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El-Tokhy FS, Helal DO, Abdel Mageed SS, Mahmoud AMA, El-Gogary RI, El-Ghany EA, Abdel-Mottaleb MMA. Re-purposing of linagliptin for enhanced wound healing and skin rejuvenation via chitosan- modified PLGA nanoplatforms. Int J Pharm 2025; 677:125664. [PMID: 40324605 DOI: 10.1016/j.ijpharm.2025.125664] [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: 03/10/2025] [Revised: 04/29/2025] [Accepted: 04/29/2025] [Indexed: 05/07/2025]
Abstract
Dipeptidyl peptidase IV (DPP IV) is a multifunctional glycoprotein implicated in the exacerbation of various inflammatory skin conditions, including wounds. Therefore, topical delivery of Linagliptin (LNG)-a DPP IV inhibitor- augmented with Lavender Oil (LO) could offer an excellent repurposed tool for the treatment of inflammatory skin diseases. LNG/ LO loaded chitosan (Cs) -modified Poly (Lactide co-Glycolic Acid) (PLGA) nanoparticles (LNG/LO-Cs/PLGA NPs) were prepared by solvent emulsification-evaporation technique. D-optimal design explored the impact of independent factors namely; ratio of LO: PLGA, percentage of surfactant, and type of PLGA on; particle size, zeta potential, and entrapment efficiency of NPs. The optimized formulation displayed positively charged, homogeneous small-sized particles (159.34 nm), with high entrapment efficiency (89.30 %w/w). The in vitro release profile of the optimized NPs showed an initial burst release (16.6 %) after one hour, followed by an extended-release pattern for three days. Transmission electron microscopy showed spherical matrix particles with a slightly denser coat. An ex-vivo skin permeation study revealed notable LNG deposition in rat skin (51 % w/w after 24 h). Confocal laser scanning microscopy confirmed the time-dependent enhanced penetration of nanocarriers into the skin. In-vivo study done on induced-wound model revealed accelerated wound healing in NPs-treated group with 86.49 % wound contraction. Biochemical analysis of the impacted skin showed lower oxidative stress, with a 2.5-fold rise in reduced glutathione, a 3.2-fold boost in total antioxidant capacity, a 3.3-fold drop in malondialdehyde, and a 4.5-fold decrease in TNF-α levels versus the positive control. Therefore,This nanosystem could stand as a novel gateway and repurposed tool for accelerated wound healing and tissue regeneration.
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Affiliation(s)
- Fatma Sa'eed El-Tokhy
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo 11829, Egypt
| | - Dina O Helal
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt; Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, Leicestershire, United Kingdom
| | - Sherif S Abdel Mageed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo 11829, Egypt
| | - Abdulla M A Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo 11829, Egypt
| | - Riham I El-Gogary
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt
| | - Elsayed A El-Ghany
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Badr University in Cairo (BUC), Cairo 11829, Egypt
| | - Mona M A Abdel-Mottaleb
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt; Université de Franche-Comté, EFS, INSERM, UMR 1098 RIGHT, F-25000 Besançon, France.
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Aschen SZ, Zhang A, O’Connell GM, Salingaros S, Andy C, Rohde CH, Spector JA. Association of Perioperative Glucagon-like Peptide-1 Receptor Agonist Use and Postoperative Outcomes. Ann Surg 2025; 281:600-607. [PMID: 39704067 PMCID: PMC12014183 DOI: 10.1097/sla.0000000000006614] [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] [Indexed: 12/21/2024]
Abstract
OBJECTIVE To assess rates of surgical complications and postoperative readmission in diabetic patients with and without active perioperative prescriptions for glucagon-like peptide-1 receptor agonist (GLP-1 RA) medications. BACKGROUND With the rapid growth of GLP-1 RA use in the United States, it is important to understand the potential effect of these drugs on surgical outcomes broadly. METHODS In this retrospective, observational cohort analysis, patients with a diagnosis of type 1 or type 2 diabetes undergoing a surgical procedure at a multicenter quaternary-care health care system between February 2020 and July 2023 were included. Propensity score matching was performed between procedures in patients with and without an active GLP-1 RA prescription. The primary outcome was 30-day readmission, and secondary outcomes were documented dehiscence, infection, hematoma, and bleeding within 180 days after surgery. RESULTS Among 74,425 surgical procedures in 21,772 patients included in the analysis, 27.2% were performed in the setting of an active GLP-1 RA prescription. In 13,129 patients [48.0% men, 52.0% women; median (interquartile range) age, 67 (57, 75)], 35,020 procedures were propensity score matched. After matching, the active GLP-1 RA prescription group had a significantly reduced risk of 30-day readmission [relative risk (RR): 0.883; 95% CI: 0.789-0.987; P = 0.028; number needed to treat (NNT): 219; 95% CI: 191-257], postoperative wound dehiscence (RR: 0.711; 95% CI: 0.577-0.877; P = 0.001; NNT: 266; 95% CI: 202-391), and postoperative hematoma (RR: 0.440; 95% CI: 0.216-0.894; P = 0.023; NNT: 1786; 95% CI: 652-2416). No significant differences were seen in rates of infection and bleeding. CONCLUSIONS An active perioperative GLP-1 RA prescription in patients with diabetes was associated with significant reductions in risk-adjusted readmission, wound dehiscence, and hematoma, and no difference in infection and bleeding rates. Further study is warranted to elucidate any causal association.
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Affiliation(s)
- Seth Z. Aschen
- Weill Cornell Medicine, Department of Surgery, New York, NY
| | - Ashley Zhang
- Columbia University Irving Medical Center, Department of Surgery, New York, NY
| | | | | | - Caroline Andy
- Weill Cornell Medicine, Division of Biostatistics, New York, NY
| | - Christine H. Rohde
- Columbia University Irving Medical Center, Department of Surgery, New York, NY
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Mahmoud MO, Al-Hamid HA, Hassan NF, El-Ansary MR, Gomaa SB. Linagliptin Mitigates DMH-Induced Colorectal Cancer in Rats: Crosstalk Between NFAT and IL-6/JAK2/STAT3/NF-κB Signaling Hubs. J Biochem Mol Toxicol 2025; 39:e70206. [PMID: 40070168 DOI: 10.1002/jbt.70206] [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: 09/07/2024] [Revised: 01/30/2025] [Accepted: 03/02/2025] [Indexed: 05/13/2025]
Abstract
Colorectal cancer (CRC) is a multicomponent disease and the second most frequent root of cancer-related deaths globally. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. It has been repurposed in recent experimental studies due to its marked anti-inflammatory activities. This study aimed to evaluate the ameliorative role of linagliptin in 1,2-dimethylhydrazine (DMH)-induced CRC via modulation of NFAT-mediated IL-6 and JAK2/STAT3/NF-κB signaling pathways. CRC model has been successfully established via a dose equal 40 mg/kg two times a week of DMH for 8-week duration. Twenty-four Wistar rats were segregated into three groups of eight rats each; normal control, DMH-induced CRC and DMH + linagliptin (10 mg/kg; p.o). Linagliptin attenuated DMH-induced oxidative stress by restoring the declined levels of some antioxidant enzymes. Linagliptin suppressed the elevated nuclear factor kappa B (NF-κB) induced by DMH which is highlighted using immunohistochemistry analysis. The anti-inflammatory role of linagliptin has been fortified by the decline in nuclear factor of activated T-cells (NFAT) mRNA expression level along with the reduction in vascular endothelial growth factor (VEGF), interlukin-6 (IL-6) and cyclooxygenase-2 (COX-2) levels. Linagliptin mitigate the protein expression of DMH-activated oncogenic janus-activated kinase/signal transducers and activators of transcription (JAK2/STAT3). Linagliptin exerted a proapoptotic effect to tumor cells manifested by a remarkable decline in B-cell lymphoma 2 (Bcl-2) and a significant elevation in Bcl-2-associated X protein (Bax) expression levels. The histopathological analysis revealed that linagliptin has inhibitory potential against the DMH induced dysplastic aberrant crypt foci (ACF) and adenocarcinoma. Linagliptin ameliorated CRC by modulating NFAT-mediated IL-6 with JAK2/STAT3/NF-κB signaling cascades.
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Affiliation(s)
- Mohamed O Mahmoud
- Biochemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Hager Abd Al-Hamid
- Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Noha F Hassan
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Mona R El-Ansary
- Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Safaa B Gomaa
- Biochemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
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Yu WH, Zhang T, Xu H. Role of Dipeptidyl Dipeptidase 4 Inhibitors in the Management of Diabetic Foot. INT J LOW EXTR WOUND 2024; 23:577-584. [PMID: 35225718 DOI: 10.1177/15347346221082776] [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] [Indexed: 11/16/2022]
Abstract
Background: Patients with diabetes mellitus face difficulties in wound healing. It is important to explore therapeutic options for diabetic complications such as ulcers. This study evaluates the role of dipeptidyl dipeptidase 4 inhibitors (DPP4i) in the management of diabetic foot. Methods: Literature search was conducted in electronic databases (Google Scholar, Ovid, PubMed, Science Direct, and Springer) and studies were selected for inclusion if they reported the incidence rate of diabetic foot ulcer during DPP4i treatment or evaluated the effect of DPP4i on wound healing. Incidence rates of foot ulcer, amputation and peripheral vascular disease were pooled to achieve overall estimates. Meta-analyses of odds ratios were performed to evaluate the risk of foot ulcer, amputation, and peripheral vascular disease with DPP4i, and to examine the effect of DPP4i treatment on ulcer healing. Results: Ten studies (532354 DPP4i and 2092010 non-DPP4i treated diabetes patients) were included. Incidence rates of foot ulcer, amputation, and peripheral vascular disease were 3.80 [95% confidence interval (CI): 0.22, 7.39], 0.82 [95%CI: 0.60, 1.05], and 22.33 [95%CI: 9.14, 35.53] per 1000 person-years respectively in patients treated with DPP4i and 3.60 [95%CI: 1.77, 5.39], 0.76 [95%CI: 0.58, 0.94], and 20.9 [95%CI: 16.04, 25.81] per 1000 person-years respectively in patients treated with non-DPP4i drugs. Risk of ulcer or amputation with DPP4i was not consistent across studies. Odds of non-healing of ulcer were significantly lower with DPP4i in comparison with controls (odds ratio: 0.27 [95%CI: 0.10, 0.71]; p = 0.008). Conclusion: Incidence rates of diabetic foot and amputation are found to be similar with DPP4i and non-DPP4i drugs. DPP4i improved wound healing of diabetic foot in 3-month randomized trials.
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Affiliation(s)
- Wen-Hui Yu
- Department of Vascular Surgery, the First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin Heilongjiang 150040, China
| | - Tong Zhang
- Department of Vascular Surgery, the First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin Heilongjiang 150040, China
| | - Heng Xu
- Department of Vascular Surgery, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150001, China
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Bajaj G, Singh V, Sagar P, Gupta R, Singhal NK. Phosphoenolpyruvate carboxykinase-1 targeted siRNA promotes wound healing in type 2 diabetic mice by restoring glucose homeostasis. Int J Biol Macromol 2024; 270:132504. [PMID: 38772464 DOI: 10.1016/j.ijbiomac.2024.132504] [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: 02/24/2024] [Revised: 05/02/2024] [Accepted: 05/17/2024] [Indexed: 05/23/2024]
Abstract
It is well-accepted that the liver plays a vital role in the metabolism of glucose and its homeostasis. Dysregulated hepatic glucose production and utilization, leads to type 2 diabetes (T2DM). In the current study, RNA sequencing and qRT-PCR analysis of nanoformulation-treated T2DM mice (TGthr group) revealed beneficial crosstalk of PCK-1 silencing with other pathways involved in T2DM. The comparison of precise genetic expression profiles of the different experimental groups showed significantly improved hepatic glucose, fatty acid metabolism and several other T2DM-associated crucial markers after the nanoformulation treatment. As a result of these improvements, we observed a significant acceleration in wound healing and improved insulin signaling in vascular endothelial cells in the TGthr group as compared to the T2DM group. Enhanced phosphorylation of PI3K/Akt pathway proteins in the TGthr group resulted in increased angiogenesis as observed by the increased expression of endothelial cell markers (CD31, CD34) thereby improving endothelial dysfunctions in the TGthr group. Additionally, therapeutic nanoformulation has been observed to improve the inflammatory cytokine profile in the TGthr group. Overall, our results demonstrated that the synthesized therapeutic nanoformulation referred to as GPR8:PCK-1siRNA holds the potential in ameliorating hyperglycemia-associated complications such as delayed wound healing in diabetes.
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Affiliation(s)
- Geetika Bajaj
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India; Department of Biotechnology, Panjab University, Sector 25, Chandigarh 160014, India
| | - Vishal Singh
- National Institute for Implementation Research on Non-Communicable Diseases, Jodhpur 342005, India
| | - Poonam Sagar
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India
| | - Ritika Gupta
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India
| | - Nitin Kumar Singhal
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India.
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Tasnim J, Hashim NM, Han HC. A comprehensive review on potential drug-drug interactions of proton pump inhibitors with antidiabetic drugs metformin and DPP-4 inhibitors. Cell Biochem Funct 2024; 42:e3967. [PMID: 38480622 DOI: 10.1002/cbf.3967] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/22/2024] [Accepted: 02/23/2024] [Indexed: 03/22/2024]
Abstract
A drug interaction is a condition in which two or more drugs are taken at the same time. Type 2 diabetes mellitus is a significant contributor to polypharmacy. Proton pump inhibitors (PPIs) are often prescribed in combination with metformin or DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin) or a combined dose of metformin and DPP-4 inhibitor to treat gastritis in diabetic patients. This review article mainly focused on evaluating the potential drug-drug interactions (DDIs) between PPIs (i.e. esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole) with metformin and PPIs with DPP-4 inhibitors. The findings demonstrated the existence of pharmacokinetic and pharmacodynamic DDIs between the aforementioned PPIs with metformin and DPP-4 inhibitors, which could impact the biological activities (i.e., hypoglycemia) of these drugs. Moreover, this review suggested that esomeprazole could be the best drug in the PPI group to be prescribed simultaneously with metformin and DPP-4 inhibitors, as most of the antidiabetic drugs of this study did not show any interaction with esomeprazole. The findings of this study also revealed that both antidiabetic drugs and PPIs could have positive interactions as PPIs have the potential to lessen the gastrointestinal side effects of metformin and DPP-4 inhibitors. To achieve the greatest therapeutic impact with the fewest side effects, careful dose control of these drugs is required. So, more extensive research on both human and animal subjects are needed to ascertain the veracity of this hypothesis.
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Affiliation(s)
- Jarin Tasnim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Najihah Mohd Hashim
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia
- Centre for Natural Products Research and Drug Discovery, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Heh Choon Han
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia
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Du Y, Wang J, Fan W, Huang R, Wang H, Liu G. Preclinical study of diabetic foot ulcers: From pathogenesis to vivo/vitro models and clinical therapeutic transformation. Int Wound J 2023; 20:4394-4409. [PMID: 37438679 PMCID: PMC10681512 DOI: 10.1111/iwj.14311] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 06/28/2023] [Indexed: 07/14/2023] Open
Abstract
Diabetic foot ulcer (DFU), a common intractable chronic complication of diabetes mellitus (DM), has a prevalence of up to 25%, with more than 17% of the affected patients at risk of amputation or even death. Vascular risk factors, including vascular stenosis or occlusion, dyslipidemia, impaired neurosensory and motor function, and skin infection caused by trauma, all increase the risk of DFU in patients with diabetes. Therefore, diabetic foot is not a single pathogenesis. Preclinical studies have contributed greatly to the pathogenesis determination and efficacy evaluation of DFU. Many therapeutic tools are currently being investigated using DFU animal models for effective clinical translation. However, preclinical animal models that completely mimic the pathogenesis of DFU remain unexplored. Therefore, in this review, the preparation methods and evaluation criteria of DFU animal models with three major pathological mechanisms: neuropathy, angiopathy and DFU infection were discussed in detail. And the advantages and disadvantages of various DFU animal models for clinical sign simulation. Furthermore, the current status of vitro models of DFU and some preclinical studies have been transformed into clinical treatment programs, such as medical dressings, growth factor therapy, 3D bioprinting and pre-vascularization, Traditional Chinese Medicine treatment. However, because of the complexity of the pathological mechanism of DFU, the clinical transformation of DFU model still faces many challenges. We need to further optimize the existing preclinical studies of DFU to provide an effective animal platform for the future study of pathophysiology and clinical treatment of DFU.
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Affiliation(s)
- Yuqing Du
- Department of Peripheral Vascular SurgeryInstitute of surgery of traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Jie Wang
- Department of Peripheral Vascular SurgeryInstitute of surgery of traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
- Endocrinology departmentShanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Weijing Fan
- Department of Peripheral Vascular SurgeryInstitute of surgery of traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Renyan Huang
- Department of Peripheral Vascular SurgeryInstitute of surgery of traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Hongfei Wang
- Department of Peripheral Vascular SurgeryInstitute of surgery of traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Guobin Liu
- Department of Peripheral Vascular SurgeryInstitute of surgery of traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
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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: 49] [Impact Index Per Article: 24.5] [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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Montaniel KRC, Bucher M, Phillips EA, Li C, Sullivan EL, Kievit P, Rugonyi S, Nathanielsz PW, Maloyan A. Dipeptidyl peptidase IV inhibition delays developmental programming of obesity and metabolic disease in male offspring of obese mothers. J Dev Orig Health Dis 2022; 13:727-740. [PMID: 35068408 PMCID: PMC9308839 DOI: 10.1017/s2040174422000010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Maternal obesity programs the offspring to metabolic diseases later in life; however, the mechanisms of programming are yet unclear, and no strategies exist for addressing its detrimental transgenerational effects. Obesity has been linked to dipeptidyl peptidase IV (DPPIV), an adipokine, and treatment of obese individuals with DPPIV inhibitors has been reported to prevent weight gain and improve metabolism. We hypothesized that DPPIV plays a role in maternal obesity-mediated programming. We measured plasma DPPIV activity in human maternal and cord blood samples from normal-weight and obese mothers at term. We found that maternal obesity increases maternal and cord blood plasma DPPIV activity but only in male offspring. Using two non-human primate models of maternal obesity, we confirmed the activation of DPPIV in the offspring of obese mothers. We then created a mouse model of maternal high-fat diet (HFD)-induced obesity, and found an early-life increase in plasma DPPIV activity in male offspring. Activation of DPPIV preceded the progression of obesity, glucose intolerance and insulin resistance in male offspring of HFD-fed mothers. We then administered sitagliptin, DPPIV inhibitor, to regular diet (RD)- and HFD-fed mothers, starting a week prior to breeding and continuing throughout pregnancy and lactation. We found that sitagliptin treatment of HFD-fed mothers delayed the progression of obesity and metabolic diseases in male offspring and had no effects on females. Our findings reveal that maternal obesity dysregulates plasma DPPIV activity in males and provide evidence that maternal inhibition of DPPIV has potential for addressing the transgenerational effects of maternal obesity.
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Affiliation(s)
- Kim Ramil C. Montaniel
- Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97232, USA
- Physiology and Pharmacology Graduate Program, Oregon Health & Science University, Portland, OR, 97232, USA
| | - Matthew Bucher
- Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR, 97232, USA
| | - Elysse A. Phillips
- Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97232, USA
| | - Cun Li
- Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX, 78227, USA
- Department of Animal Sciences, University of Wyoming, Laramie, WY, 82071, USA
| | - Elinor L. Sullivan
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA
- Department of Psychiatry, Oregon Health & Science University, Beaverton, OR, 97006, USA
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97232, USA
| | - Paul Kievit
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA
| | - Sandra Rugonyi
- Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97232, USA
| | - Peter W. Nathanielsz
- Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX, 78227, USA
- Department of Animal Sciences, University of Wyoming, Laramie, WY, 82071, USA
| | - Alina Maloyan
- Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, 97232, USA
- Physiology and Pharmacology Graduate Program, Oregon Health & Science University, Portland, OR, 97232, USA
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Lee CH, Huang CH, Hung KC, Huang SC, Kuo CC, Liu SJ. Nanofibrous Vildagliptin/PLGA Membranes Accelerate Diabetic Wound Healing by Angiogenesis. Pharmaceuticals (Basel) 2022; 15:1358. [PMID: 36355530 PMCID: PMC9696371 DOI: 10.3390/ph15111358] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 10/27/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022] Open
Abstract
The inhibition of dipeptidyl peptidase-4 (DPP4) significantly enhances the wound closure rate in diabetic patients with chronic foot ulcers. DPP4 inhibitors are only prescribed for enteral, but topical administration, if feasible, to a wound would have more encouraging outcomes. Nanofibrous drug-eluting poly-D-L-lactide-glycolide (PLGA) membranes that sustainably release a high concentration of vildagliptin were prepared to accelerate wound healing in diabetes. Solutions of vildagliptin and PLGA in hexafluoroisopropanol were electrospun into nanofibrous biodegradable membranes. The concentration of the drug released in vitro from the vildagliptin-eluting PLGA membranes was evaluated, and it was found that effective bioactivity of vildagliptin can be discharged from the nanofibrous vildagliptin-eluting membranes for 30 days. Additionally, the electrospun nanofibrous PLGA membranes modified by blending with vildagliptin had smaller fiber diameters (336.0 ± 69.1 nm vs. 743.6 ± 334.3 nm, p < 0.001) and pore areas (3405 ± 1437 nm2 vs. 8826 ± 4906 nm2, p < 0.001), as well as a higher hydrophilicity value (95.2 ± 2.2° vs. 113.9 ± 4.9°, p = 0.004), and showed a better water-retention ability within 24 h compared with PLGA membranes. The vildagliptin-eluting PLGA membrane also enhanced the diabetic wound closure rate for two weeks (11.4 ± 3.0 vs. 18.7 ± 2.6 %, p < 0.001) and the level of the angiogenesis using CD31 expression (1.73 ± 0.39 vs. 0.45 ± 0.17 p = 0.006 for Western blot; 2.2 ± 0.5 vs. 0.7 ± 0.1, p < 0.001 for immunofluorescence). These results demonstrate that nanofibrous drug-eluting PLGA membranes loaded with vildagliptin are an effective agent for sustained drug release and, therefore, for accelerating cutaneous wound healing in the management of diabetic wounds.
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Affiliation(s)
- Chen-Hung Lee
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan
| | - Chien-Hao Huang
- Linkou Medical Center, Division of Hepatology, Department of Gastroenterology and Hepatology, Chang-Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Kuo-Chun Hung
- Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital-Linkou, Chang Gung University College of Medicine, Taoyuan 33302, Taiwan
| | - Shu-Chun Huang
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, New Taipei Municipal Tucheng Hospital, New Taipei 23652, Taiwan
- Department of Physical Medicine & Rehabilitation, Chang Gung Memorial Hospital-Linkou, Taoyuan 33305, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chi-Ching Kuo
- Research and Development Center of Smart Textile Technology, Institute of Organic and Polymeric Materials, National Taipei University of Technology, Taipei 10608, Taiwan
| | - Shih-Jung Liu
- Bone and Joint Research Center, Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Linkou, Taoyuan 33305, Taiwan
- Department of Mechanical Engineering, Chang Gung University, Taoyuan 33302, Taiwan
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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: 508] [Impact Index Per Article: 169.3] [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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12
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Linagliptin ameliorates acetic acid-induced colitis via modulating AMPK/SIRT1/PGC-1α and JAK2/STAT3 signaling pathway in rats. Toxicol Appl Pharmacol 2022; 438:115906. [PMID: 35122774 DOI: 10.1016/j.taap.2022.115906] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 01/20/2022] [Accepted: 01/28/2022] [Indexed: 12/11/2022]
Abstract
Ulcerative colitis is a chronic inflammatory disease, profoundly affecting the patient's quality of life and is associated with various complications. Linagliptin, a potent DPP- IV inhibitor, shows favorable anti-inflammatory effects in several animal model pathologies. To this end, the present study aimed to investigate the anti-inflammatory effect of linagliptin in a rat model of acetic acid-induced colitis. Moreover, the molecular mechanisms behind this effect were addressed. Accordingly, colitis was established by the administration of a 2 ml 6% acetic acid intrarectally and treatment with linagliptin (5 mg/kg) started 24 h after colitis induction and continued for 7 days. On one hand, the DPP-IV inhibitor alleviated the severity of colitis as evidenced by a decrease of disease activity index (DAI) scores, colon weight/length ratio, macroscopic damage, and histopathological deteriorations. Additionally, linagliptin diminished colon inflammation via attenuation of TNF-α, IL-6, and NF-κB p65 besides restoration of anti-inflammatory cytokine IL-10. On the other hand, linagliptin increased levels of p-AMPK, SIRT1, and PGC-1α while abolishing the increment in p-JAK2 and p-STAT3. In parallel linagliptin reduced mTOR levels and upregulated expression levels of SHP and MKP-1 which is postulated to mediate AMPK-driven JAK2/STAT3 inhibition. Based on these findings, linagliptin showed promising anti-inflammatory activity against acetic acid-induced colitis that is mainly attributed to the activation of the AMPK-SIRT1-PGC-1α pathway as well as suppression of the JAK2/STAT3 signaling pathway that might be partly mediated through AMPK activation.
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13
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Manigrasso MB, Rabbani P, Egaña-Gorroño L, Quadri N, Frye L, Zhou B, Reverdatto S, Ramirez LS, Dansereau S, Pan J, Li H, D’Agati VD, Ramasamy R, DeVita RJ, Shekhtman A, Schmidt AM. Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice. Sci Transl Med 2021; 13:eabf7084. [PMID: 34818060 PMCID: PMC8669775 DOI: 10.1126/scitranslmed.abf7084] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The macro- and microvascular complications of type 1 and 2 diabetes lead to increased disease severity and mortality. The receptor for advanced glycation end products (RAGE) can bind AGEs and multiple proinflammatory ligands that accumulate in diabetic tissues. Preclinical studies indicate that RAGE antagonists have beneficial effects on numerous complications of diabetes. However, these antagonists target the extracellular domains of RAGE, which bind distinct RAGE ligands at diverse sites in the immunoglobulin-like variable domain and two constant domains. The cytoplasmic tail of RAGE (ctRAGE) binds to the formin, Diaphanous-1 (DIAPH1), and this interaction is important for RAGE signaling. To comprehensively capture the breadth of RAGE signaling, we developed small-molecule antagonists of ctRAGE-DIAPH1 interaction, termed RAGE229. We demonstrated that RAGE229 is effective in suppressing RAGE-DIAPH1 binding, Förster resonance energy transfer, and biological activities in cellular assays. Using solution nuclear magnetic resonance spectroscopy, we defined the molecular underpinnings of the interaction of RAGE229 with RAGE. Through in vivo experimentation, we showed that RAGE229 assuaged short- and long-term complications of diabetes in both male and female mice, without lowering blood glucose concentrations. Last, the treatment with RAGE229 reduced plasma concentrations of TNF-α, IL-6, and CCL2/JE-MCP1 in diabetic mice, in parallel with reduced pathological and functional indices of diabetes-like kidney disease. Targeting ctRAGE-DIAPH1 interaction with RAGE229 mitigated diabetic complications in rodents by attenuating inflammatory signaling.
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Affiliation(s)
- Michaele B. Manigrasso
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Piul Rabbani
- Hansjörg Wyss Department of Plastic Surgery, NYU Langone Health, New York, NY 10016, USA
| | - Lander Egaña-Gorroño
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Nosirudeen Quadri
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Laura Frye
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Boyan Zhou
- Departments of Population Health (Biostatistics) and Environmental Medicine, NYU Langone Health, New York, NY 10016, USA
| | - Sergey Reverdatto
- Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA
| | - Lisa S. Ramirez
- Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA
| | - Stephen Dansereau
- Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA
| | - Jinhong Pan
- Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA
| | - Huilin Li
- Departments of Population Health (Biostatistics) and Environmental Medicine, NYU Langone Health, New York, NY 10016, USA
| | - Vivette D. D’Agati
- Department of Pathology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Ravichandran Ramasamy
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
| | - Robert J. DeVita
- RJD Medicinal Chemistry and Drug Discovery Consulting LLC, Westfield, NJ 07091, USA
| | - Alexander Shekhtman
- Department of Chemistry, State University of New York at Albany, Albany, NY 12222, USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Division of Endocrinology, Diabetes and Metabolism, NYU Langone Health, New York, NY 10016, USA
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14
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Torrecillas-Baena B, Gálvez-Moreno MÁ, Quesada-Gómez JM, Dorado G, Casado-Díaz A. Influence of Dipeptidyl Peptidase-4 (DPP4) on Mesenchymal Stem-Cell (MSC) Biology: Implications for Regenerative Medicine - Review. Stem Cell Rev Rep 2021; 18:56-76. [PMID: 34677817 DOI: 10.1007/s12015-021-10285-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2021] [Indexed: 12/16/2022]
Abstract
Dipeptidyl peptidase IV (DPP4) is a ubiquitous protease that can be found in membrane-anchored or soluble form. Incretins are one of the main DPP4 substrates. These hormones regulate glucose levels, by stimulating insulin secretion and decreasing glucagon production. Because DPP4 levels are high in diabetes, DPP4 inhibitor (DPP4i) drugs derived from gliptin are widespread used as hypoglycemic agents for its treatment. However, as DPP4 recognizes other substrates such as chemokines, growth factors and neuropeptides, pleiotropic effects have been observed in patients treated with DPP4i. Several of these substrates are part of the stem-cell niche. Thus, they may affect different physiological aspects of mesenchymal stem-cells (MSC). They include viability, differentiation, mobilization and immune response. MSC are involved in tissue homeostasis and regeneration under both physiological and pathological conditions. Therefore, such cells and their secretomes have a high clinical potential in regenerative medicine. In this context, DPP4 activity may modulate different aspects of MSC regenerative capacity. Therefore, the aim of this review is to analyze the effect of different DPP4 substrates on MSC. Likewise, how the regulation of DPP4 activity by DPP4i can be applied in regenerative medicine. That includes treatment of cardiovascular and bone pathologies, cutaneous ulcers, organ transplantation and pancreatic beta-cell regeneration, among others. Thus, DPP4i has an important clinical potential as a complement to therapeutic strategies in regenerative medicine. They involve enhancing the differentiation, immunomodulation and mobilization capacity of MSC for regenerative purposes.
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Affiliation(s)
- Bárbara Torrecillas-Baena
- Unidad de Gestión Clínica de Endocrinología y Nutrición - GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, Avda. Menéndez Pidal s/n, 14004, Córdoba, Spain
| | - María Ángeles Gálvez-Moreno
- Unidad de Gestión Clínica de Endocrinología y Nutrición - GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, Avda. Menéndez Pidal s/n, 14004, Córdoba, Spain
| | - José Manuel Quesada-Gómez
- Unidad de Gestión Clínica de Endocrinología y Nutrición - GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, Avda. Menéndez Pidal s/n, 14004, Córdoba, Spain
| | - Gabriel Dorado
- Dep. Bioquímica y Biología Molecular, Campus Rabanales C6-1-E17, Campus de Excelencia Internacional Agroalimentario (ceiA3), Universidad de Córdoba, CIBERFES, 14071, Córdoba, Spain
| | - Antonio Casado-Díaz
- Unidad de Gestión Clínica de Endocrinología y Nutrición - GC17, Instituto Maimónides de Investigación Biomédica de Córdoba, Hospital Universitario Reina Sofía, CIBERFES, Avda. Menéndez Pidal s/n, 14004, Córdoba, Spain.
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15
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Spiller S, Clauder F, Bellmann-Sickert K, Beck-Sickinger AG. Improvement of wound healing by the development of ECM-inspired biomaterial coatings and controlled protein release. Biol Chem 2021; 402:1271-1288. [PMID: 34392636 DOI: 10.1515/hsz-2021-0144] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 03/19/2021] [Indexed: 12/22/2022]
Abstract
Implant design has evolved from biochemically inert substrates, minimizing cell and protein interaction, towards sophisticated bioactive substrates, modulating the host response and supporting the regeneration of the injured tissue. Important aspects to consider are the control of cell adhesion, the discrimination of bacteria and non-local cells from the desired tissue cell type, and the stimulation of implant integration and wound healing. Here, the extracellular matrix acts as a role model providing us with inspiration for sophisticated designs. Within this scope, small bioactive peptides have proven to be miscellaneously deployable for the mediation of surface, cell and matrix interactions. Combinations of adhesion ligands, proteoglycans, and modulatory proteins should guide multiple aspects of the regeneration process and cooperativity between the different extracellular matrix components, which bears the chance to maximize the therapeutic efficiency and simultaneously lower the doses. Hence, efforts to include multiple of these factors in biomaterial design are well worth. In the following, multifunctional implant coatings based on bioactive peptides are reviewed and concepts to implement strong surface anchoring for stable cell adhesion and a dynamic delivery of modulator proteins are discussed.
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Affiliation(s)
- Sabrina Spiller
- Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstr. 34, D-04103Leipzig, Germany
| | - Franziska Clauder
- Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstr. 34, D-04103Leipzig, Germany
| | - Kathrin Bellmann-Sickert
- Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstr. 34, D-04103Leipzig, Germany
| | - Annette G Beck-Sickinger
- Institute of Biochemistry, Faculty of Life Sciences, Leipzig University, Brüderstr. 34, D-04103Leipzig, Germany
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16
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Yazbeck R, Jaenisch SE, Abbott CA. Dipeptidyl peptidase 4 inhibitors: Applications in innate immunity? Biochem Pharmacol 2021; 188:114517. [PMID: 33722535 PMCID: PMC7954778 DOI: 10.1016/j.bcp.2021.114517] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 12/25/2022]
Abstract
Dipeptidyl peptidase (DPP)-4 inhibitors are a class of orally available, small molecule inhibitors that prolong the insulinotropic activity of the incretin hormone glucagon-like peptide-1 (GLP-1) and are highly effective for the treatment of Type-2 diabetes. DPP4 can also cleave several immunoregulatory peptides including chemokines. Emerging evidence continues to implicate DPP4 inhibitors as immunomodulators, with recent findings suggesting DPP4 inhibitors modify specific aspects of innate immunity. This review summarises recent insights into how DPP4 inhibitors could be implicated in endothelial, neutrophil and monocyte/macrophage mediated immunity. Additionally, this review highlights additional avenues of research with DPP4 inhibitors in the context of the COVID-19 pandemic.
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Affiliation(s)
- R Yazbeck
- College of Medicine and Public Health & Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia; College of Science and Engineering, Flinders University, Adelaide, Australia.
| | - S E Jaenisch
- College of Medicine and Public Health & Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia; College of Science and Engineering, Flinders University, Adelaide, Australia.
| | - C A Abbott
- College of Medicine and Public Health & Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia; College of Science and Engineering, Flinders University, Adelaide, Australia.
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17
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Molavi Z, Razi S, Mirmotalebisohi SA, Adibi A, Sameni M, Karami F, Niazi V, Niknam Z, Aliashrafi M, Taheri M, Ghafouri-Fard S, Jeibouei S, Mahdian S, Zali H, Ranjbar MM, Yazdani M. Identification of FDA approved drugs against SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and 3-chymotrypsin-like protease (3CLpro), drug repurposing approach. Biomed Pharmacother 2021; 138:111544. [PMID: 34311539 PMCID: PMC8011644 DOI: 10.1016/j.biopha.2021.111544] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 03/04/2021] [Accepted: 03/23/2021] [Indexed: 01/08/2023] Open
Abstract
The RNA-dependent RNA polymerase (RdRp) and 3C-like protease (3CLpro) from SARS-CoV-2 play crucial roles in the viral life cycle and are considered the most promising targets for drug discovery against SARS-CoV-2. In this study, FDA-approved drugs were screened to identify the probable anti-RdRp and 3CLpro inhibitors by molecular docking approach. The number of ligands selected from the PubChem database of NCBI for screening was 1760. Ligands were energy minimized using Open Babel. The RdRp and 3CLpro protein sequences were retrieved from the NCBI database. For Homology Modeling predictions, we used the Swiss model server. Their structure was then energetically minimized using SPDB viewer software and visualized in the CHIMERA UCSF software. Molecular dockings were performed using AutoDock Vina, and candidate drugs were selected based on binding affinity (∆G). Hydrogen bonding and hydrophobic interactions between ligands and proteins were visualized using Ligplot and the Discovery Studio Visualizer v3.0 software. Our results showed 58 drugs against RdRp, which had binding energy of - 8.5 or less, and 69 drugs to inhibit the 3CLpro enzyme with a binding energy of - 8.1 or less. Six drugs based on binding energy and number of hydrogen bonds were chosen for the next step of molecular dynamics (MD) simulations to investigate drug-protein interactions (including Nilotinib, Imatinib and dihydroergotamine for 3clpro and Lapatinib, Dexasone and Relategravir for RdRp). Except for Lapatinib, other drugs-complexes were stable during MD simulation. Raltegravir, an anti-HIV drug, was observed to be the best compound against RdRp based on docking binding energy (-9.5 kcal/mole) and MD results. According to the MD results and binding energy, dihydroergotamine is a suitable candidate for 3clpro inhibition (-9.6 kcal/mol). These drugs were classified into several categories, including antiviral, antibacterial, anti-inflammatory, anti-allergic, cardiovascular, anticoagulant, BPH and impotence, antipsychotic, antimigraine, anticancer, and so on. The common prescription-indications for some of these medication categories appeared somewhat in line with manifestations of COVID-19. We hope that they can be beneficial for patients with certain specific symptoms of SARS-CoV-2 infection, but they can also probably inhibit viral enzymes. We recommend further experimental evaluations in vitro and in vivo on these FDA-approved drugs to assess their potential antiviral effect on SARS-CoV-2.
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Affiliation(s)
- Zahra Molavi
- Proteomics Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Sara Razi
- Proteomics Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran; Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Seyed Amir Mirmotalebisohi
- Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirjafar Adibi
- Departments of Orthopedics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marzieh Sameni
- Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farshid Karami
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Niazi
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Niknam
- Proteomics Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
| | | | - Mohammad Taheri
- Urology and Nephrology Research Cenetr, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Jeibouei
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soodeh Mahdian
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Hakimeh Zali
- Proteomics Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Mehdi Ranjbar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran.
| | - Mohsen Yazdani
- Institute of Biochemistry and Biophysics, Tehran University, Tehran, Iran.
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18
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Hansen HH, Grønlund RV, Baader-Pagler T, Haebel P, Tammen H, Larsen LK, Jelsing J, Vrang N, Klein T. Characterization of combined linagliptin and Y2R agonist treatment in diet-induced obese mice. Sci Rep 2021; 11:8060. [PMID: 33850212 PMCID: PMC8044192 DOI: 10.1038/s41598-021-87539-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/31/2021] [Indexed: 02/01/2023] Open
Abstract
Dipeptidyl peptidase IV (DPP-IV) inhibitors improve glycemic control by prolonging the action of glucagon-like peptide-1 (GLP-1). In contrast to GLP-1 analogues, DPP-IV inhibitors are weight-neutral. DPP-IV cleavage of PYY and NPY gives rise to PYY3-36 and NPY3-36 which exert potent anorectic action by stimulating Y2 receptor (Y2R) function. This invites the possibility that DPP-IV inhibitors could be weight-neutral by preventing conversion of PYY/NPY to Y2R-selective peptide agonists. We therefore investigated whether co-administration of an Y2R-selective agonist could unmask potential weight lowering effects of the DDP-IV inhibitor linagliptin. Male diet-induced obese (DIO) mice received once daily subcutaneous treatment with linagliptin (3 mg/kg), a Y2R-selective PYY3-36 analogue (3 or 30 nmol/kg) or combination therapy for 14 days. While linagliptin promoted marginal weight loss without influencing food intake, the PYY3-36 analogue induced significant weight loss and transient suppression of food intake. Both compounds significantly improved oral glucose tolerance. Because combination treatment did not further improve weight loss and glucose tolerance in DIO mice, this suggests that potential negative modulatory effects of DPP-IV inhibitors on endogenous Y2R peptide agonist activity is likely insufficient to influence weight homeostasis. Weight-neutrality of DPP-IV inhibitors may therefore not be explained by counter-regulatory effects on PYY/NPY responses.
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Affiliation(s)
| | | | - Tamara Baader-Pagler
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co., Biberach, Germany
| | - Peter Haebel
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co., Biberach, Germany
| | | | | | - Jacob Jelsing
- Gubra, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | - Niels Vrang
- Gubra, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | - Thomas Klein
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co., Biberach, Germany
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19
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Valdés-Mora F, Salomon R, Gloss BS, Law AMK, Venhuizen J, Castillo L, Murphy KJ, Magenau A, Papanicolaou M, Rodriguez de la Fuente L, Roden DL, Colino-Sanguino Y, Kikhtyak Z, Farbehi N, Conway JRW, Sikta N, Oakes SR, Cox TR, O'Donoghue SI, Timpson P, Ormandy CJ, Gallego-Ortega D. Single-cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype. Cell Rep 2021; 35:108945. [PMID: 33852842 DOI: 10.1016/j.celrep.2021.108945] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 10/29/2020] [Accepted: 03/14/2021] [Indexed: 01/02/2023] Open
Abstract
Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.
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MESH Headings
- Animals
- Breast Neoplasms/genetics
- Breast Neoplasms/metabolism
- Breast Neoplasms/pathology
- Cancer-Associated Fibroblasts/metabolism
- Cancer-Associated Fibroblasts/pathology
- Carcinoma, Basal Cell/genetics
- Carcinoma, Basal Cell/metabolism
- Carcinoma, Basal Cell/pathology
- Cell Lineage/genetics
- Chemokine CXCL12/genetics
- Chemokine CXCL12/metabolism
- Collagen Type I, alpha 1 Chain/genetics
- Collagen Type I, alpha 1 Chain/metabolism
- Extracellular Matrix/metabolism
- Extracellular Matrix/pathology
- Female
- Gene Expression Regulation, Neoplastic
- High-Throughput Nucleotide Sequencing
- Humans
- Mammary Glands, Animal/metabolism
- Mammary Glands, Animal/pathology
- Mammary Glands, Animal/virology
- Mammary Neoplasms, Animal/genetics
- Mammary Neoplasms, Animal/metabolism
- Mammary Neoplasms, Animal/pathology
- Mammary Tumor Virus, Mouse/growth & development
- Mammary Tumor Virus, Mouse/pathogenicity
- Matrix Metalloproteinase 3/genetics
- Matrix Metalloproteinase 3/metabolism
- Mice
- Neoplasm Metastasis
- Pregnancy
- Single-Cell Analysis
- Transcriptome
- Tumor Microenvironment/genetics
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Affiliation(s)
- Fátima Valdés-Mora
- Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
| | - Robert Salomon
- Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Institute for Biomedical Materials and Devices, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Brian Stewart Gloss
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Andrew Man Kit Law
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Jeron Venhuizen
- Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Lesley Castillo
- Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Kendelle Joan Murphy
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Astrid Magenau
- Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Michael Papanicolaou
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; School of Life Sciences, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Laura Rodriguez de la Fuente
- Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Daniel Lee Roden
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Yolanda Colino-Sanguino
- Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Personalised Medicine, Children's Cancer Institute, Sydney, NSW 2031, Australia; St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia
| | - Zoya Kikhtyak
- Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Nona Farbehi
- Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | | | - Neblina Sikta
- Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Samantha Richelle Oakes
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Thomas Robert Cox
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Seán Ignatius O'Donoghue
- Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; CSIRO Data61, Eveleigh, NSW 2015, Australia; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Kensington, NSW 2052, Australia
| | - Paul Timpson
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Christopher John Ormandy
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - David Gallego-Ortega
- St. Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, NSW 2010, Australia; Garvan-Weizmann Centre for Cellular Genomics. Garvan Institute of Medical Research, Sydney, NSW 2010, Australia; Cancer Theme, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia.
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Jiang Y, Yao Y, Li J, Wang Y, Cheng J, Zhu Y. Functional Dissection of CD26 and Its Pharmacological Inhibition by Sitagliptin During Skin Wound Healing. Med Sci Monit 2021; 27:e928933. [PMID: 33735157 PMCID: PMC7986725 DOI: 10.12659/msm.928933] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Skin fibroblasts are primary mediators underlying wound healing and therapeutic targets in scar prevention and treatment. CD26 is a molecular marker to distinguish fibroblast subpopulations and plays an important role in modulating the biological behaviors of dermal fibroblasts and influencing skin wound repair. Therapeutic targeting of specific fibroblast subsets is expected to reduce skin scar formation more efficiently. MATERIAL AND METHODS Skin burn and excisional wound healing models were surgically established in mice. The expression patterns of CD26 during wound healing were determined by immunohistochemical staining, real-time RT-PCR, and western blot assays. Normal fibroblasts from intact skin (NFs) and fibroblasts in wounds (WFs) were isolated and sorted by fluorescence-activated cell sorting (FACS) into 4 subgroups - CD26⁺ NFs, CD26⁻ NFs, CD26⁺ WFs, and CD26⁻ WFs - for comparisons of their capacities of proliferation, migration, and collagen synthesis. Pharmacological inhibition of CD26 by sitagliptin in skin fibroblasts and during wound healing were further assessed both in vitro and in vivo. RESULTS Increased CD26 expression was observed during skin wound healing in both models. The CD26⁺ fibroblasts isolated from wounds had significantly stronger abilities to proliferate, migrate, and synthesize collagen than other fibroblast subsets. Sitagliptin treatment potently diminished CD26 expression, impaired the proliferation, migration, and collagen synthesis of fibroblasts in vitro, and diminished scar formation in vivo. CONCLUSIONS Our data reveal that CD26 is functionally involved in skin wound healing by regulating cell proliferation, migration, and collagen synthesis in fibroblasts. Pharmacological inhibition of CD26 by sitagliptin might be a viable strategy to reduce skin scar formation.
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Affiliation(s)
- Yue Jiang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Yuan Yao
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Jin Li
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Yanling Wang
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Jie Cheng
- Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
| | - Yumin Zhu
- Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Nanjing, Jiangsu, China (mainland)
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Worthen CA, Cui Y, Orringer JS, Johnson TM, Voorhees JJ, Fisher GJ. CD26 Identifies a Subpopulation of Fibroblasts that Produce the Majority of Collagen during Wound Healing in Human Skin. J Invest Dermatol 2020; 140:2515-2524.e3. [PMID: 32407715 PMCID: PMC7655599 DOI: 10.1016/j.jid.2020.04.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/13/2020] [Accepted: 04/17/2020] [Indexed: 12/23/2022]
Abstract
Fibroblasts produce collagens and other proteins that form the bulk of the extracellular matrix (ECM) in connective tissues. Emerging data point to functional heterogeneity of fibroblasts. However, the lack of subtype-specific markers hinders our understanding of the different roles of fibroblasts in ECM biology, wound healing, diseases, and aging. We have investigated the utility of the cell surface protein CD26 to identify functionally distinct fibroblast subpopulations in human skin. Using flow cytometry and immunohistology, we found that CD26, in combination with the cell surface glycoprotein CD90, identifies a distinct subpopulation of cells, which express relatively high levels of COL1A1, a hallmark of fibroblasts. Importantly, the population of CD26+ fibroblasts is selectively increased after wounding of human skin. These cells account for the majority of COL1A1 expression during the ECM remodeling phase of healing. The proportion of CD26+ fibroblasts in the skin of young and aged individuals is similar, indicating that the loss of collagen production during aging does not involve selective reduction of CD26+ fibroblasts. In culture, the majority of freshly isolated CD26- fibroblasts gain expression of CD26+. Taken together, these data provide a foundation for targeting CD26+ fibroblasts to modulate wound healing in human skin.
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Affiliation(s)
- Christal A Worthen
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Yilei Cui
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Jeffrey S Orringer
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Timothy M Johnson
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - John J Voorhees
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Gary J Fisher
- Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
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22
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Patel PM, Jones VA, Kridin K, Amber KT. The role of Dipeptidyl Peptidase-4 in cutaneous disease. Exp Dermatol 2020; 30:304-318. [PMID: 33131073 DOI: 10.1111/exd.14228] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/21/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022]
Abstract
Dipeptidyl peptidase-4 (DPP4) is a multifunctional, transmembrane glycoprotein present on the cell surface of various tissues. It is present in multiple molecular forms including cell surface and soluble. The role of DPP4 and its inhibition in cutaneous dermatoses have been a recent point of investigation. DPP4 exerts a notable influence on T-cell biology, the induction of skin-specific lymphocytes, and the homeostasis between regulatory and effector T cells. Moreover, DPP4 interacts with a broad range of molecules, including adenosine deaminase, caveolin-1, CXCR4 receptor, M6P/insulin-like growth factor II-receptor and fibroblast activation protein-α, triggering downstream effects that modulate the immune response, cell adhesion and chemokine activity. DPP4 expression on melanocytes, keratinocytes and fibroblasts further alters cell function and, thus, has crucial implications in cutaneous pathology. As a result, DPP4 plays a significant role in bullous pemphigoid, T helper type 1-like reactions, cutaneous lymphoma, melanoma, wound healing and fibrotic disorders. This review illustrates the multifactorial role of DPP4 expression, regulation, and inhibition in cutaneous diseases.
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Affiliation(s)
- Payal M Patel
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
| | - Virginia A Jones
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
| | - Khalaf Kridin
- Department of Dermatology, University of Lübeck, Lübeck, Germany
| | - Kyle T Amber
- Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA
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23
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Wang H, Li Y, Zhang X, Xu Z, Zhou J, Shang W. DPP-4 Inhibitor Linagliptin Ameliorates Oxidized LDL-Induced THP-1 Macrophage Foam Cell Formation and Inflammation. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:3929-3940. [PMID: 33061298 PMCID: PMC7524190 DOI: 10.2147/dddt.s249846] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 08/12/2020] [Indexed: 12/13/2022]
Abstract
Introduction Atherosclerosis is one of the major causes of cardiovascular diseases. Lipid uptake and accumulation in macrophages play a major role in atherosclerotic plaque formation from its initiation to advanced atheroma formation. The dipeptidyl peptidase-4 (DPP-4) inhibitor Linagliptin is commonly used to lower blood glucose in type 2 diabetes patients. Recent studies report that Linagliptin has cardiovascular protective and anti-inflammatory effects. Methods THP-1 macrophage cells were treated with 100 nM PMA for 72 hour to induce foam cell formation. The differentiated cells were exposed to 100 μg/mL ox-LDL in the presence or absence of the DPP-4 inhibitor Linagliptin. The expression levels of DPP-4 and inflammatory cytokines were detected by RT-PCR, ELISA, and Western blot experiments. The cellular ROS level was measured by staining the cells with the fluorescent probe DCFH-DA. The separation of lipoprotein fractions was achieved by high-performance liquid chromatography (HPLC). The cells were labeled with fluorescent-labeled cholesterol to measure cholesterol efflux, and lipid droplets were revealed by Nile red staining. Results The presence of Linagliptin significantly reduced ox-LDL-induced cytokine production (IL-1β and IL-6) and ROS production. Linagliptin ameliorated ox-LDL-induced lipid accumulation and impaired cholesterol efflux in macrophages. Mechanistically, this study showed that Linagliptin mitigated ox-LDL-induced expression of the scavenger receptors CD36 and LOX-1, but not SRA. Furthermore, Linagliptin increased the expression of the cholesterol transporter ABCG1, but not ABCA1. Conclusion Linagliptin possesses a potent inhibitory effect on THP-1 macrophage-derived foam cell formation in response to ox-LDL. This effect could be mediated through a decrease in the expression of CD36 and LOX-1 on macrophages and an increase in the expression of the cholesterol transporter ABCG1. This study indicates that the DPP-4 inhibitor Linagliptin plays a critical role in preventing foam cell formation in vitro. However, future research using an atherosclerotic animal model is necessary to determine its effectiveness and to prove its potential implication in the prevention and treatment of atherosclerosis.
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Affiliation(s)
- Haoran Wang
- Department of Endocrinology, The Ninth People's Hospital of Chongqing, Chongqing 400700, People's Republic of China
| | - Yue Li
- Department of Cardiology, The Ninth People's Hospital of Chongqing, Chongqing 400700, People's Republic of China
| | - Xiaoliang Zhang
- Department of Cardiology, The Ninth People's Hospital of Chongqing, Chongqing 400700, People's Republic of China
| | - Zhonglin Xu
- Department of Cardiology, The Ninth People's Hospital of Chongqing, Chongqing 400700, People's Republic of China
| | - Jianzhong Zhou
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400700, People's Republic of China
| | - Wei Shang
- Department of Cardiology, The Ninth People's Hospital of Chongqing, Chongqing 400700, People's Republic of China
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The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs. Pharmaceuticals (Basel) 2020; 13:ph13040060. [PMID: 32244718 PMCID: PMC7243111 DOI: 10.3390/ph13040060] [Citation(s) in RCA: 217] [Impact Index Per Article: 43.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 03/27/2020] [Accepted: 03/29/2020] [Indexed: 12/19/2022] Open
Abstract
Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and economic burden in the near future. Hence, the need for therapeutic alternatives to the current available treatments that, although various, do not guarantee a rapid and definite reparative process, appears necessary. We here analyzed current treatments for wound healing, but mainly focused the attention on few classes of drugs that are already in the market with different indications, but that have shown in preclinical and few clinical trials the potentiality to be used in the treatment of impaired wound healing. In particular, repurposing of the antiglycemic agents dipeptidylpeptidase 4 (DPP4) inhibitors and metformin, but also, statins and phenyotin have been analyzed. All show encouraging results in the treatment of chronic wounds, but additional, well designed studies are needed to allow these drugs access to the clinics in the therapy of impaired wound healing.
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Aksoy H, Çevik Ö, Şen A, Göğer F, Şekerler T, Şener A. Effect of Horse-chestnut seed extract on matrix metalloproteinase-1 and -9 during diabetic wound healing. J Food Biochem 2019; 43:e12758. [PMID: 31353546 DOI: 10.1111/jfbc.12758] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Revised: 11/05/2018] [Accepted: 11/29/2018] [Indexed: 12/13/2022]
Abstract
The effects of aqueous-ethanol extract of Horse chestnut (HCE) on MMP-1 and MMP-9 expressions during cutaneous wound healing in diabetic rats were investigated in this study. The expressions of MMP-1 and MMP-9, wound closure, myeloperoxidase (MPO) activity, hydroxyproline, and malondialdehyde (MDA) levels in wound tissue were measured. Quercetin glucuronide in HCE was identified as main compound using a LC-MS/MS. The hydroxyproline level was significantly increased in the treated group versus control after the 3rd and 7th days (p < 0.05). The MDA level and MPO activity were significantly lower in the treatment group (p < 0.05). MMP-1 gene expression level in treated rats was increased in the 7th day while it was reduced in 14th day. MMP-9 gene expression level in treated rats was decreased in 7th, and 14th days compared to control (p < 0.05). These results show that HCE accelerated the cutaneous wound-healing process in diabetic rats via MMP-1 and MMP-9 regulation. PRACTICAL APPLICATIONS: The main function of MMPs is to degrade and deposite the various components of the extracellular matrix. Also, they participate physiological processes such as inflammation, angiogenesis, and tissue remodeling. Horse chestnut seeds (HC) are known to be rich in saponins and flavonoids. HC are used for the treatment of abdominal pain, stomach ache, cold, hemorrhoids, arterial stiffness, rheumatism, oedema, diarrhea, chronic venous insufficiency and also as an antihemorrhagic and antipyretic in traditional medicine. It has been shown that HC has anti-inflammatory, antioedema, vessel protective, and free radical scavenging properties. This study indicates that HCE could be an effective agent for wound healing in diabetic wound model via its ability to suppress the MMP-9 gene expression and regulates MMP-1 gene expression besides its antioxidative, anti-inflammatory effects.
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Affiliation(s)
- Halil Aksoy
- Faculty of Pharmacy, Department of Biochemistry, Marmara University, İstanbul, Turkey
| | - Özge Çevik
- Faculty of Medicine, Department of Biochemistry, Adnan Menderes University, Aydin, Turkey
| | - Ali Şen
- Faculty of Pharmacy, Department of Pharmacognosy, Marmara University, İstanbul, Turkey
| | - Fatih Göğer
- Faculty of Pharmacy, Department of Pharmacognosy, Anadolu University, Eskişehir, Turkey
| | - Turgut Şekerler
- Faculty of Pharmacy, Department of Biochemistry, Marmara University, İstanbul, Turkey
| | - Azize Şener
- Faculty of Pharmacy, Department of Biochemistry, Marmara University, İstanbul, Turkey
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Stuermer EK, Besser M, Terberger N, Koester V, Bachmann HS, Severing AL. Side effects of frequently used oral antidiabetics on wound healing in vitro. Naunyn Schmiedebergs Arch Pharmacol 2018; 392:371-380. [PMID: 30535571 DOI: 10.1007/s00210-018-01597-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 11/27/2018] [Indexed: 11/24/2022]
Abstract
Lifestyle diseases such as diabetes and arteriosclerosis are rising in the increasingly aging society, and the number of patients with daily intake of glucose-lowering medication has also increased. Interestingly, knowledge about oral antidiabetics with regard to wound healing is scarce. Therefore, the aim of this study was to identify possible (side) effects of the most frequently prescribed oral antidiabetics on skin cells and wound healing. Four oral antidiabetics of different substance classes (i.e., metformin, glibenclamide, sitagliptin, repaglinide) were investigated with regard to the promotion of cell metabolism and migration of human skin fibroblasts and keratinocytes by XTT and scratch assays. In addition, histological and immunohistochemical analyses were performed in a 3D wound model to address the impact of the antidiabetics on regeneration processes, such as cell migration, fibroblast activity, epidermal thickness, and cell apoptosis. In comparison to systemic application, metformin displayed the most adverse effects in vitro in nearly all analyses, interestingly at serum equivalent concentrations. In contrast, sitagliptin and glibenclamide had a slight but insignificant effect on fibroblasts compared with keratinocytes. Repaglinide tended to have a negative influence on keratinocyte metabolism. Interestingly, antidiabetics generally induced a significantly enhanced rate of apoptosis in fibroblasts, with the exception of repaglinide.Antidiabetics influenced key players in wound healing, namely, keratinocytes and fibroblasts. Particularly, metformin impaired human skin cells. These findings should be kept in mind in further studies because of their putative relevance in patients suffering from chronic wounds that do not respond to various wound therapies.
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Affiliation(s)
- Ewa Klara Stuermer
- Institute of Translational Wound Research, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Street 10, 58453, Witten, Germany.
| | - M Besser
- Institute of Translational Wound Research, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Street 10, 58453, Witten, Germany
| | - N Terberger
- Institute of Translational Wound Research, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Street 10, 58453, Witten, Germany
| | - V Koester
- Institute of Translational Wound Research, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Street 10, 58453, Witten, Germany
| | - H S Bachmann
- Institute of Pharmacology and Toxicology, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Witten, Germany
| | - A L Severing
- Institute of Translational Wound Research, Centre for Biomedical Education and Research (ZBAF), Witten/Herdecke University, Stockumer Street 10, 58453, Witten, Germany
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Nagae K, Uchi H, Morino-Koga S, Tanaka Y, Oda M, Furue M. Glucagon-like peptide-1 analogue liraglutide facilitates wound healing by activating PI3K/Akt pathway in keratinocytes. Diabetes Res Clin Pract 2018; 146:155-161. [PMID: 30367901 DOI: 10.1016/j.diabres.2018.10.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 10/01/2018] [Accepted: 10/22/2018] [Indexed: 11/30/2022]
Abstract
AIMS Diabetes induces various skin troubles including foot ulcer. This type of skin ulcer is refractory but the pathogenesis is not so certain. Recent study show that glucagon-like peptide-1 (GLP-1) analogues reduce foot complications with diabetes (Pérez et al., 2015), however, the role of GLP-1/GLP-1R axis is not fully understood, and clear evidence of GLP-1 to facilitate wound closure is still lacking. In this study, we investigated whether a potent GLP-1R agonist liraglutide affects wound healing process. METHODS The expression of GLP-1R in HaCaT cells were indentified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunoblotting analysis. To assess the effect on wound closure in keratinocytes, we performed in vitro scratch assay using the IncuCyte system (Essen BioSciences, Ann Arborm MI). We applied ointment containing liraglutide on full-thickness wounds in the dorsum of female balb/c mice (n = 6) until healing. To investigate the effect on PI3K/Akt pathway, we used IncuCyte system in HaCaT treated with PI3K inhibitor and Akt inhibitor. RESULTS Keratinocytes expressed GLP-1R and liraglutide induced their migration. Liraglutide facilitated the wound healing in mice. Liraglutide upregulated keratinocyte migration via PI3K/Akt activation. CONCLUSIONS Our study suggests that liraglutide may be a potential target drug to improve skin ulcer with diabetes through its specific receptor GLP-1.
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Affiliation(s)
- Konosuke Nagae
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan.
| | - Hiroshi Uchi
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan
| | - Saori Morino-Koga
- Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto 860-8555, Japan
| | - Yuka Tanaka
- Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan
| | - Mari Oda
- Department of Dermatology, Hamanomachi Hospital, 3-3-1 Nagahama, Chuo-ku, Fukuoka 810-8539, Japan
| | - Masutaka Furue
- Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan; Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan
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Ku HC, Liang YJ. Incretin-based therapy for diabetic ulcers: from bench to bedside. Expert Opin Investig Drugs 2018; 27:989-996. [PMID: 30449201 DOI: 10.1080/13543784.2018.1548607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Diabetic foot ulcers are a serious complication of diabetes and are associated with pain, disability, and poor quality of life. Incretin-based therapy is available for type-2 diabetes. Aside from glucose control, such treatment can impart numerous beneficial effects. AREAS COVERED This review summarizes the preclinical and clinical evidence supporting incretin-based treatment approaches for diabetic ulcers. EXPERT OPINION Incretin-based therapy may have a role in the treatment of diabetic foot ulcers; the benefits of such treatment arise from attenuation of inflammatory response, improvement of keratinocyte migration, induction of angiogenesis, and the enhancement of tissue remodeling. Large-scale clinical trials are required to determine the advantages of GLP-1 receptor agonists and DPP4 inhibitors. Future research on the topical application of incretin-based therapy is necessary. Such therapeutic approaches may provide new hope in improving the treatment of impaired diabetic foot ulcers.
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Affiliation(s)
- Hui-Chun Ku
- a Department and Institute of Life Science , Fu-Jen Catholic University , New Taipei City , Taiwan
| | - Yao-Jen Liang
- a Department and Institute of Life Science , Fu-Jen Catholic University , New Taipei City , Taiwan.,b Graduate Institute of Applied Science and Engineering , Fu-Jen Catholic University , New Taipei City , Taiwan
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29
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Wolak M, Staszewska T, Juszczak M, Gałdyszyńska M, Bojanowska E. Anti-inflammatory and pro-healing impacts of exendin-4 treatment in Zucker diabetic rats: Effects on skin wound fibroblasts. Eur J Pharmacol 2018; 842:262-269. [PMID: 30391742 DOI: 10.1016/j.ejphar.2018.10.053] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 10/30/2018] [Accepted: 10/31/2018] [Indexed: 02/07/2023]
Abstract
Using male Zucker diabetic fatty (ZDF) rats implanted subcutaneously with polyethylene mesh pieces stimulating granulation tissue development, we investigated the effects of the in vivo and in vitro treatment with exendin-4, a glucagon-like peptide-1 agonist displaying a variety of antidiabetic actions, on the markers of metabolism, inflammation, and healing in addition to skin wound fibroblast/myofibroblast activities. Exendin-4 at increasing doses of 3-10 μg/kg or 0.9% saline was injected daily to ZDF rats pre-implanted with the mesh for 3 weeks. Then, fibroblasts/myofibroblasts isolated from the granulation tissue in both groups were further exposed in vitro to exendin-4 at concentrations of 0-100 nmol/l. After a 3-week administration period, cumulative food and water intake and body weight were reduced significantly. The serum and fibroblast culture medium C-reactive protein (CRP) concentrations and matrix metalloprotease-9/tissue matrix metalloproteinase inhibitor-1 (MMP-9/TIMP-1) ratio in the fibroblast culture medium were diminished significantly in the exendin-4 pretreated group, indicating the increased expression of anti-inflammatory and pro-healing biomarkers. In vivo exendin-4 treatment also increased the number of living fibroblasts/myofibroblasts in cell cultures. The subsequent in vitro exposure to exendin-4 significantly increased metabolic activity and total collagen content in fibroblast/myofibroblast colonies derived from exendin-4-pretreated rats but reduced the number of viable cells. A cytotoxic effect was noted at the highest exendin-4 concentrations used. To conclude, the treatment of diabetic rats with exendin-4 had beneficial effects on systemic and tissue metabolic, inflammatory, and healing markers and on fibroblast functions crucial for wound repair but showed some cytotoxicity on these cells.
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Affiliation(s)
- Monika Wolak
- Department of Behavioral Pathophysiology, Medical University of Łódź, 60 Narutowicza Street, 90-136 Łódź, Poland
| | - Teresa Staszewska
- Department of Behavioral Pathophysiology, Medical University of Łódź, 60 Narutowicza Street, 90-136 Łódź, Poland
| | - Marlena Juszczak
- Department of Pathophysiology and Experimental Neuroendocrinology, Medical University of Łódź, 60 Narutowicza Street, 90-136 Łódź, Poland
| | - Małgorzata Gałdyszyńska
- Department of Neuropeptide Research, Medical University of Łódź, 60 Narutowicza Street, 90-136 Łódź, Poland
| | - Ewa Bojanowska
- Department of Behavioral Pathophysiology, Medical University of Łódź, 60 Narutowicza Street, 90-136 Łódź, Poland.
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30
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Shih CM, Huang CY, Huang CY, Wang KH, Wei PL, Chang YJ, Fong TH, Pan JL, Lee AW. A dipeptidyl peptidase-4 inhibitor promotes wound healing in normoglycemic mice by modulating keratinocyte activity. Exp Dermatol 2018; 27:1134-1141. [PMID: 30028901 DOI: 10.1111/exd.13751] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 07/13/2018] [Indexed: 12/13/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a well-known and novel class of oral antihyperglycaemic drugs. DPP-4 inhibition facilitates ulcer healing in patients with diabetes. However, the actual mechanisms, which are independent of lower blood glucose levels, are still unknown. Therefore, the aim of this study was to analyse the effect of the DPP-4 inhibitor sitagliptin on wound healing through a glucose-independent pathway. In this study, DPP-4 inhibitors facilitate keratinocyte differentiation and the proliferation, increase blood flow in the cutaneous of wounds in healthy C57BL/6 mice. Additionally, the administration of the DPP-4 inhibitor ameliorates wound healing and enhances adiponectin expression in healthy C57BL/6 mice. Taken together, our results reveal a protective role for the DPP-4 inhibitor sitagliptin in wound healing by regulating adiponectin and phospho-eNOS levels in keratinocytes. Based on these results, the DPP-4 inhibitor may have therapeutic potential for healing wounds through a diabetes-independent mechanism.
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Affiliation(s)
- Chun-Ming Shih
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chun-Yao Huang
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chien-Yu Huang
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan
| | - Kuo-Hsien Wang
- Department of Dermatology, Taipei Medical University Hospital, Taipei, Taiwan
| | - Po-Li Wei
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, Graduate Institute of Clinical Medicine, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Cancer Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yu-Jia Chang
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Graduate Institute of Cancer Biology and Drug Discovery, Graduate Institute of Clinical Medicine, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Cancer Center, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Tsorng-Harn Fong
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jun-Liang Pan
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Cardiology and Cardiovascular Research Center, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Ai-Wei Lee
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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31
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Wang X, Zheng P, Huang G, Yang L, Zhou Z. Dipeptidyl peptidase-4(DPP-4) inhibitors: promising new agents for autoimmune diabetes. Clin Exp Med 2018; 18:473-480. [PMID: 30022375 DOI: 10.1007/s10238-018-0519-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 07/08/2018] [Indexed: 12/16/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors constitute a novel class of anti-diabetic agents confirmed to improve glycemic control and preserve β-cell function in type 2 diabetes. Three major large-scale studies, EXAMINE, SAVOR-TIMI 53, and TECOS, have confirmed the cardiovascular safety profile of DPP-4 inhibitors. Based on these results, DPP-4 inhibitors have gained widespread use in type 2 diabetes treatment. It is currently unknown, however, whether DPP-4 inhibitors have similar therapeutic efficacy against autoimmune diabetes. Several in vitro and in vivo studies have addressed this issue, but the results remain controversial. In this review, we summarize experimental findings and preliminary clinical trial results, and identify potentially effective immune modulation targets of DPP-4 inhibitors for autoimmune diabetes.
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Affiliation(s)
- Xia Wang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.,Department of Metabolism and Endocrinology, Hunan Provincial People's Hospital, Changsha, Hunan, China
| | - Peilin Zheng
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Lin Yang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China. .,Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
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Linagliptin attenuates chronic post-ischemia pain: Possible anti-inflammatory and anti-oxidant mechanisms. Eur J Pharmacol 2018; 828:110-118. [DOI: 10.1016/j.ejphar.2018.03.039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 03/27/2018] [Accepted: 03/28/2018] [Indexed: 02/08/2023]
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Wilgus TA. Alerting the body to tissue injury: The role of alarmins and DAMPs in cutaneous wound healing. CURRENT PATHOBIOLOGY REPORTS 2018; 6:55-60. [PMID: 29862143 DOI: 10.1007/s40139-018-0162-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Purpose of review Tissue injury stimulates an inflammatory response that is mediated in part by alarmins. Alarmins are a group of endogenous molecules that trigger inflammation in response to damage. This class of molecules is becoming increasingly recognized for their ability to influence wound healing. This article will provide an overview of alarmins and outline the latest findings on these mediators in cutaneous wound healing. Recent findings In addition to stimulating inflammatory cells, recent evidence suggests that alarmins can act on other cells in the skin to affect wound closure and the extent of scar tissue production. This review will focus on HMGB-1 and IL-33, two alarmins that have received recent attention in the wound healing field. Summary Because a properly regulated inflammatory response is critical for optimal healing, further research must be done to fully understand the role of alarmins in the wound repair process.
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34
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Monickaraj F, McGuire P, Das A. Cathepsin D plays a role in endothelial-pericyte interactions during alteration of the blood-retinal barrier in diabetic retinopathy. FASEB J 2017; 32:2539-2548. [PMID: 29263022 DOI: 10.1096/fj.201700781rr] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Inflammation plays an important role in the pathogenesis of diabetic retinopathy. We have previously demonstrated the effect of cathepsin D (CD) on the mechanical disruption of retinal endothelial cell junctions and increased vasopermeability, as well as increased levels of CD in retinas of diabetic mice. Here, we have also examined the effect of CD on endothelial-pericyte interactions, as well as the effect of dipeptidyl peptidase-4 (DPP4) inhibitor on CD in endothelial-pericyte interactions in vitro and in vivo. Cocultured cells that were treated with pro-CD demonstrated a significant decrease in the expression of platelet-derived growth factor receptor-β, a tyrosine kinase receptor that is required for pericyte cell survival; N-cadherin, the key adherens junction protein between endothelium and pericytes; and increases in the vessel destabilizing agent, angiopoietin-2. The effect was reversed in cells that were treated with DPP4 inhibitor along with pro-CD. With pro-CD treatment, there was a significant increase in the phosphorylation of the downstream signaling protein, PKC-α, and Ca2+/calmodulin-dependent protein kinase II in endothelial cells and pericytes, which disrupts adherens junction structure and function, and this was significantly reduced with DPP4 inhibitor treatment. Increased CD levels, vasopermeability, and alteration in junctional-related proteins were observed in the retinas of diabetic rats, which were significantly changed with DPP4 inhibitor treatment. Thus, DPP4 inhibitors may be used as potential adjuvant therapeutic agents to treat increased vascular leakage observed in patients with diabetic macular edema.-Monickaraj, F., McGuire, P., Das, A. Cathepsin D plays a role in endothelial-pericyte interactions during alteration of the blood-retinal barrier in diabetic retinopathy.
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Affiliation(s)
- Finny Monickaraj
- Department of Surgery, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.,Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.,New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico, USA
| | - Paul McGuire
- Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA
| | - Arup Das
- Department of Surgery, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.,Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA.,New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico, USA
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35
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Yang Y, Zhao C, Liang J, Yu M, Qu X. Effect of Dipeptidyl Peptidase-4 Inhibitors on Bone Metabolism and the Possible Underlying Mechanisms. Front Pharmacol 2017; 8:487. [PMID: 28790917 PMCID: PMC5524773 DOI: 10.3389/fphar.2017.00487] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 07/07/2017] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus has been demonstrated to be closely associated with osteoporosis. Accordingly, hypoglycemic therapy is considered effective in treating metabolic bone disease. Recently, the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors, a new type of antidiabetic drug, on bone metabolism have been widely studied. This review mainly describes the effects of DPP-4 inhibitors on bone metabolism, including their effects on bone mineral density, bone quality, and fracture risk. In addition, the potential underlying mechanisms are discussed. Based on the current progress in this research field, DPP-4 inhibitors have been proved to reduce fracture risk. In addition, sitagliptin, a strong and highly selective DPP-4 inhibitor, showed its beneficial effects on bone metabolism by improving bone mineral density, bone quality, and bone markers. With regard to the potential underlying mechanisms, DPP-4 inhibitors may promote bone formation and reduce bone resorption through DPP-4 substrates and DPP-4-related energy metabolism. Vitamin D and other related signaling pathways also play a role in affecting bone metabolism. Although these assumptions are controversial, they provide a translational pharmacology approach for the clinical use of DPP-4 inhibitors in the treatment of metabolic diseases. Prior to the use of these drugs in clinic, further studies should be conducted to determine the appropriate type of DPP-4 inhibitor, the people who would benefit the most from this therapy, appropriate dose and duration, and the effects of the treatment.
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Affiliation(s)
- Yinqiu Yang
- Department of Endocrinology, Zhongshan Hospital, Fudan UniversityShanghai, China
| | - Chenhe Zhao
- Department of Endocrinology, Zhongshan Hospital, Fudan UniversityShanghai, China
| | - Jing Liang
- Department of Endocrinology, Zhongshan Hospital, Fudan UniversityShanghai, China
| | - Mingxiang Yu
- Department of Endocrinology, Zhongshan Hospital, Fudan UniversityShanghai, China
| | - Xinhua Qu
- Department of Orthopedics, Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of MedicineShanghai, China
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36
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Abstract
Scarring and fibrosis are an enormous public health concern, resulting in excessive morbidity and mortality in addition to countless lost health care dollars. Recent advances in cell and developmental biology promise a better understanding of scarring and fibrosis and may translate to new clinical therapies.
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37
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Dei Cas A, Spigoni V, Cito M, Aldigeri R, Ridolfi V, Marchesi E, Marina M, Derlindati E, Aloe R, Bonadonna RC, Zavaroni I. Vildagliptin, but not glibenclamide, increases circulating endothelial progenitor cell number: a 12-month randomized controlled trial in patients with type 2 diabetes. Cardiovasc Diabetol 2017; 16:27. [PMID: 28231835 PMCID: PMC5324295 DOI: 10.1186/s12933-017-0503-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 02/03/2017] [Indexed: 12/19/2022] Open
Abstract
Background Fewer circulating endothelial progenitor cells (EPCs) and increased plasma (C-term) stromal cell-derived factor 1α (SDF-1α), a substrate of DPP-4, are biomarkers, and perhaps mediators, of cardiovascular risk and mortality. Short-term/acute treatment with DPP-4 inhibitors improve EPC bioavailability; however, long-term effects of DPP-4i on EPCs bioavailability/plasma (C-term) SDF-1α are unknown. Methods Randomized (2:1) open-label trial to compare the effects of vildagliptin (V) (100 mg/day) vs glibenclamide (G) (2.5 mg bid to a maximal dose of 5 mg bid) on circulating EPC levels at 4 and 12 months of treatment in 64 patients with type 2 diabetes in metformin failure. At baseline, and after 4 and 12 months, main clinical/biohumoral parameters, inflammatory biomarkers, concomitant therapies, EPC number (CD34+/CD133+/KDR+/106 cytometric events) and plasma (C-term) SDF-1α (R&D system) were assessed. Results Baseline characteristics were comparable in the two groups. V and G similarly and significantly (p < 0.0001) improved glucose control. At 12 months, V significantly increased EPC number (p < 0.05) and significantly reduced (C-term) SDF-1α plasma levels (p < 0.01) compared to G, with no differences in inflammatory biomarkers. Conclusions V exerts a long-term favorable effect on EPC and (C-term) SDF-1α levels at glucose equipoise, thereby implying a putative beneficial effect on vascular integrity. Trial registration Clinical Trials number: NCT01822548; name: Effect of Vildagliptin vs. Glibenclamide on Circulating Endothelial Progenitor Cell Number Type 2 Diabetes. Registered 28 March, 2013
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Affiliation(s)
- Alessandra Dei Cas
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy. .,Azienda Ospedaliero-Universitaria of Parma, Parma, Italy.
| | - Valentina Spigoni
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy
| | - Monia Cito
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy
| | - Raffaella Aldigeri
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy
| | | | | | - Michela Marina
- Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Eleonora Derlindati
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy
| | - Rosalia Aloe
- Biochemistry, Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Riccardo C Bonadonna
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy.,Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
| | - Ivana Zavaroni
- Endocrinology and Metabolic Diseases, Department of Medicine and Surgery, University of Parma, Via Gramsci, 14, 43126, Parma, Italy.,Azienda Ospedaliero-Universitaria of Parma, Parma, Italy
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38
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Baticic Pucar L, Pernjak Pugel E, Detel D, Varljen J. Involvement of DPP IV/CD26 in cutaneous wound healing process in mice. Wound Repair Regen 2017; 25:25-40. [PMID: 27868279 DOI: 10.1111/wrr.12498] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 11/14/2016] [Indexed: 12/26/2022]
Abstract
Dipeptidyl peptidase IV (DPP IV/CD26) is a widely distributed multifunctional protein that plays a significant role in different physiological as well as pathological processes having a broad spectrum of bioactive substrates and immunomodulative properties. It has potential influence on different processes crucial for wound healing, including cell adhesion, migration, apoptosis, and extracellular matrix degradation. However, despite its known enzymatic and immunomodulative functions, limited data characterize the role of DPP IV/CD26 in cutaneous wound healing mechanisms. The aim of this study was to investigate the process of wound healing in conditions of CD26 deficiency in order to obtain better insights on the role of DPP IV/CD26 in cutaneous regeneration. Experimental wounds were made on the dorsal part of CD26 deficient (CD26-/- ) and wild-type mice (C57BL/6). The process of cutaneous wound healing was monitored on defined time schedule postwounding by macroscopic, microscopic, and biochemical analyses. Obtained results revealed a better rate of wound closure, revascularization and cell proliferation in CD26-/- mice, with enhanced local expression of hypoxia-inducible factor 1α and vascular endothelial growth factor. CD26 deficiency induced prompt macrophage recruitment at the site of skin damage but did not influence mobilization of T-cells in comparison with wild-type mice. CD26-/- mice have significantly higher values of IP-10 in serum and control skins compared with wild-type mice but values in wounds did not differ significantly on days 2, 4, and 7 of wound healing. DPP IV/CD26 activity was found to be decreased 4 days postwounding in serum and 2, 4, and 7 days postwounding in wounds of wild-type animals compared with control skins. These findings contribute to better understanding of wound healing mechanisms and could give a support in finding new therapeutic approaches for wound healing and tissue regeneration.
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Affiliation(s)
- Lara Baticic Pucar
- Department of Chemistry and Biochemistry, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, Rijeka, 51000, Hrvatska-Croatia
| | - Ester Pernjak Pugel
- Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Hrvatska-Croatia
| | - Dijana Detel
- Department of Chemistry and Biochemistry, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, Rijeka, 51000, Hrvatska-Croatia
| | - Jadranka Varljen
- Department of Chemistry and Biochemistry, Faculty of Medicine, University of Rijeka, Brace Branchetta 20, Rijeka, 51000, Hrvatska-Croatia
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Roan JN, Cheng HN, Young CC, Lee CJ, Yeh ML, Luo CY, Tsai YS, Lam CF. Exendin-4, a glucagon-like peptide-1 analogue, accelerates diabetic wound healing. J Surg Res 2017; 208:93-103. [DOI: 10.1016/j.jss.2016.09.024] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 08/19/2016] [Accepted: 09/09/2016] [Indexed: 10/21/2022]
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40
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Nakamura Y, Inagaki M, Tsuji M, Gocho T, Handa K, Hasegawa H, Yura A, Kawakami T, Ohsawa I, Goto Y, Gotoh H, Kiuchi Y. Linagliptin Has Wide-Ranging Anti-Inflammatory Points of Action in Human Umbilical Vein Endothelial Cells. JAPANESE CLINICAL MEDICINE 2016; 7:27-32. [PMID: 27980448 PMCID: PMC5140011 DOI: 10.4137/jcm.s39317] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 10/31/2016] [Accepted: 11/04/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND Because of the potential anti-inflammatory effects, linagliptin, a therapeutic dipeptidyl peptidase-4 inhibitor, is used as an effective drug for diabetic patients for whom inflammation is a prognosis-related factor. We investigated the anti-inflammatory mechanism of linagliptin using seven markers. METHODS We pretreated human umbilical vein endothelial cells (HUVECs), with linagliptin and lipopolysaccharide (LPS). The cytosolic fractions were evaluated for protein kinase A (PKA), protein kinase B (PKB), protein kinase C (PKC), ratio of reactive oxygen species (ROS) and Cu/Zn superoxide dismutase (SOD), activator protein 1 (AP-1), and adenosine 3′,5′-cyclic monophosphate (cAMP). RESULTS Linagliptin increased the PKA and PKC activities and the cAMP levels in LPS-treated cells. However, it inhibited LPS-induced PKB phosphorylation, ratio of ROS and Cu/Zn SOD, and LPS-stimulated AP-1 nuclear translocation. CONCLUSION We reaffirmed the anti-inflammatory and antioxidant effects of linagliptin. These effects might be related to the three protein kinases. Our findings suggest that linagliptin has a wide range of anti-inflammatory effects.
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Affiliation(s)
- Yuya Nakamura
- Department of Internal Medicine, Saiyu Soka Hospital, Soka City, Saitama-ken, Japan.; Department of Pharmacology, School of Medicine, Showa University, Shinagawa-ku, Tokyo, Japan
| | - Masahiro Inagaki
- Department of Chemistry, College of Arts and Sciences, Showa University, Fujiyoshida City, Yamanashi-ken, Japan
| | - Mayumi Tsuji
- Department of Pharmacology, School of Medicine, Showa University, Shinagawa-ku, Tokyo, Japan
| | - Toshihiko Gocho
- Department of Pharmacology, School of Medicine, Showa University, Shinagawa-ku, Tokyo, Japan
| | - Kazuaki Handa
- Department of Pharmacology, School of Medicine, Showa University, Shinagawa-ku, Tokyo, Japan
| | - Hitomi Hasegawa
- Department of Pharmacology, School of Medicine, Showa University, Shinagawa-ku, Tokyo, Japan
| | - Akihiko Yura
- Department of Toyosu Clinic Preventive Medicine Center, School of Medicine, Showa University, Koto-ku, Tokyo, Japan
| | - Tomoko Kawakami
- Department of Toyosu Clinic Preventive Medicine Center, School of Medicine, Showa University, Koto-ku, Tokyo, Japan
| | - Isao Ohsawa
- Department of Internal Medicine, Saiyu Soka Hospital, Soka City, Saitama-ken, Japan
| | - Yoshikazu Goto
- Department of Internal Medicine, Saiyu Soka Hospital, Soka City, Saitama-ken, Japan
| | - Hiromichi Gotoh
- Department of Internal Medicine, Saiyu Soka Hospital, Soka City, Saitama-ken, Japan
| | - Yuji Kiuchi
- Department of Pharmacology, School of Medicine, Showa University, Shinagawa-ku, Tokyo, Japan
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Shigiyama F, Kumashiro N, Miyagi M, Iga R, Kobayashi Y, Kanda E, Uchino H, Hirose T. Linagliptin improves endothelial function in patients with type 2 diabetes: A randomized study of linagliptin effectiveness on endothelial function. J Diabetes Investig 2016; 8:330-340. [PMID: 27868359 PMCID: PMC5415473 DOI: 10.1111/jdi.12587] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 10/02/2016] [Accepted: 10/13/2016] [Indexed: 12/29/2022] Open
Abstract
AIMS/INTRODUCTION The present multicenter, prospective, controlled, open and randomized three-arm parallel study was designed to compare the effects of linagliptin with those of metformin on endothelial function. MATERIALS AND METHODS Type 2 diabetes patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0% and <8.0%, n = 96) were randomized to continue metformin 750 mg/day (control group, n = 29), metformin at 1,500 mg/day (metformin group, n = 26) and metformin 750 mg/day supplemented with linagliptin 5 mg/day (linagliptin add-on group, n = 29) and treated for 16 weeks. Vascular endothelial function was evaluated by flow-mediated dilation. The primary end-point was changes in flow-mediated dilation at 16 weeks relative to baseline. RESULTS Linagliptin significantly improved flow-mediated dilation from baseline (4.9 ± 2.7%) to 16 weeks (6.3 ± 2.7%, P < 0.05), whereas the other groups did not show any changes. Hemoglobin A1c at 16 weeks was significantly lower in the metformin and linagliptin add-on groups compared with the control (6.6 ± 0.6%, 6.5 ± 0.5% and 7.0 ± 0.6%, respectively). Single and multiple regression analyses showed that apolipoprotein B correlated significantly with change in flow-mediated dilation, and apolipoprotein B was decreased only in the linagliptin add-on group (-6.0 ± 11.3 mg/dL, P < 0.01). CONCLUSIONS Linagliptin for 16 weeks improved endothelial function with a modest improvement in glycemic control. This effect was mediated, at least in part, by reduction in apolipoprotein B. Linagliptin has a protective role on endothelial function in patients with type 2 diabetes with moderate hyperglycemia.
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Affiliation(s)
- Fumika Shigiyama
- Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Naoki Kumashiro
- Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Masahiko Miyagi
- Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Ryo Iga
- Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Yuka Kobayashi
- Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Eiichiro Kanda
- Department of Nephrology, Tokyo Kyosai Hospital, Tokyo, Japan.,Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroshi Uchino
- Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University School of Medicine, Tokyo, Japan
| | - Takahisa Hirose
- Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University School of Medicine, Tokyo, Japan
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Barchetta I, Cimini FA, Bloise D, Cavallo MG. Dipeptidyl peptidase-4 inhibitors and bone metabolism: is vitamin D the link? Acta Diabetol 2016; 53:839-44. [PMID: 27379733 DOI: 10.1007/s00592-016-0882-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 06/27/2016] [Indexed: 01/23/2023]
Abstract
AIMS Dipeptidyl peptidase-4 inhibitors (DPP4-Is) represent a promising class of agents for type 2 diabetes treatment. Experimental models and clinical studies have reported positive effects of DPP4-Is on bone; however, how DPP4-Is positively impact bone homeostasis in humans remains an unanswered question. Aim of this study investigated the relationship between treatment with DPP4-Is and vitamin D balance in patients with type 2 diabetes. METHODS This is a cross-sectional study. A total of 295 consecutive individuals with type 2 diabetes referring to our diabetes outpatient clinics were enrolled; among them, 53 % were in treatment with DPP4-Is. Metabolic profile and routine biochemistry were assessed by standard methods; serum 25(OH) vitamin D levels [25(OH)D] were measured by colorimetric method (LAISON, DiaSorin). RESULTS DPP4-Is-treated participants had significantly higher serum 25(OH)D levels then those undertaking other antidiabetic therapies (18.4 ± 10.7 vs. 14.9 ± 8.6 ng/ml, p = 0.004); this association persisted after adjusting for all major confounders. Increased 25(OH)D concentrations also correlated with the duration of DPP4-Is treatment and with a stronger DPP4 inhibitory activity. CONCLUSIONS DPP4-Is treatment is associated with improved vitamin D balance in people with type 2 diabetes; our findings suggest that vitamin D may underlie the link between DPP4-Is and bone metabolism.
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Affiliation(s)
- I Barchetta
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - F A Cimini
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy
| | - D Bloise
- Diabetes Unit, San Giuseppe Hospital of Marino, Rome, Italy
| | - M G Cavallo
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.
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Nakamura Y, Hasegawa H, Tsuji M, Oguchi T, Mihara M, Suzuki H, Nishida K, Inoue M, Shimizu T, Ohsawa I, Gotoh H, Goto Y, Inagaki M, Oguchi K. Linagliptin inhibits lipopolysaccharide-stimulated interleukin-6 production, intranuclear p65 expression, and p38 mitogen-activated protein kinase phosphorylation in human umbilical vein endothelial cells. RENAL REPLACEMENT THERAPY 2016. [DOI: 10.1186/s41100-016-0030-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Salazar JJ, Ennis WJ, Koh TJ. Diabetes medications: Impact on inflammation and wound healing. J Diabetes Complications 2016; 30:746-52. [PMID: 26796432 PMCID: PMC4834268 DOI: 10.1016/j.jdiacomp.2015.12.017] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Revised: 12/15/2015] [Accepted: 12/16/2015] [Indexed: 12/25/2022]
Abstract
Chronic wounds are a common complication in patients with diabetes that often lead to amputation. These non-healing wounds are described as being stuck in a persistent inflammatory state characterized by accumulation of pro-inflammatory macrophages, cytokines and proteases. Some medications approved for management of type 2 diabetes have demonstrated anti-inflammatory properties independent of their marketed insulinotropic effects and thus have underappreciated potential to promote wound healing. In this review, the potential for insulin, metformin, specific sulfonylureas, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors to promote healing is evaluated by reviewing human and animal studies on inflammation and wound healing. The available evidence indicates that diabetic medications have potential to prevent wounds from becoming arrested in the inflammatory stage of healing and to promote wound healing by downregulating pro-inflammatory cytokines, upregulating growth factors, lowering matrix metalloproteinases, stimulating angiogenesis, and increasing epithelization. However, no clinical recommendations currently exist on the potential for specific diabetic medications to impact healing of chronic wounds. Thus, we encourage further research that may guide physicians on providing personalized diabetes treatments that achieve glycemic goals while promoting healing in patients with chronic wounds.
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Affiliation(s)
- Jay J Salazar
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA
| | - William J Ennis
- Department of Surgery, University of Illinois at Chicago, Chicago, IL, USA; Center for Tissue Repair and Regeneration, University of Illinois at Chicago, Chicago, IL, USA
| | - Timothy J Koh
- Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA; Center for Tissue Repair and Regeneration, University of Illinois at Chicago, Chicago, IL, USA.
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Modulation of myocardial injury and collagen deposition following ischaemia-reperfusion by linagliptin and liraglutide, and both together. Clin Sci (Lond) 2016; 130:1353-62. [PMID: 27129181 DOI: 10.1042/cs20160061] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Accepted: 04/26/2016] [Indexed: 12/21/2022]
Abstract
Studies have indicated that dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists reduce infarct size after myocardial ischaemia. Whether these agents modify cardiac remodelling after ischaemia is unclear. Furthermore, it is not known if combination of the two types of drugs is superior to either agent alone. We investigated the modulatory effect of the DPP-4 inhibitor linagliptin alone, the GLP-1 activator liraglutide alone, or the two agents together on myocardial infarct size, left ventricular contractile function and cardiac remodelling signals after a brief period of left coronary artery (LCA) occlusion. C57BL/6 mice were treated with vehicle, the DPP-4 inhibitor linagliptin, the GLP-1 activator liraglutide, or both agents together for 5 days, and then subjected to LCA occlusion (1 h) and reperfusion (3 h). Ischaemia-reperfusion increased reactive oxygen species (ROS) generation and expression of NADPH oxidase (p47(phox), p22(phox) and gp91(phox) subtypes), collagens, fibronectin and proinflammatory cytokines (interleukin 6, tumour necrosis factor α and monocyte chemoattractant protein-1) in the LCA-supplied regions. Pre-treatment with linagliptin or liraglutide reduced infarct size, protected cardiomyocytes from injury and preserved cardiac contractile function in a similar fashion. It is interesting that profibrotic (collagen deposition) signals were expressed soon after ischaemia-reperfusion. Both linagliptin and liraglutide suppressed ROS generation, NADPH oxidase and proinflammatory signals, and reduced collagen deposition. Addition of linagliptin or liraglutide had no significant additive effect above and beyond that of liraglutide and linagliptin given alone. In conclusion, linagliptin and liraglutide can improve cardiac contractile function and indices of cardiac remodelling, which may be related to their role in inhibition of ROS production and proinflammatory cytokines after ischaemia.
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Abstract
Current literature shows an association of diabetes and secondary complications with chronic inflammation. Evidence of these immunological changes include altered levels of cytokines and chemokines, changes in the numbers and activation states of various leukocyte populations, apoptosis, and fibrosis during diabetes. Therefore, treatment of diabetes and its complications may include pharmacological strategies to reduce inflammation. Apart from anti-inflammatory drugs, various hypoglycemic agents have also been found to reduce inflammation that could contribute to improved outcomes. Extensive studies have been carried out with thiazolidinediones (peroxisome proliferator-activated receptor-γ agonist), dipeptidyl peptidase-4 inhibitors, and metformin (AMP-activated protein kinase activator) with each of these classes of compounds showing moderate-to-strong anti-inflammatory action. Sulfonylureas and alpha glucosidase inhibitors appeared to exert modest effects, while the injectable agents, insulin and glucagon-like peptide-1 receptor agonists, may improve secondary complications due to their anti-inflammatory potential. Currently, there is a lack of clinical data on anti-inflammatory effects of sodium–glucose cotransporter type 2 inhibitors. Nevertheless, for all these glucose-lowering agents, it is essential to distinguish between anti-inflammatory effects resulting from better glucose control and effects related to intrinsic anti-inflammatory actions of the pharmacological class of compounds.
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Affiliation(s)
- Vishal Kothari
- Department of Nutrition and Dietetics, Boshell Diabetes and Metabolic Diseases Research Program, Auburn University, Auburn, AL, USA
| | - John A Galdo
- Department of Pharmacy Practice, Samford University, Birmingham, AL, USA
| | - Suresh T Mathews
- Department of Nutrition and Dietetics, Samford University, Birmingham, AL, USA
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Saboo A, Rathnayake A, Vangaveti VN, Malabu UH. Wound healing effects of dipeptidyl peptidase-4 inhibitors: An emerging concept in management of diabetic foot ulcer-A review. Diabetes Metab Syndr 2016; 10:113-119. [PMID: 25990796 DOI: 10.1016/j.dsx.2015.04.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVE Dipeptidyl peptidase-4 (DPP-4) inhibitors have a well-known effect on glycaemic control in patients with diabetes but little is known on their wound healing role in this group of population. This paper reviews the effects of DPP-4 inhibitors on wound healing of diabetic foot ulcers. METHODS Published data on effects and mechanism of DDP-4 inhibitors on wound healing were derived from Medline, PubMed and Google Scholar search of English language literature from 1994 to 2014 using the key words such as "DPP-4 inhibitors", "endothelial healing" "diabetes" and "chronic ulcers". RESULTS DPP-4 inhibitors show a potential benefit in processes of wound healing in diabetic chronic foot ulcers. The enzyme inhibitors promote recruitment of endothelial progenitor cells and allow the final scaffolding of wounds. Furthermore DPP-4 inhibitors augment angiogenesis and have widespread effects on optimising the immune response to persistent hypoxia in chronic diabetes wounds. CONCLUSION DPP-4 inhibitors show promise in the local wound healing of diabetic foot ulcers in addition to its already established glycaemic control. In the light of high rate of amputations due to non-healing ulcers with profound psychological and economical liability, more investigations on the usefulness of DPP-4 inhibitors in the high risk diabetes population are needed.
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Affiliation(s)
- Apoorva Saboo
- Translational Research in Endocrinology and Diabetes [TREAD], College of Medicine and Dentistry, James Cook University, The Townsville Hospital, 100 Angus Smith Drive, Douglas 4814, QLD, Australia
| | - Ayeshmanthe Rathnayake
- Translational Research in Endocrinology and Diabetes [TREAD], College of Medicine and Dentistry, James Cook University, The Townsville Hospital, 100 Angus Smith Drive, Douglas 4814, QLD, Australia
| | - Venkat N Vangaveti
- Translational Research in Endocrinology and Diabetes [TREAD], College of Medicine and Dentistry, James Cook University, The Townsville Hospital, 100 Angus Smith Drive, Douglas 4814, QLD, Australia
| | - Usman H Malabu
- Translational Research in Endocrinology and Diabetes [TREAD], College of Medicine and Dentistry, James Cook University, The Townsville Hospital, 100 Angus Smith Drive, Douglas 4814, QLD, Australia.
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Abstract
Vascular endothelial cells play a major role in maintaining cardiovascular homeostasis. Endothelial dysfunction, characterized by reduced endothelium-dependent relaxations or accompanied by enhanced endothelium-dependent contractions, is a hallmark of and plays a pivotal role in the pathogenesis of hypertension. Endothelial dysfunction in hypertension has been linked to decreases in nitric oxide (NO) bioavailability, reflecting the impaired generation of NO and/or the enhanced inactivation of NO by reactive oxygen species. Many of these conditions can be improved by glucagon-like peptide 1 (GLP-1), a proglucagon-derived hormone secreted by intestinal endocrine L-type cells, which is rapidly inactivated by an enzyme dipeptidyl peptidase 4 in circulation. On one hand, GLP-1 analogues or dipeptidyl peptidase 4 inhibitors upregulate endothelial nitric oxide synthase expression and increase endothelial nitric oxide synthase phosphorylation, resulting in improved production of NO and thus endothelium-dependent relaxations. On the other hand, GLP-1 and related agents attenuate endothelium-dependent contractions by reducing reactive oxygen species generation and cyclooxygenase-2 expression. GLP-1 elevating agents and GLP-1 receptor agonists improve endothelial function in hypertension, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events.
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Solini A, Rossi C, Duranti E, Taddei S, Natali A, Virdis A. Saxagliptin prevents vascular remodeling and oxidative stress in db/db mice. Role of endothelial nitric oxide synthase uncoupling and cyclooxygenase. Vascul Pharmacol 2016; 76:62-71. [DOI: 10.1016/j.vph.2015.10.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 07/23/2015] [Accepted: 10/04/2015] [Indexed: 12/17/2022]
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50
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KIMURA K, NAKAMURA Y, HASEGAWA H, TSUJI M, OGUCHI T, TSUCHIYA H, GOTOH H, GOTO Y, INAGAKI M, OGUCHI K. Pleiotropic Effects of Linagliptin Monotherapy on Levels of Nitric Oxide, Nitric Oxide Synthase, and Superoxide Dismutase in Hemodialysis Patients with Diabetes. ACTA ACUST UNITED AC 2016. [DOI: 10.15369/sujms.28.9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Kengo KIMURA
- Department of Pharmacology, Showa University School of Medicine
| | - Yuya NAKAMURA
- Department of Pharmacology, Showa University School of Medicine
- Saiyu Soka Hospital
| | - Hitomi HASEGAWA
- Department of Pharmacology, Showa University School of Medicine
| | - Mayumi TSUJI
- Department of Pharmacology, Showa University School of Medicine
| | | | | | | | | | - Masahiro INAGAKI
- Department of Chemistry, College of Arts and Sciences, Showa University
| | - Katsuji OGUCHI
- Department of Pharmacology, Showa University School of Medicine
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