu YJ, Dong L. Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants. J Med Chem 2023; 66:11593-11631. [PMID: 37647598 DOI: 10.1021/acs.jmedchem.3c00412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Considerable effort has been made to achieve less frequent dosing in the development of DPP-4 inhibitors. Enthusiasm for long-acting DPP-4 inhibitors is based on the promise that such agents with less frequent dosing regimens are associated with improved patient adherence, but the rational design of long-acting DPP-4 inhibitors remains a major challenge. In this Perspective, the development of long-acting DPP-4 inhibitors is comprehensively summarized to highlight the evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades. The determinants for long duration of action are then examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical pharmacokinetic and pharmacodynamic profiles. More importantly, several possible approaches for the rational design of long-acting drugs are discussed. We hope that this information will facilitate the design and development of safer and more effective long-acting DPP-4 inhibitors and other oral drugs.
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Affiliation(s)
- Qing Li
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Xiaoyan Deng
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Yan-Jun Xu
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Lin Dong
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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24
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Song M, Chen Y. Local anaesthetic procaine derivatives protect rat against diabetic nephropathy via inhibition of DPP-4, inflammation and oxidative stress. Chem Biol Drug Des 2023; 102:26-37. [PMID: 37076428 DOI: 10.1111/cbdd.14252] [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: 12/21/2022] [Revised: 03/16/2023] [Accepted: 04/04/2023] [Indexed: 04/21/2023]
Abstract
Diabetic nephropathy (DN) is a serious devastating disease. However, the current clinical options to treat DN are not adequate. Thus, in the present study, we intend to develop novel series of procaine-embedded thiazole-pyrazoles as protective agent against DN. The compounds were tested for inhibition of dipeptidyl peptidase (DPP)-4, -8, and - 9 enzyme subtypes, where they selectively and potently inhibit DPP-4 as compared to other subtypes. The top three ranked DPP-4 inhibitors (8i, 8e and 8k) were further screened for inhibitory activity against NF-ĸB transcription. Among these three, compound 8i was identified as the most potent NF-ĸB inhibitor. The pharmacological benefit of compound 8i was further established in streptozotocin-induced diabetic nephropathy in rats. Compound 8i showed marked improvements in blood glucose, ALP, ALT, total protein, serum lipid profile such as total cholesterol, triglyceride, HDL levels and renal functions such as urine volume, urinary protein excretion, serum creatinine, blood urea nitrogen and creatinine clearance as compared to nontreated diabetic control group. It also reduces oxidative stress (MDA, SOD and GPx) and inflammation (TNF-α, IL-1β and IL-6) in the rats as compared to disease control group rats. This study demonstrated the discovery of procaine-embedded thiazole-pyrazole compounds as a novel class of agent against diabetic nephropathy.
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Affiliation(s)
- Miaomiao Song
- Department of Anesthesiology, Fengxian District Central Hospital, Shanghai, China
| | - Yaping Chen
- Department of Anesthesiology, Jinshan Hospital, Fudan University, Shanghai, China
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25
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Nainu F, Frediansyah A, Mamada SS, Permana AD, Salampe M, Chandran D, Emran TB, Simal-Gandara J. Natural products targeting inflammation-related metabolic disorders: A comprehensive review. Heliyon 2023; 9:e16919. [PMID: 37346355 PMCID: PMC10279840 DOI: 10.1016/j.heliyon.2023.e16919] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 05/31/2023] [Accepted: 06/01/2023] [Indexed: 06/23/2023] Open
Abstract
Currently, the incidence of metabolic disorders is increasing, setting a challenge to global health. With major advancement in the diagnostic tools and clinical procedures, much has been known in the etiology of metabolic disorders and their corresponding pathophysiologies. In addition, the use of in vitro and in vivo experimental models prior to clinical studies has promoted numerous biomedical breakthroughs, including in the discovery and development of drug candidates to treat metabolic disorders. Indeed, chemicals isolated from natural products have been extensively studied as prospective drug candidates to manage diabetes, obesity, heart-related diseases, and cancer, partly due to their antioxidant and anti-inflammatory properties. Continuous efforts have been made in parallel to improve their bioactivity and bioavailability using selected drug delivery approaches. Here, we provide insights on recent progress in the role of inflammatory-mediated responses on the initiation of metabolic disorders, with particular reference to diabetes mellitus, obesity, heart-related diseases, and cancer. In addition, we discussed the prospective role of natural products in the management of diabetes, obesity, heart-related diseases, and cancers and provide lists of potential biological targets for high throughput screening in drug discovery and development. Lastly, we discussed findings observed in the preclinical and clinical studies prior to identifying suitable approaches on the phytochemical drug delivery systems that are potential to be used in the treatment of metabolic disorders.
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Affiliation(s)
- Firzan Nainu
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar 90245, Indonesia
| | - Andri Frediansyah
- Research Center for Food Technology and Processing (PRTPP), National Research and Innovation Agency (BRIN), Yogyakarta 55861, Indonesia
| | - Sukamto S. Mamada
- Department of Pharmacy, Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar 90245, Indonesia
| | - Andi Dian Permana
- Department of Pharmaceutical Science and Technology, Faculty of Pharmacy, Hasanuddin University, Tamalanrea, Makassar 90245, Indonesia
| | | | - Deepak Chandran
- Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, India
| | - Talha Bin Emran
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI 02912, USA
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | - Jesus Simal-Gandara
- Universidade de Vigo, Nutrition and Bromatology Group, Analytical Chemistry and Food Science Department, Faculty of Science, E32004 Ourense, Spain
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26
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Saini K, Sharma S, Khan Y. DPP-4 inhibitors for treating T2DM - hype or hope? an analysis based on the current literature. Front Mol Biosci 2023; 10:1130625. [PMID: 37287751 PMCID: PMC10242023 DOI: 10.3389/fmolb.2023.1130625] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 05/08/2023] [Indexed: 06/09/2023] Open
Abstract
DPP-4 inhibition is an interesting line of therapy for treating Type 2 Diabetes Mellitus (T2DM) and is based on promoting the incretin effect. Here, the authors have presented a brief appraisal of DPP-4 inhibitors, their modes of action, and the clinical efficiency of currently available drugs based on DPP-4 inhibitors. The safety profiles as well as future directions including their potential application in improving COVID-19 patient outcomes have also been discussed in detail. This review also highlights the existing queries and evidence gaps in DPP-4 inhibitor research. Authors have concluded that the excitement surrounding DPP-4 inhibitors is justified because in addition to controlling blood glucose level, they are good at managing risk factors associated with diabetes.
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27
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Kang SJ, Kim JE. Development of Clinically Optimized Sitagliptin and Dapagliflozin Complex Tablets: Pre-Formulation, Formulation, and Human Bioequivalence Studies. Pharmaceutics 2023; 15:pharmaceutics15041246. [PMID: 37111730 PMCID: PMC10141516 DOI: 10.3390/pharmaceutics15041246] [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: 03/23/2023] [Revised: 04/09/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023] Open
Abstract
The purpose of this study is to derive an optimal drug release formulation with human clinical bioequivalence in developing a sitagliptin phosphate monohydrate-dapagliflozin propanediol hydrate fixed-dose combination (FDC) tablet as a treatment for type 2 diabetes mellitus. As a treatment for type 2 diabetes mellitus, the combined prescription of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is common. Therefore, this study simplified the number of individual drugs taken and improved drug compliance by developing FDC tablets containing sitagliptin phosphate monohydrate as a DPP-4 inhibitor and dapagliflozin propanediol hydrate as an SGLT-2 inhibitor. To derive the optimal dosage form, we prepared single-layer tablets, double-layer tablets, and dry-coated tablets and evaluated the drug control release ability, tableting manufacturability, quality, and stability. Single-layer tablets caused problems with stability and drug dissolution patterns. When the dissolution test was performed on the dry-coated tablets, a corning effect occurred, and the core tablet did not completely disintegrate. However, in the quality evaluation of the double-layer tablets, the hardness was 12-14 kilopond, the friability was 0.2%, and the disintegration was within 3 min. In addition, the stability test revealed that the double-layer tablet was stable for 9 months under room temperature storage conditions and 6 months under accelerated storage conditions. In the drug release test, only the FDC double-layer tablet showed the optimal drug release pattern that satisfied each drug release rate. In addition, the FDC double-layer tablet showed a high dissolution rate of over 80% in the form of immediate-release tablets within 30 min in a pH 6.8 dissolution solution. In the human clinical trial, we co-administered a single dose of a sitagliptin phosphate monohydrate-dapagliflozin propanediol hydrate FDC double-layered tablet and the reference drug (Forxiga®, Januvia®) in healthy adult volunteers. This study showed clinically equivalent results in the stability and pharmacodynamic characteristics between the two groups.
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Affiliation(s)
- So-Jin Kang
- Department of Pharmaceutical Engineering, Catholic University of Daegu, Hayang-Ro 13-13, Gyeongsan 38430, Republic of Korea
| | - Joo-Eun Kim
- Department of Biopharmaceutical Chemistry, School of Applied Chemistry, Kookmin University, Seoul 02707, Republic of Korea
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28
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Lesgards JF. Benefits of Whey Proteins on Type 2 Diabetes Mellitus Parameters and Prevention of Cardiovascular Diseases. Nutrients 2023; 15:nu15051294. [PMID: 36904293 PMCID: PMC10005124 DOI: 10.3390/nu15051294] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 02/27/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality, and it is a major risk factor for the early onset of cardiovascular diseases (CVDs). More than genetics, food, physical activity, walkability, and air pollution are lifestyle factors, which have the greatest impact on T2DM. Certain diets have been shown to be associated with lower T2DM and cardiovascular risk. Diminishing added sugar and processed fats and increasing antioxidant-rich vegetable and fruit intake has often been highlighted, as in the Mediterranean diet. However, less is known about the interest of proteins in low-fat dairy and whey in particular, which have great potential to improve T2DM and could be used safely as a part of a multi-target strategy. This review discusses all the biochemical and clinical aspects of the benefits of high-quality whey, which is now considered a functional food, for prevention and improvement of T2DM and CVDs by insulin- and non-insulin-dependent mechanisms.
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Affiliation(s)
- Jean-François Lesgards
- Ingénierie des Peptides Thérapeutiques, Ambrilia-Cellpep, Faculté de Médecine Nord, Aix-Marseille University, Boulevard Pierre Dramard, 13015 Marseille, France
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29
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Akashi N, Umemoto T, Yamada H, Fujiwara T, Yamamoto K, Taniguchi Y, Sakakura K, Wada H, Momomura SI, Fujita H. Teneligliptin, a DPP-4 Inhibitor, Improves Vascular Endothelial Function via Divergent Actions Including Changes in Circulating Endothelial Progenitor Cells. Diabetes Metab Syndr Obes 2023; 16:1043-1054. [PMID: 37077576 PMCID: PMC10108873 DOI: 10.2147/dmso.s403125] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 04/03/2023] [Indexed: 04/20/2023] Open
Abstract
PURPOSE Dipeptidyl peptidase-4 (DPP-4) inhibitors increase endothelial progenitor cells (EPCs) in peripheral blood circulation. However, the underlying mechanisms and effects on vascular endothelial function remain unclear. We evaluated whether the DPP-4 inhibitor teneligliptin increases circulating EPCs by inhibiting stromal-derived factor-1α (SDF-1α) and improves flow-mediated vascular dilatation (FMD) in type 2 diabetes mellitus patients with acute coronary syndrome (ACS) or its risk factors. PATIENTS AND METHODS This single-center, open-label, prospective, randomized controlled trial evaluated 17 patients (hemoglobin A1c ≤7.5% and peak creatinine phosphokinase <2000 IU/mL) with ACS or a history of ACS or multiple cardiovascular risk factors. Metabolic variables of glucose and lipids, circulating EPCs, plasma DPP-4 activity, and SDF-1α levels, and FMD were evaluated at baseline and 28 ± 4 weeks after enrollment. Patients were randomly assigned to either the teneligliptin (n = 8) or control (n = 9) groups. RESULTS The DPP-4 activity (∆-509.5 ± 105.7 vs ∆32.8 ± 53.4 μU/mL) and SDF-1α levels (∆-695.6 ± 443.2 vs ∆11.1 ± 193.7 pg/mL) were significantly decreased after 28 weeks in the teneligliptin group than those in the control group. The number of EPCs showed an increasing trend in the teneligliptin treated group; albeit this did not reach statistical significance. Glucose and lipid levels were not significantly different between the groups before and after 28 weeks. However, FMD was significantly improved in the teneligliptin group when compared to the control group (∆3.8% ± 2.1% vs ∆-0.3% ± 2.9%, P=0.006). CONCLUSION Teneligliptin improved FMD through a mechanism other than increasing the number of circulating EPCs.
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Affiliation(s)
- Naoyuki Akashi
- Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Tomio Umemoto
- Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan
- Correspondence: Tomio Umemoto, Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama, 330-8503, Japan, Tel +81-48-647-2111, Fax +81-48-648-5188, Email
| | - Hodaka Yamada
- Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Takayuki Fujiwara
- Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan
| | - Kei Yamamoto
- Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Yousuke Taniguchi
- Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Kenichi Sakakura
- Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Hiroshi Wada
- Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Shin-ichi Momomura
- Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Hideo Fujita
- Division of Cardiovascular Medicine, Jichi Medical University Saitama Medical Center, Saitama, Japan
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30
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DeMarsilis A, Reddy N, Boutari C, Filippaios A, Sternthal E, Katsiki N, Mantzoros C. Pharmacotherapy of type 2 diabetes: An update and future directions. Metabolism 2022; 137:155332. [PMID: 36240884 DOI: 10.1016/j.metabol.2022.155332] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/07/2022] [Accepted: 10/07/2022] [Indexed: 11/06/2022]
Abstract
Type 2 diabetes (T2D) is a widely prevalent disease with substantial economic and social impact for which multiple conventional and novel pharmacotherapies are currently available; however, the landscape of T2D treatment is constantly changing as new therapies emerge and the understanding of currently available agents deepens. This review aims to provide an updated summary of the pharmacotherapeutic approach to T2D. Each class of agents is presented by mechanism of action, details of administration, side effect profile, cost, and use in certain populations including heart failure, non-alcoholic fatty liver disease, obesity, chronic kidney disease, and older individuals. We also review targets of novel therapeutic T2D agent development. Finally, we outline an up-to-date treatment approach that starts with identification of an individualized goal for glycemic control then selection, initiation, and further intensification of a personalized therapeutic plan for T2D.
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Affiliation(s)
- Antea DeMarsilis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Niyoti Reddy
- Department of Medicine, School of Medicine, Boston University, Boston, USA
| | - Chrysoula Boutari
- Second Propedeutic Department of Internal Medicine, Hippocration Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Filippaios
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Elliot Sternthal
- Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Sindos, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus.
| | - Christos Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA; Section of Endocrinology, VA Boston Healthcare System, Harvard Medical School, Boston, MA 02115, USA
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31
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Rusinov VL, Sapozhnikova IM, Spasov AA, Chupakhin ON. Fused azoloazines with antidiabetic activity. Russ Chem Bull 2022. [DOI: 10.1007/s11172-022-3687-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/01/2023]
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Nakagawa Y, Toyoda M, Saito N, Kaneyama N, Shimizu T, Mabuchi T, Fukagawa M. Clinical Phenotypes and the Clinical Course of Bullous Pemphigoid Receiving Dipeptidyl Pepitidase-4 Inhibitor Treatment: An Analysis of Cases in a Single Japanese Center. Intern Med 2022. [PMID: 36328578 DOI: 10.2169/internalmedicine.0815-22] [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] [Indexed: 11/08/2022] Open
Abstract
Objective Several studies have shown an increased risk of bullous pemphigoid (BP) when receiving dipeptidyl pepitidase-4 inhibitor (DPP-4i) treatment. The present study explored the associations of DPP-4i treatment with the clinical phenotypes and clinical course of BP. Methods We analyzed data of 146 patients with BP at Tokai University School of Medicine from December 1, 2009, to December 31, 2021. We obtained data by a retrospective medical record review and compared the bullous pemphigoid disease area index (BPDAI) between diabetes patients receiving DPP-4i treatment and those not receiving DPP-4i treatment. We employed multivariable linear regression models to explore the association between the DPP-4i treatment and the BPDAI scores. Results Among 53 BP patients with diabetes, 33 had developed BP during treatment with DPP-4i agents, among which vildagliptin was the most frequently used. The urticaria/erythema scores of the BPDAI were significantly lower in patients who developed BP while receiving DPP-4i treatment than among others. Of note, 69.2% of the patients who stopped DPP-4i treatment experienced complete remission, and the clinical course was more favorable in patients with lower scores for urticaria/erythema than among others. Conclusion These findings suggest that, in patients who developed BP while receiving DPP-4i treatment, a noninflammatory phenotype may indicate a high likelihood that DPP-4i treatment contributes to the development of BP. The discontinuation of DPP-4i should be carefully considered in close consultation with dermatologists.
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Affiliation(s)
- Yosuke Nakagawa
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Japan
| | - Masao Toyoda
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Japan
| | - Nobumichi Saito
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Japan
| | - Noriko Kaneyama
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Japan
| | - Tomomichi Shimizu
- Department of Dermatology, Tokai University School of Medicine, Japan
| | - Tomotaka Mabuchi
- Department of Dermatology, Tokai University School of Medicine, Japan
| | - Masafumi Fukagawa
- Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Japan
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Li JH, Florez JC. On the Verge of Precision Medicine in Diabetes. Drugs 2022; 82:1389-1401. [PMID: 36123514 PMCID: PMC9531144 DOI: 10.1007/s40265-022-01774-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2022] [Indexed: 11/03/2022]
Abstract
The epidemic of type 2 diabetes (T2D) is a significant global public health challenge and a major cause of morbidity and mortality. Despite the recent proliferation of pharmacological agents for the treatment of T2D, current therapies simply treat the symptom, i.e. hyperglycemia, and do not directly address the underlying disease process or modify the disease course. This article summarizes how genomic discovery has contributed to unraveling the heterogeneity in T2D, reviews relevant discoveries in the pharmacogenetics of five commonly prescribed glucose-lowering agents, presents evidence supporting how pharmacogenetics can be leveraged to advance precision medicine, and calls attention to important research gaps to its implementation to guide treatment choices.
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Affiliation(s)
- Josephine H Li
- Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Simches Research Building, CPZN 5.250, 185 Cambridge St, Boston, MA, 02114, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Jose C Florez
- Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Simches Research Building, CPZN 5.250, 185 Cambridge St, Boston, MA, 02114, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, USA.
- Programs in Metabolism and Medical & Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
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Fleury L, Deracinois B, Dugardin C, Nongonierma AB, FitzGerald RJ, Flahaut C, Cudennec B, Ravallec R. In Vivo and In Vitro Comparison of the DPP-IV Inhibitory Potential of Food Proteins from Different Origins after Gastrointestinal Digestion. Int J Mol Sci 2022; 23:8365. [PMID: 35955493 PMCID: PMC9369239 DOI: 10.3390/ijms23158365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
Dipeptidyl-peptidase IV (DPP-IV) plays an essential role in glucose metabolism by inactivating incretins. In this context, food-protein-derived DPP-IV inhibitors are promising glycemic regulators which may act by preventing the onset of type 2 diabetes in personalized nutrition. In this study, the DPP-IV-inhibitory potential of seven proteins from diverse origins was compared for the first time in vitro and in vivo in rat plasma after the intestinal barrier (IB) passage of the indigested proteins. The DPP-IV-inhibitory potentials of bovine hemoglobin, caseins, chicken ovalbumin, fish gelatin, and pea proteins were determined in rat plasma thirty minutes after oral administration. In parallel, these proteins, together with bovine whey and gluten proteins, were digested using the harmonized INFOGEST protocol adapted for proteins. The DPP-IV half-maximal inhibitory concentration (IC50) was determined in situ using Caco-2 cells. The DPP-IV-inhibitory activity was also measured after IB passage using a Caco2/HT29-MTX mixed-cell model. The peptide profiles were analyzed using reversed-phase high-performance liquid chromatography tandem mass spectrometry (RP-HPLC-MS/MS) with MS data bioinformatics management, and the IC50 of the identified peptides was predicted in silico. The in vitro and in vivo DPP-IV-inhibitory activity of the proteins differed according to their origin. Vegetable proteins and hemoglobin yielded the highest DPP-IV-inhibitory activity in vivo. However, no correlation was found between the in vivo and in vitro results. This may be partially explained by the differences between the peptidome analysis and the in silico predictions, as well as the study complexity.
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Affiliation(s)
- Léa Fleury
- UMR-T 1158, BioEcoAgro, University of Lille, 59650 Lille, France; (L.F.); (B.D.); (C.D.); (C.F.)
| | - Barbara Deracinois
- UMR-T 1158, BioEcoAgro, University of Lille, 59650 Lille, France; (L.F.); (B.D.); (C.D.); (C.F.)
| | - Camille Dugardin
- UMR-T 1158, BioEcoAgro, University of Lille, 59650 Lille, France; (L.F.); (B.D.); (C.D.); (C.F.)
| | - Alice B. Nongonierma
- Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland; (A.B.N.); (R.J.F.)
| | - Richard J. FitzGerald
- Department of Biological Sciences, University of Limerick, V94 T9PX Limerick, Ireland; (A.B.N.); (R.J.F.)
| | - Christophe Flahaut
- UMR-T 1158, BioEcoAgro, University of Lille, 59650 Lille, France; (L.F.); (B.D.); (C.D.); (C.F.)
| | - Benoit Cudennec
- UMR-T 1158, BioEcoAgro, University of Lille, 59650 Lille, France; (L.F.); (B.D.); (C.D.); (C.F.)
| | - Rozenn Ravallec
- UMR-T 1158, BioEcoAgro, University of Lille, 59650 Lille, France; (L.F.); (B.D.); (C.D.); (C.F.)
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Blair Sarbacker G, Bzowyckyj AS, Patel R. Part Three: A Brief Primer of Non-Insulin Treatments for Type 2 Diabetes Mellitus in Older People. Sr Care Pharm 2022; 37:251-259. [DOI: 10.4140/tcp.n.2022.251] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Diabetes is a heterogeneous condition that manifests differently in each patient. Fortunately, there are multiple different medication classes that can be used to help patients achieve their treatment goals. Diabetes is highly prevalent in older people, including patients who have been
living with the condition for many years and those who are newly diagnosed. It is essential for senior care pharmacists to evaluate patient-specific goals, compelling indications, and risks and benefits of treatment. When evaluating therapy appropriateness, pharmacists must take into consideration
the impact of medication therapy beyond glucose-lowering effects, including the overall impact on cardiovascular, renal, heart failure, and weight-related outcomes.
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Affiliation(s)
| | | | - Reena Patel
- 2Pacific University Oregon School of Pharmacy, Hillsboro, Oregon
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36
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Zhang J, Liao D, Chen R, Zhu F, Ma Y, Gao L, Qu G, Cui C, Sun Z, Lei X, Gao SS. Tuning an Imine Reductase for the Asymmetric Synthesis of Azacycloalkylamines by Concise Structure-Guided Engineering. Angew Chem Int Ed Engl 2022; 61:e202201908. [PMID: 35322515 DOI: 10.1002/anie.202201908] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Indexed: 12/27/2022]
Abstract
Although imine reductases (IREDs) are emerging as attractive reductive aminases (RedAms), their substrate scope is still narrow, and rational engineering is rare. Focusing on hydrogen bond reorganization and cavity expansion, a concise strategy combining rational cavity design, combinatorial active-site saturation test (CAST), and thermostability engineering was designed, that transformed the weakly active IR-G36 into a variant M5 with superior performance for the synthesis of (R)-3-benzylamino-1-Boc-piperidine, with a 4193-fold improvement in catalytic efficiency, a 16.2 °C improvement in Tm , and a significant increase in the e.e. value from 78 % (R) to >99 % (R). M5 exhibits broad substrate scope for the synthesis of diverse azacycloalkylamines, and the reaction was demonstrated on a hectogram-scale under industrially relevant conditions. Our study provides a compelling example of the preparation of versatile and efficient IREDs, with exciting opportunities in medicinal and process chemistry as well as synthetic biology.
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Affiliation(s)
- Jun Zhang
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China
| | - Daohong Liao
- Jiangsu JITRI Molecular Engineering Inst. Co., Ltd., Jiangsu, 215500, China
| | | | - Fangfang Zhu
- College of Biotechnology, Tianjin University of Science & Techno, Tianjin, 300457, China
| | - Yaqing Ma
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Lei Gao
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100091, China
| | - Ge Qu
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China
| | - Chengsen Cui
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China
| | - Zhoutong Sun
- Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China
| | - Xiaoguang Lei
- Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100091, China
| | - Shu-Shan Gao
- State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China
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Tekin S, Beytur A, Cakir M, Taslıdere A, Erden Y, Tekin C, Sandal S. Protective effect of saxagliptin against renal ischaemia reperfusion injury in rats. Arch Physiol Biochem 2022; 128:608-618. [PMID: 31979992 DOI: 10.1080/13813455.2020.1715442] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Saxagliptin is an effective and selective dipeptidyl peptidase-4 (DPP-4) inhibitor. This study was designed to determine possible protective effects of saxagliptin against damage caused by renal ischaemia/reperfusion (I/R) in rats. In this study, 40 rats were divided into 4 groups (n = 10 for each). Group 1 (Control), Group 2 (I/R) in both kidneys ischaemia of 45 min was performed, and then reperfusion was applied for 24 h. Saxagliptin (Group 3: 2 mg/kg and Group 4: 10 mg/kg) was administered by oral gavage to the animals in treatment groups, before the I/R. Saxagliptin decreased the markers (BUN, Cre, NGAL, KIM-1 and IL-18) of acute renal damage in blood and kidney tissue. Saxagliptin provided increase in antioxidant enzyme levels and decrease in MDA and apoptosis. Histological results showed that the administration of saxagliptin exhibited a protective effect against renal damage caused by I/R. These results indicates that saxagliptin provide protection against kidney injury caused by I/R.
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Affiliation(s)
- Suat Tekin
- Faculty of Medicine, Department of Physiology, Inonu University, Malatya, Turkey
| | - Asiye Beytur
- Faculty of Medicine, Department of Physiology, Inonu University, Malatya, Turkey
| | - Murat Cakir
- Faculty of Medicine, Department of Physiology, Yozgat Bozok University, Yozgat, Turkey
| | - Aslı Taslıdere
- Faculty of Medicine, Department of Histology and Embryology, Inonu University, Malatya, Turkey
| | - Yavuz Erden
- Faculty of Science, Department of Molecular Biology and Genetics, Bartin University, Bartin, Turkey
| | - Cigdem Tekin
- Health Services Vocational School, Inonu University, Malatya, Turkey
| | - Suleyman Sandal
- Faculty of Medicine, Department of Physiology, Inonu University, Malatya, Turkey
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Is Time-Restricted Eating Safe in the Treatment of Type 2 Diabetes?-A Review of Intervention Studies. Nutrients 2022; 14:nu14112299. [PMID: 35684097 PMCID: PMC9182892 DOI: 10.3390/nu14112299] [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: 04/21/2022] [Revised: 05/20/2022] [Accepted: 05/24/2022] [Indexed: 11/17/2022] Open
Abstract
Time-restricted eating (TRE) has been shown to improve body weight and glucose metabolism in people at high risk of type 2 diabetes. However, the safety of TRE in the treatment of type 2 diabetes is unclear. We investigated the safety of TRE interventions in people with type 2 diabetes by identifying published and ongoing studies. Moreover, we identified the commonly used antidiabetic drugs and discussed the safety of TRE in people with type 2 diabetes considering the use of these drugs. In addition, we addressed the research needed before TRE can be recommended in the treatment of type 2 diabetes. A literature search was conducted to identify published (MEDLINE PubMed) and ongoing studies (ClinicalTrials.gov) on TRE in people with type 2 diabetes. To assess the usage of antidiabetic drugs and to discuss pharmacodynamics and pharmacokinetics in a TRE context, the most used antidiabetic drugs were identified and analysed. Statistics regarding sale of pharmaceuticals were obtained from MEDSTAT.DK which are based on data from the national Register of Medicinal Product Statistics, and from published studies on medication use in different countries. Four published studies investigating TRE in people with type 2 diabetes were identified as well as 14 ongoing studies. The completed studies suggested that TRE is safe among people with type 2 diabetes. Common antidiabetic drugs between 2010 and 2019 were metformin, insulin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sulfonylureas, and sodium-glucose cotransporter-2 inhibitors. Existing studies suggest that TRE is not associated with major safety issues in people with type 2 diabetes as long as medication is monitored and adjusted. However, because of low generalisability of the few studies available, more studies are needed to make concrete recommendations regarding efficacy and safety of TRE in people with type 2 diabetes.
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Yang X, Feng P, Ji R, Ren Y, Wei W, Hölscher C. Therapeutic application of GLP-1 and GIP receptor agonists in Parkinson's disease. Expert Opin Ther Targets 2022; 26:445-460. [PMID: 35584372 DOI: 10.1080/14728222.2022.2079492] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Diabetes is a risk factor for Parkinson's disease (PD) and shares similar dysregulated insulin pathways. Glucagon-like peptide-1 (GLP-1) analogs originally designed to treat diabetes have shown potent neuroprotective activity in preclinical studies of PD. They are neuroprotective by inhibiting inflammation, improving neuronal survival, maintenance of synapses, and dopaminergic transmission in the brain. Building on this, three clinical studies have reported impressive effects in patients with PD, testing exendin-4 (Exenatide, Bydureon) or liraglutide (Victoza, Saxenda). Glucose-dependent insulinotropic peptide (GIP) is another peptide hormone that has shown good effects in animal models of PD. Novel dual GLP-1/GIP agonists have been developed that can penetrate the blood-brain barrier (BBB) and show superior effects in animal models compared to GLP-1 drugs. AREAS COVERED The review summarizes preclinical and clinical studies testing GLP-1R agonists and dual GLP-1/GIPR agonists in PD and discusses possible mechanisms of action. EXPERT OPINION Current strategies to treat PD by lowering the levels of alpha-synuclein have not shown effects in clinical trials. It is time to move on from the 'misfolding protein' hypothesis. Growth factors such as GLP-1 that can cross the BBB have already shown impressive effects in patients and are the future of drug discovery in PD.
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Affiliation(s)
- Xiaoyan Yang
- Department of Neurology, Huadong Hospital Affiliated to Fudan University, No. 221 West Yan' an Road, Shanghai, China
| | - Peng Feng
- Department of Neurology, The Second Affiliated Hospital of Shanxi Medical University, No. 382 Wuyi Road, Taiyuan, 030001, Shanxi Province, China
| | - Rong Ji
- Department of Neurology, Huadong Hospital Affiliated to Fudan University, No. 221 West Yan' an Road, Shanghai, China
| | - Yiqing Ren
- Department of Neurology, Huadong Hospital Affiliated to Fudan University, No. 221 West Yan' an Road, Shanghai, China
| | - Wenshi Wei
- Department of Neurology, Huadong Hospital Affiliated to Fudan University, No. 221 West Yan' an Road, Shanghai, China
| | - Christian Hölscher
- Department of Neurology, The Second Affiliated Hospital of Shanxi Medical University, No. 382 Wuyi Road, Taiyuan, 030001, Shanxi Province, China.,Academy of Chinese Medical Science, Henan University of Traditional Chinese Medicine, No. 233 Zhongyuan Road, Zhengzhou, China
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40
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Yin R, Xu Y, Wang X, Yang L, Zhao D. Role of Dipeptidyl Peptidase 4 Inhibitors in Antidiabetic Treatment. Molecules 2022; 27:3055. [PMID: 35630534 PMCID: PMC9147686 DOI: 10.3390/molecules27103055] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/02/2022] [Accepted: 05/07/2022] [Indexed: 02/07/2023] Open
Abstract
In recent years, important changes have occurred in the field of diabetes treatment. The focus of the treatment of diabetic patients has shifted from the control of blood glucose itself to the overall management of risk factors, while adjusting blood glucose goals according to individualization. In addition, regulators need to approve new antidiabetic drugs which have been tested for cardiovascular safety. Thus, the newest class of drugs has been shown to reduce major adverse cardiovascular events, including sodium-glucose transporter 2 (SGLT2) and some glucagon like peptide 1 receptor (GLP1) analog. As such, they have a prominent place in the hyperglycemia treatment algorithms. In recent years, the role of DPP4 inhibitors (DPP4i) has been modified. DPP4i have a favorable safety profile and anti-inflammatory profile, do not cause hypoglycemia or weight gain, and do not require dose escalation. In addition, it can also be applied to some types of chronic kidney disease patients and elderly patients with diabetes. Overall, DPP4i, as a class of safe oral hypoglycemic agents, have a role in the management of diabetic patients, and there is extensive experience in their use.
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Affiliation(s)
| | | | | | | | - Dong Zhao
- Beijing Key Laboratory of Diabetes Prevention and Research, Center for Endocrine Metabolic and Immune Diseases, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China; (R.Y.); (Y.X.); (X.W.); (L.Y.)
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41
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Inhibitory activity of xanthoangelol isolated from Ashitaba ( Angelica keiskei Koidzumi) towards α-glucosidase and dipeptidyl peptidase-IV: in silico and in vitro studies. Heliyon 2022; 8:e09501. [PMID: 35637670 PMCID: PMC9142856 DOI: 10.1016/j.heliyon.2022.e09501] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/11/2022] [Accepted: 05/16/2022] [Indexed: 11/25/2022] Open
Abstract
In Indonesia, the sap of Angelica keiskei Koidzumi has been utilized traditionally as a blood-sugar reducer, nonetheless, its molecular mechanism still needs to be studied. This study aimed to isolate xanthoangelol (XA) from the yellow sap of A. keiskei planted in Mount Rinjani, Indonesia, and to investigate its mechanism by in silico and in vitro methods towards α-glucosidase and dipeptidyl peptidase-IV (DPP-IV). The dried yellow sap was macerated using ethanol, subjected to liquid-liquid extraction using a different polarity of solvents, further gradient-eluted with column chromatography. The isolated compound, formed as yellow crystals, melting point 114–114.4 °C, λmax 368 nm, m/z 393.20 [M + H]+, was confirmed as XA. Acarbose, an α-glucosidase inhibitor, and sitagliptin, a DPP-IV inhibitor, respectively, were employed as the reference drugs for both the in silico and in vitro studies. XA interacts with essential amino acid residues 232–237 in the N-terminal N-loop of α-glucosidase by forming a hydrogen bond with Ala234, a salt-bridge with Asp232, and 9 hydrophobic interactions (binding energy -7.81 kcal/mol; Ki = 1.99 μM). These binding modes resemble those of acarbose. Moreover, XA forms hydrogen bonds with Glu205 and Glu206 in the subsite S2 and π-π interaction with Phe357 in the extensive subsite S2 of DPP-IV (binding energy -8.34 kcal/mol; Ki = 0.873 μM), which are similar to those of sitagliptin. XA inhibits both α-glucosidase (IC50 XA = 14.45 μM; IC50 acarbose = 207 μM) and DPP-IV (IC50 XA = 10.49 μM; IC50 sitagliptin = 0.87 μM). Taken together, XA isolated from the yellow sap of A. keiskei Koidzumi might possess the potential to be further developed as an inhibitor of α-glucosidase and DPP-IV.
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Kong P, Cui ZY, Huang XF, Zhang DD, Guo RJ, Han M. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention. Signal Transduct Target Ther 2022; 7:131. [PMID: 35459215 PMCID: PMC9033871 DOI: 10.1038/s41392-022-00955-7] [Citation(s) in RCA: 424] [Impact Index Per Article: 141.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/08/2023] Open
Abstract
Atherosclerosis is a chronic inflammatory vascular disease driven by traditional and nontraditional risk factors. Genome-wide association combined with clonal lineage tracing and clinical trials have demonstrated that innate and adaptive immune responses can promote or quell atherosclerosis. Several signaling pathways, that are associated with the inflammatory response, have been implicated within atherosclerosis such as NLRP3 inflammasome, toll-like receptors, proprotein convertase subtilisin/kexin type 9, Notch and Wnt signaling pathways, which are of importance for atherosclerosis development and regression. Targeting inflammatory pathways, especially the NLRP3 inflammasome pathway and its regulated inflammatory cytokine interleukin-1β, could represent an attractive new route for the treatment of atherosclerotic diseases. Herein, we summarize the knowledge on cellular participants and key inflammatory signaling pathways in atherosclerosis, and discuss the preclinical studies targeting these key pathways for atherosclerosis, the clinical trials that are going to target some of these processes, and the effects of quelling inflammation and atherosclerosis in the clinic.
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Affiliation(s)
- Peng Kong
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Zi-Yang Cui
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Xiao-Fu Huang
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Dan-Dan Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Rui-Juan Guo
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China
| | - Mei Han
- Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Hebei Medical University, Shijiazhuang, 050017, PR China.
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Zhang J, Liao D, Chen R, Zhu F, Ma Y, Gao L, Qu G, Cui C, Sun Z, Lei X, Gao S. Tuning an Imine Reductase for the Asymmetric Synthesis of Azacycloalkylamines by Concise Structure‐Guided Engineering. Angew Chem Int Ed Engl 2022. [DOI: 10.1002/ange.202201908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Jun Zhang
- State Key Laboratory of Microbial Resources, Institute of Microbiology Chinese Academy of Sciences Beijing 100101 China
- Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences Tianjin 300308 China
| | - Daohong Liao
- Jiangsu JITRI Molecular Engineering Inst. Co., Ltd. Jiangsu 215500 China
| | | | - Fangfang Zhu
- College of Biotechnology Tianjin University of Science & Techno Tianjin 300457 China
| | - Yaqing Ma
- State Key Laboratory of Microbial Resources, Institute of Microbiology Chinese Academy of Sciences Beijing 100101 China
| | - Lei Gao
- Beijing National Laboratory for Molecular Sciences Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology College of Chemistry and Molecular Engineering Synthetic and Functional Biomolecules Center Peking-Tsinghua Center for Life Sciences Peking University Beijing 100091 China
| | - Ge Qu
- Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences Tianjin 300308 China
| | - Chengsen Cui
- Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences Tianjin 300308 China
| | - Zhoutong Sun
- Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences Tianjin 300308 China
| | - Xiaoguang Lei
- Beijing National Laboratory for Molecular Sciences Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology College of Chemistry and Molecular Engineering Synthetic and Functional Biomolecules Center Peking-Tsinghua Center for Life Sciences Peking University Beijing 100091 China
| | - Shu‐Shan Gao
- State Key Laboratory of Microbial Resources, Institute of Microbiology Chinese Academy of Sciences Beijing 100101 China
- Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences Tianjin 300308 China
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Potential of Diterpenes as Antidiabetic Agents: Evidence from Clinical and Pre-Clinical Studies. Pharmacol Res 2022; 179:106158. [PMID: 35272043 DOI: 10.1016/j.phrs.2022.106158] [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: 01/06/2022] [Revised: 02/18/2022] [Accepted: 03/03/2022] [Indexed: 11/20/2022]
Abstract
Diterpenes are a diverse group of structurally complex natural products with a wide spectrum of biological activities, including antidiabetic potential. In the last 25 years, numerous diterpenes have been investigated for antidiabetic activity, with some of them reaching the stage of clinical trials. However, these studies have not been comprehensively reviewed in any previous publication. Herein, we critically discussed the literature on the potential of diterpenes as antidiabetic agents, published from 1995 to September, 2021. In the period under review, 427 diterpenes were reported to have varying degrees of antidiabetic activity. Steviol glycosides, stevioside (1) and rebaudioside A (2), were the most investigated diterpenes with promising antidiabetic property using in vitro and in vivo models, as well as human subjects. All the tested pimaranes consistently showed good activity in preclinical evaluations against diabetes. Inhibitions of α-glucosidase and protein tyrosine phosphatase 1B (PTP 1B) activities and peroxisome proliferator-activated receptors gamma (PPAR-γ) agonistic property, were the most frequently used assays for studying the antidiabetic activity of diterpenes. The molecular mechanisms of action of the diterpenes include increased GLUT4 translocation, and activation of phosphoinositide 3-kinase (PI3K) and AMP-activated protein kinase (AMPK)-dependent signaling pathways. Our data revealed that diterpenes hold promising antidiabetic potential. Stevioside (1) and rebaudioside A (2) are the only diterpenes that were advanced to the clinical trial stage of the drug discovery pipeline. Diterpenes belonging to the abietane, labdane, pimarane and kaurane class have shown promising activity in in vitro and in vivo models of diabetes and should be further investigated.
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Nasr NE, Sadek KM. Role and mechanism(s) of incretin-dependent therapies for treating diabetes mellitus. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:18408-18422. [PMID: 35031999 DOI: 10.1007/s11356-022-18534-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 01/03/2022] [Indexed: 06/14/2023]
Abstract
Diabetes mellitus (DM) is a worldwide ailment which leads to chronic complications like cardiac disorders, renal perturbations, limb amputation and blindness. Type one diabetes (T1DM), Type two diabetes (T2DM), Another types of diabetes, such as genetic errors in function of β-cell and action of insulin, cystic fibrosis, chemical-instigated diabetes or following tissue transplantation), and pregnancy DM (GDM). In response to nutritional ingestion, the gut may release a pancreatic stimulant that affects carbohydrate metabolism. The duodenum produces a 'chemical excitant' that stimulates pancreatic output, and researchers have sought to cure diabetes using gut extract injections, coining the word 'incretin' to describe the phenomena. Incretins include GIP and GLP-1. The 'enteroinsular axis' is the link between pancreas and intestine. Nutrient, neuronal and hormonal impulses from intestine to cells secreting insulin were thought to be part of this axis. In addition, the hormonal component, incretin, must meet two requirements: (1) it secreted by foods, mainly carbohydrates, and (2) it must induce an insulinotropic effect which is glucose-dependent. In this review, we clarify the ability of using incretin-dependent treatments for treating DM.
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Affiliation(s)
- Nasr E Nasr
- Department of Biochemistry, Faculty of Veterinary Medicine, Kafr El-Sheikh University, Kafr El-Sheikh, Egypt
| | - Kadry M Sadek
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt.
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Florentin M, Kostapanos MS, Papazafiropoulou AK. Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment. World J Diabetes 2022; 13:85-96. [PMID: 35211246 PMCID: PMC8855136 DOI: 10.4239/wjd.v13.i2.85] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/29/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
The last few years important changes have occurred in the field of diabetes treatment. The priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors, while individualization of glycemic target is suggested. Furthermore, regulatory authorities now require evidence of cardiovascular (CV) safety in order to approve new antidiabetic agents. The most novel drug classes, i.e., sodium-glucose transporter 2 inhibitors (SGLT2-i) and some glucagon-like peptide-1 receptor agonists (GLP-1 RA), have been demonstrated to reduce major adverse CV events and, thus, have a prominent position in the therapeutic algorithm of hyperglycemia. In this context, the role of previously used hypoglycemic agents, including dipeptidyl peptidase 4 (DPP-4) inhibitors, has been modified. DPP-4 inhibitors have a favorable safety profile, do not cause hypoglycemia or weight gain and do not require dose uptitration. Furthermore, they can be administered in patients with chronic kidney disease after dose modification and elderly patients with diabetes. Still, though, they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with SGLT2-i and GLP-1 RA. Overall, DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.
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Affiliation(s)
- Matilda Florentin
- Department of Internal Medicine, School of Medicine, University of Ioannina, Ioannina 45221, Greece
| | - Michael S Kostapanos
- Lipid Clinic, Department of General Medicine, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Athanasia K Papazafiropoulou
- 1st Department of Internal Medicine and Diabetes Center, Tzaneio General Hospital of Piraeus, Athens 18536, Greece
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Verhulst E, Garnier D, De Meester I, Bauvois B. Validating Cell Surface Proteases as Drug Targets for Cancer Therapy: What Do We Know, and Where Do We Go? Cancers (Basel) 2022; 14:624. [PMID: 35158891 PMCID: PMC8833564 DOI: 10.3390/cancers14030624] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/20/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023] Open
Abstract
Cell surface proteases (also known as ectoproteases) are transmembrane and membrane-bound enzymes involved in various physiological and pathological processes. Several members, most notably dipeptidyl peptidase 4 (DPP4/CD26) and its related family member fibroblast activation protein (FAP), aminopeptidase N (APN/CD13), a disintegrin and metalloprotease 17 (ADAM17/TACE), and matrix metalloproteinases (MMPs) MMP2 and MMP9, are often overexpressed in cancers and have been associated with tumour dysfunction. With multifaceted actions, these ectoproteases have been validated as therapeutic targets for cancer. Numerous inhibitors have been developed to target these enzymes, attempting to control their enzymatic activity. Even though clinical trials with these compounds did not show the expected results in most cases, the field of ectoprotease inhibitors is growing. This review summarizes the current knowledge on this subject and highlights the recent development of more effective and selective drugs targeting ectoproteases among which small molecular weight inhibitors, peptide conjugates, prodrugs, or monoclonal antibodies (mAbs) and derivatives. These promising avenues have the potential to deliver novel therapeutic strategies in the treatment of cancers.
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Affiliation(s)
- Emile Verhulst
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2000 Antwerp, Belgium; (E.V.); (I.D.M.)
| | - Delphine Garnier
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, F-75006 Paris, France;
| | - Ingrid De Meester
- Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2000 Antwerp, Belgium; (E.V.); (I.D.M.)
| | - Brigitte Bauvois
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, F-75006 Paris, France;
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Lu W, Cui Y, Zhang L. Isofraxidin exerts anti-diabetic, antilipidemic, and antioxidant effects and protects renal tissues via inhibition of NF-ĸB in Streptozotocin-induced diabetic rats. Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-021-00204-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Guardado-Mendoza R, Garcia-Magaña MA, Martínez-Navarro LJ, Macías-Cervantes HE, Aguilar-Guerrero R, Suárez-Pérez EL, Aguilar-García A. Effect of linagliptin plus insulin in comparison to insulin alone on metabolic control and prognosis in hospitalized patients with SARS-CoV-2 infection. Sci Rep 2022; 12:536. [PMID: 35017617 PMCID: PMC8752656 DOI: 10.1038/s41598-021-04511-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 12/07/2021] [Indexed: 01/08/2023] Open
Abstract
To evaluate the effect of the combination of linagliptin and insulin on metabolic control and prognosis in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hyperglycemia. A parallel double-blind randomized clinical trial including hospitalized patients with SARS-CoV-2 infection and hyperglycemia, randomized to receive 5 mg linagliptin + insulin (LI group) or insulin alone (I group) was performed. The main outcomes were the need for assisted mechanical ventilation and glucose levels during hospitalization. Subjects were screened for eligibility at hospital admission if they were not with assisted mechanical ventilation and presented hyperglycemia, and a total of 73 patients with SARS-CoV-2 infection and hyperglycemia were randomized to the LI group (n = 35) or I group (n = 38). The average hospital stay was 12 ± 1 vs 10 ± 1 days for the I and LI groups, respectively (p = 0.343). There were no baseline clinical differences between the study groups, but the percentage of males was higher in the LI group (26 vs 18, p = 0.030). The improvements in fasting and postprandial glucose levels were better in the LI group that the I group (122 ± 7 vs 149 ± 10, p = 0.033; and 137 ± 7 vs 173 ± 12, p = 0.017, respectively), and insulin requirements tended to be lower in the LI group than the I group. Three patients in the LI group and 12 in the I group required assisted mechanical ventilation (HR 0.258, CI 95% 0.092–0.719, p = 0.009); 2 patients in the LI group and 6 in the I group died after a follow-up of 30 days (p = 0.139). No major side effects were observed. The combination of linagliptin and insulin in hospitalized patients with SARS-CoV-2 infection and hyperglycemia reduced the relative risk of assisted mechanical ventilation by 74% and improved better pre and postprandial glucose levels with lower insulin requirements, and no higher risk of hypoglycemia. This study is registered at clinicaltrials.gov, number NCT04542213 on 09/03/2020.
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Affiliation(s)
- Rodolfo Guardado-Mendoza
- Research Department, Hospital Regional de Alta Especialidad del Bajío, and University of Guanajuato, Blvd.Milenio #130, Col. San Carlos la Roncha, CP 37660, León, Guanajuato, Mexico.
| | - Miguel Angel Garcia-Magaña
- Internal Medicine Department, Hospital Regional de Alta Especialidad del Bajío, León, Guanajuato, Mexico
| | | | - Hilda Elizabeth Macías-Cervantes
- Internal Medicine Department, Unidad Médica de Alta Especialidad T1, Instituto Mexicano del Seguro Social, León, Guanajuato, Mexico
| | - Rodolfo Aguilar-Guerrero
- Internal Medicine Department, Unidad Médica de Alta Especialidad T1, Instituto Mexicano del Seguro Social, León, Guanajuato, Mexico
| | - Erick L Suárez-Pérez
- Department of Biostatistics and Epidemiology, Graduated School of Public Health, University of Puerto Rico, San Juan, USA
| | - Alberto Aguilar-García
- Endocrinology Department, Hospital Regional de Alta Especialidad del Bajío, León, Guanajuato, Mexico
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Amin M, Chondra U, Mostafa E, Alam M. Green seaweed Ulva lactuca, a potential source of bioactive peptides revealed by in silico analysis. INFORMATICS IN MEDICINE UNLOCKED 2022. [DOI: 10.1016/j.imu.2022.101099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022] Open
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