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Petrov V, Aleksandrova T, Pashev A. Synthetic Approaches to Novel DPP-IV Inhibitors-A Literature Review. Molecules 2025; 30:1043. [PMID: 40076268 PMCID: PMC11902039 DOI: 10.3390/molecules30051043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/19/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Dipeptidyl peptidase IV (DPP-IV) is a serine protease whose inhibition has been an object of considerable interest in the context of developing novel treatments for type 2 diabetes mellitus. The development of novel DPP-IV inhibitors from natural or synthetic origin has seen a growing scientific interest in recent years, especially during the SARS-CoV-2 pandemic, when DPP-IV inhibitors were found to be of beneficial therapeutic value for COVID-19 patients. The present manuscript aims to summarize the most recent information on the synthesis of different DPP-IV inhibitors, emphasizing the various heterocyclic scaffolds that can be found in them. Special attention is devoted to DPP-IV inhibitors that are currently in clinical trials. Different synthetic approaches for the construction of DPP-IV inhibitors are discussed, as well as the most recent developments in the field.
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Affiliation(s)
| | | | - Aleksandar Pashev
- Department of Chemistry and Biochemistry, Faculty of Pharmacy, Medical University—Pleven, 1 St. Kliment Ohridski Str., 5800 Pleven, Bulgaria; (V.P.); (T.A.)
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Ahmadi M, Ghafouri-Fard S, Najari-Hanjani P, Morshedzadeh F, Malakoutian T, Abbasi M, Akbari H, Amoli MM, Saffarzadeh N. "Hyperglycemic Memory": Observational Evidence to Experimental Inference. Curr Diabetes Rev 2025; 21:64-78. [PMID: 38369731 DOI: 10.2174/0115733998279869231227091944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/01/2023] [Accepted: 11/29/2023] [Indexed: 02/20/2024]
Abstract
Several epidemiological studies have appreciated the impact of "duration" and "level" of hyperglycemia on the initiation and development of chronic complications of diabetes. However, glycemic profiles could not fully explain the presence/absence and severity of diabetic complications. Genetic issues and concepts of "hyperglycemic memory" have been introduced as additional influential factors involved in the pathobiology of late complications of diabetes. In the extended phase of significant diabetes randomized, controlled clinical trials, including DCCT/EDIC and UKPDS, studies have concluded that the quality of glycemic or metabolic control at the early time around the diabetes onset could maintain its protective or detrimental impact throughout the following diabetes course. There is no reliable indication of the mechanism by which the transient exposure to a given glucose concentration level could evoke a consistent cellular response at target tissues at the molecular levels. Some biological phenomena, such as the production and the concentration of advanced glycation end products (AGEs), reactive oxygen species (ROS) and protein kinase C (PKC) pathway activations, epigenetic changes, and finally, the miRNAs-mediated pathways, may be accountable for the development of hyperglycemic memory. This work summarizes evidence from previous experiments that may substantiate the hyperglycemic memory soundness by its justification in molecular terms.
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Affiliation(s)
- Mohsen Ahmadi
- Department of Medical Genetics, School of Medicine, 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
| | - Parisa Najari-Hanjani
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Firouzeh Morshedzadeh
- Department of Genetics, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Tahereh Malakoutian
- Department of Nephrology, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohsen Abbasi
- Department of Emergency Medicine, Iran University of Medical Sciences, Tehran, Iran
- Hasheminejad Kidney Centre, Iran University of Medical Sciences, Anesthesiology Section, Tehran, Iran
| | - Hounaz Akbari
- Department of Nephrology, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Mohammad Amoli
- Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Negin Saffarzadeh
- Department of Nephrology, Hasheminejad Kidney Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Ma X, Huang T, Li X, Zhou X, Pan H, Du A, Zeng Y, Yuan K, Wang Z. Exploration of the link between COVID-19 and gastric cancer from the perspective of bioinformatics and systems biology. Front Med (Lausanne) 2024; 11:1428973. [PMID: 39371335 PMCID: PMC11449776 DOI: 10.3389/fmed.2024.1428973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 09/04/2024] [Indexed: 10/08/2024] Open
Abstract
Background Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has caused a global pandemic. Gastric cancer (GC) poses a great threat to people's health, which is a high-risk factor for COVID-19. Previous studies have found some associations between GC and COVID-19, whereas the underlying molecular mechanisms are not well understood. Methods We employed bioinformatics and systems biology to explore these links between GC and COVID-19. Gene expression profiles of COVID-19 (GSE196822) and GC (GSE179252) were obtained from the Gene Expression Omnibus (GEO) database. After identifying the shared differentially expressed genes (DEGs) for GC and COVID-19, functional annotation, protein-protein interaction (PPI) network, hub genes, transcriptional regulatory networks and candidate drugs were analyzed. Results We identified 209 shared DEGs between COVID-19 and GC. Functional analyses highlighted immune-related pathways as key players in both diseases. Ten hub genes (CDK1, KIF20A, TPX2, UBE2C, HJURP, CENPA, PLK1, MKI67, IFI6, IFIT2) were identified. The transcription factor/gene and miRNA/gene interaction networks identified 38 transcription factors (TFs) and 234 miRNAs. More importantly, we identified ten potential therapeutic agents, including ciclopirox, resveratrol, etoposide, methotrexate, trifluridine, enterolactone, troglitazone, calcitriol, dasatinib and deferoxamine, some of which have been reported to improve and treat GC and COVID-19. Conclusion This research offer valuable insights into the molecular interplay between COVID-19 and GC, potentially guiding future therapeutic strategies.
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Affiliation(s)
| | | | | | | | | | | | | | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Sadowski J, Klaudel T, Rombel-Bryzek A, Bułdak RJ. Cognitive dysfunctions in the course of SARS‑CoV‑2 virus infection, including NeuroCOVID, frontal syndrome and cytokine storm (Review). Biomed Rep 2024; 21:103. [PMID: 38800038 PMCID: PMC11117100 DOI: 10.3892/br.2024.1791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 04/05/2024] [Indexed: 05/29/2024] Open
Abstract
During the coronavirus disease 2019 (COVID-19) pandemic, cognitive impairment of varying degrees of severity began to be observed in a significant percentage of patients. The present study discussed the impact of immunological processes on structural and functional changes in the central nervous system and the related cognitive disorders. The purpose of the present review was to analyse and discuss available information from the scientific literature considering the possible relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection and cognitive impairment, including NeuroCOVID, frontal syndrome and cytokine storm. A systematic literature review was conducted using: Google Scholar, Elsevier and the PubMed database. When searching for materials, the following keywords were used: 'cognitive dysfunctions', 'SARS-CoV-2', 'COVID-19', 'Neuro-SARS2', 'NeuroCOVID', 'frontal syndrome', 'cytokine storm', 'Long COVID-19'. A total of 96 articles were included in the study. The analysis focused on the characteristics of each study's materials, methods, results and conclusions. SARS-CoV-2 infection may induce or influence existing cognitive disorders of various nature and severity. The influence of immunological factors related to the response against SARS-CoV-2 on the disturbance of cerebral perfusion, the functioning of nerve cells and the neuroprotective effect has been demonstrated. Particular importance is attached to the cytokine storm and the related difference between pro- and anti-inflammatory effects, oxidative stress, disturbances in the regulation of the hypothalamic-pituitary-adrenal axis and the stress response of the body.
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Affiliation(s)
- Jakub Sadowski
- Student Scientific Society of Clinical Biochemistry and Regenerative Medicine, Department of Clinical Biochemistry and Laboratory Diagnostics, Institute of Medical Sciences, University of Opole, 45-050 Opole, Poland
| | - Tomasz Klaudel
- Student Scientific Society of Clinical Biochemistry and Regenerative Medicine, Department of Clinical Biochemistry and Laboratory Diagnostics, Institute of Medical Sciences, University of Opole, 45-050 Opole, Poland
| | - Agnieszka Rombel-Bryzek
- Department of Clinical Biochemistry and Laboratory Diagnostics, Institute of Medical Sciences, University of Opole, 45-050 Opole, Poland
| | - Rafał Jakub Bułdak
- Department of Clinical Biochemistry and Laboratory Diagnostics, Institute of Medical Sciences, University of Opole, 45-050 Opole, Poland
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Reina E, Franco LS, Carneiro TR, Barreiro EJ, Lima LM. Stereochemical insights into β-amino- N-acylhydrazones and their impact on DPP-4 inhibition. RSC Adv 2024; 14:6617-6626. [PMID: 38390500 PMCID: PMC10882265 DOI: 10.1039/d4ra00450g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Accepted: 02/17/2024] [Indexed: 02/24/2024] Open
Abstract
Dipeptidyl peptidase IV (DPP-4) is a key enzyme that regulates several important biological processes and it is better known to be targeted by gliptins as a modern validated approach for the management of type 2 diabetes mellitus (T2DM). However, new generations of DPP-4 inhibitors capable of controlling inflammatory processes associated with chronic complications of T2DM are still needed. In this scenario, we report here the design by molecular modelling of new β-amino-N-acylhydrazones, their racemic synthesis, chiral resolution, determination of physicochemical properties and their DPP4 inhibitory potency. Theoretical and experimental approaches allowed us to propose a preliminary SAR, as well as to identify LASSBio-2124 (6) as a new lead for DPP-4 inhibition, with good physicochemical properties, favourable eudismic ratio, scalable synthesis and anti-diabetes effect in a proof-of-concept model. These findings represent an interesting starting point for the development of a new generation of DPP-4 inhibitors, useful in the treatment of T2DM and comorbidities.
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Affiliation(s)
- Eduardo Reina
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro (UFRJ), CCS, Cidade Universitária Rio de Janeiro-RJ Brazil
| | - Lucas Silva Franco
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro (UFRJ), CCS, Cidade Universitária Rio de Janeiro-RJ Brazil
- Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro Rio de Janeiro-RJ Brazil
| | - Teiliane Rodrigues Carneiro
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro (UFRJ), CCS, Cidade Universitária Rio de Janeiro-RJ Brazil
| | - Eliezer J Barreiro
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro (UFRJ), CCS, Cidade Universitária Rio de Janeiro-RJ Brazil
- Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro Rio de Janeiro-RJ Brazil
| | - Lidia Moreira Lima
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Universidade Federal do Rio de Janeiro (UFRJ), CCS, Cidade Universitária Rio de Janeiro-RJ Brazil
- Pós-graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro Rio de Janeiro-RJ Brazil
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Drakul M, Čolić M. Immunomodulatory activity of dipeptidyl peptidase-4 inhibitors in immune-related diseases. Eur J Immunol 2023; 53:e2250302. [PMID: 37732495 DOI: 10.1002/eji.202250302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/22/2023] [Accepted: 09/20/2023] [Indexed: 09/22/2023]
Abstract
Dipeptidyl peptidase-4 (DPP-4), also known as CD26, is a 110-kDa cell surface glycoprotein with enzymatic and signal transducing activity. DPP-4/CD26 is expressed by various cells, including CD4+ and CD8+ T cells, B cells, dendritic cells, macrophages, and NK cells. DPP-4 inhibitors (DPP-4i) were introduced to clinics in 2006 as new oral antihyperglycemic drugs approved for type 2 diabetes mellitus treatment. In addition to glucose-lowering effects, emerging data, from clinical studies and their animal models, suggest that DPP-4i could display anti-inflammatory and immunomodulatory effects as well, but the molecular and immunological mechanisms of these actions are insufficiently investigated. This review focuses on the modulatory activity of DPP-4i in the immune system and the possible application of DPP-4i in other immune-related diseases in patients with or without diabetes.
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Affiliation(s)
- Marija Drakul
- Medical Faculty Foča, University of East Sarajevo, Foča, Bosnia and Herzegovina
| | - Miodrag Čolić
- Medical Faculty Foča, University of East Sarajevo, Foča, Bosnia and Herzegovina
- Serbian Academy of Sciences and Arts, Belgrade, Serbia
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Jedrzejewska A, Kawecka A, Braczko A, Romanowska-Kocejko M, Stawarska K, Deptuła M, Zawrzykraj M, Franczak M, Krol O, Harasim G, Walczak I, Pikuła M, Hellmann M, Kutryb-Zając B. Changes in Adenosine Deaminase Activity and Endothelial Dysfunction after Mild Coronavirus Disease-2019. Int J Mol Sci 2023; 24:13140. [PMID: 37685949 PMCID: PMC10487738 DOI: 10.3390/ijms241713140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/17/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Endothelial cells are a preferential target for SARS-CoV-2 infection. Previously, we have reported that vascular adenosine deaminase 1 (ADA1) may serve as a biomarker of endothelial activation and vascular inflammation, while ADA2 plays a critical role in monocyte and macrophage function. In this study, we investigated the activities of circulating ADA isoenzymes in patients 8 weeks after mild COVID-19 and related them to the parameters of inflammation and microvascular/endothelial function. Post-COVID patients revealed microvascular dysfunction associated with the changes in circulating parameters of endothelial dysfunction and inflammatory activation. Interestingly, serum total ADA and ADA2 activities were diminished in post-COVID patients, while ADA1 remained unchanged in comparison to healthy controls without a prior diagnosis of SARS-CoV-2 infection. While serum ADA1 activity tended to positively correspond with the parameters of endothelial activation and inflammation, sICAM-1 and TNFα, serum ADA2 activity correlated with IL-10. Simultaneously, post-COVID patients had lower circulating levels of ADA1-anchoring protein, CD26, that may serve as an alternative receptor for virus binding. This suggests that after the infection CD26 is rather maintained in cell-attached form, enabling ADA1 complexing. This study points to the possible role of ADA isoenzymes in cardiovascular complications after mild COVID-19.
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Affiliation(s)
- Agata Jedrzejewska
- Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.J.); (A.K.); (A.B.); (K.S.); (M.F.); (O.K.); (G.H.); (I.W.)
| | - Ada Kawecka
- Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.J.); (A.K.); (A.B.); (K.S.); (M.F.); (O.K.); (G.H.); (I.W.)
| | - Alicja Braczko
- Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.J.); (A.K.); (A.B.); (K.S.); (M.F.); (O.K.); (G.H.); (I.W.)
| | - Marzena Romanowska-Kocejko
- Department of Cardiac Diagnostics, Medical University of Gdansk, 80-210 Gdansk, Poland; (M.R.-K.); (M.H.)
| | - Klaudia Stawarska
- Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.J.); (A.K.); (A.B.); (K.S.); (M.F.); (O.K.); (G.H.); (I.W.)
| | - Milena Deptuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Medical University of Gdansk, 80-211 Gdansk, Poland; (M.D.); (M.P.)
| | - Małgorzata Zawrzykraj
- Division of Clinical Anatomy, Department of Anatomy, Medical University of Gdansk, 80-210 Gdansk, Poland;
| | - Marika Franczak
- Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.J.); (A.K.); (A.B.); (K.S.); (M.F.); (O.K.); (G.H.); (I.W.)
| | - Oliwia Krol
- Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.J.); (A.K.); (A.B.); (K.S.); (M.F.); (O.K.); (G.H.); (I.W.)
| | - Gabriela Harasim
- Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.J.); (A.K.); (A.B.); (K.S.); (M.F.); (O.K.); (G.H.); (I.W.)
| | - Iga Walczak
- Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.J.); (A.K.); (A.B.); (K.S.); (M.F.); (O.K.); (G.H.); (I.W.)
| | - Michał Pikuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Division of Embryology, Medical University of Gdansk, 80-211 Gdansk, Poland; (M.D.); (M.P.)
| | - Marcin Hellmann
- Department of Cardiac Diagnostics, Medical University of Gdansk, 80-210 Gdansk, Poland; (M.R.-K.); (M.H.)
| | - Barbara Kutryb-Zając
- Department of Biochemistry, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.J.); (A.K.); (A.B.); (K.S.); (M.F.); (O.K.); (G.H.); (I.W.)
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Song Y, Huang T, Pan H, Du A, Wu T, Lan J, Zhou X, Lv Y, Xue S, Yuan K. The influence of COVID-19 on colorectal cancer was investigated using bioinformatics and systems biology techniques. Front Med (Lausanne) 2023; 10:1169562. [PMID: 37457582 PMCID: PMC10348756 DOI: 10.3389/fmed.2023.1169562] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 06/15/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction Coronavirus disease 2019 (COVID-19) is a global pandemic and highly contagious, posing a serious threat to human health. Colorectal cancer (CRC) is a risk factor for COVID-19 infection. Therefore, it is vital to investigate the intrinsic link between these two diseases. Methods In this work, bioinformatics and systems biology techniques were used to detect the mutual pathways, molecular biomarkers, and potential drugs between COVID-19 and CRC. Results A total of 161 common differentially expressed genes (DEGs) were identified based on the RNA sequencing datasets of the two diseases. Functional analysis was performed using ontology keywords, and pathway analysis was also performed. The common DEGs were further utilized to create a protein-protein interaction (PPI) network and to identify hub genes and key modules. The datasets revealed transcription factors-gene interactions, co-regulatory networks with DEGs-miRNAs of common DEGs, and predicted possible drugs as well. The ten predicted drugs include troglitazone, estradiol, progesterone, calcitriol, genistein, dexamethasone, lucanthone, resveratrol, retinoic acid, phorbol 12-myristate 13-acetate, some of which have been investigated as potential CRC and COVID-19 therapies. Discussion By clarifying the relationship between COVID-19 and CRC, we hope to provide novel clues and promising therapeutic drugs to treat these two illnesses.
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Affiliation(s)
- Yujia Song
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hongyuan Pan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Animal Science and Technology, Guangxi University, Nanning, China
| | - Ao Du
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Tian Wu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, College of Animal Science and Technology, Guangxi University, Nanning, China
| | - Jiang Lan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyi Zhou
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yue Lv
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Shuai Xue
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Mani S, Kaur A, Jakhar K, Kumari G, Sonar S, Kumar A, Das S, Kumar S, Kumar V, Kundu R, Pandey AK, Singh UP, Majumdar T. Targeting DPP4-RBD interactions by sitagliptin and linagliptin delivers a potential host-directed therapy against pan-SARS-CoV-2 infections. Int J Biol Macromol 2023; 245:125444. [PMID: 37385308 PMCID: PMC10293653 DOI: 10.1016/j.ijbiomac.2023.125444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 07/01/2023]
Abstract
Highly mutated SARS-CoV-2 is known aetiological factor for COVID-19. Here, we have demonstrated that the receptor binding domain (RBD) of the spike protein can interact with human dipeptidyl peptidase 4 (DPP4) to facilitate virus entry, in addition to the usual route of ACE2-RBD binding. Significant number of residues of RBD makes hydrogen bonds and hydrophobic interactions with α/β-hydrolase domain of DPP4. With this observation, we created a strategy to combat COVID-19 by circumventing the catalytic activity of DPP4 using its inhibitors. Sitagliptin, linagliptin or in combination disavowed RBD to establish a heterodimer complex with both DPP4 and ACE2 which is requisite strategy for virus entry into the cells. Both gliptins not only impede DPP4 activity, but also prevent ACE2-RBD interaction, crucial for virus growth. Sitagliptin, and linagliptin alone or in combination have avidity to impede the growth of pan-SARS-CoV-2 variants including original SARS-CoV-2, alpha, beta, delta, and kappa in a dose dependent manner. However, these drugs were unable to alter enzymatic activity of PLpro and Mpro. We conclude that viruses hijack DPP4 for cell invasion via RBD binding. Impeding RBD interaction with both DPP4 and ACE2 selectively by sitagliptin and linagliptin is an potential strategy for efficiently preventing viral replication.
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Affiliation(s)
- Shailendra Mani
- Translational Health Science and Technology Institute, Faridabad, India
| | | | - Kamini Jakhar
- Translational Health Science and Technology Institute, Faridabad, India
| | | | - Sudipta Sonar
- Translational Health Science and Technology Institute, Faridabad, India
| | - Amit Kumar
- National Institute of Immunology, New Delhi, India
| | - Sudesna Das
- CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | | | - Vijay Kumar
- National Institute of Immunology, New Delhi, India
| | - Rakesh Kundu
- Department of Zoology, Visva-Bharati University, Santiniketan, West Bengal, India
| | - Anil Kumar Pandey
- Department of Physiology, ESIC Medical College & Hospital, Faridabad, India
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Gu H, Liu Y, Zhao Y, Qu H, Li Y, Ahmed AA, Liu HY, Hu P, Cai D. Hepatic Anti-Oxidative Genes CAT and GPX4 Are Epigenetically Modulated by RORγ/NRF2 in Alphacoronavirus-Exposed Piglets. Antioxidants (Basel) 2023; 12:1305. [PMID: 37372035 DOI: 10.3390/antiox12061305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/12/2023] [Accepted: 06/17/2023] [Indexed: 06/29/2023] Open
Abstract
As a member of alpha-coronaviruses, PEDV could lead to severe diarrhea and dehydration in newborn piglets. Given that lipid peroxides in the liver are key mediators of cell proliferation and death, the role and regulation of endogenous lipid peroxide metabolism in response to coronavirus infection need to be illuminated. The enzymatic activities of SOD, CAT, mitochondrial complex-I, complex-III, and complex-V, along with the glutathione and ATP contents, were significantly decreased in the liver of PEDV piglets. In contrast, the lipid peroxidation biomarkers, malondialdehyde, and ROS were markedly elevated. Moreover, we found that the peroxisome metabolism was inhibited by the PEDV infection using transcriptome analysis. These down-regulated anti-oxidative genes, including GPX4, CAT, SOD1, SOD2, GCLC, and SLC7A11, were further validated by qRT-PCR and immunoblotting. Because the nuclear receptor RORγ-driven MVA pathway is critical for LPO, we provided new evidence that RORγ also controlled the genes CAT and GPX4 involved in peroxisome metabolism in the PEDV piglets. We found that RORγ directly binds to these two genes using ChIP-seq and ChIP-qPCR analysis, where PEDV strongly repressed the binding enrichments. The occupancies of histone active marks such as H3K9/27ac and H3K4me1/2, together with active co-factor p300 and polymerase II at the locus of CAT and GPX4, were significantly decreased. Importantly, PEDV infection disrupted the physical association between RORγ and NRF2, facilitating the down-regulation of the CAT and GPX4 genes at the transcriptional levels. RORγ is a potential factor in modulating the CAT and GPX4 gene expressions in the liver of PEDV piglets by interacting with NRF2 and histone modifications.
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Affiliation(s)
- Haotian Gu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Yaya Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Yahui Zhao
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Huan Qu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Yanhua Li
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China
| | - Abdelkareem A Ahmed
- Biomedical Research Institute, Darfur University College, Nyala 56022, Sudan
| | - Hao-Yu Liu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China
| | - Ping Hu
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China
| | - Demin Cai
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- International Joint Research Laboratory in Universities of Jiangsu Province of China for Domestic Animal Germplasm Resources and Genetic Improvement, Yangzhou 225009, China
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Foresta A, Ojeda-Fernandez L, Macaluso G, Roncaglioni MC, Tettamanti M, Fortino I, Leoni O, Genovese S, Baviera M. Dipeptidyl Peptidase-4 Inhibitors, Glucagon-like Peptide-1 Receptor Agonists, and Sodium-Glucose Cotransporter-2 Inhibitors and COVID-19 Outcomes. Clin Ther 2023; 45:e115-e126. [PMID: 36933975 PMCID: PMC9974363 DOI: 10.1016/j.clinthera.2023.02.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 02/21/2023] [Accepted: 02/22/2023] [Indexed: 03/05/2023]
Abstract
PURPOSE It has been reported that dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have a role in modulation of inflammation associated with coronavirus disease 2019 (COVID-19). This study assessed the effect of these drug classes on COVID-19-related outcomes. METHODS Using a COVID-19 linkable administrative database, we selected patients aged ≥40 years with at least 2 prescriptions of DPP-4i, GLP-1 RA, or SGLT-2i or any other antihyperglycemic drug and a diagnosis of COVID-19 from February 15, 2020, to March 15, 2021. Adjusted odds ratios (ORs) with 95% CIs were used to calculate the association between treatments and all-cause and in-hospital mortality and COVID-19-related hospitalization. A sensitivity analysis was performed by using inverse probability treatment weighting. FINDINGS Overall, 32,853 subjects were included in the analysis. Multivariable models showed a reduction of the risk for COVID-19 outcomes for users of DPP-4i, GLP-1 RA, and SGLT-2i compared with nonusers, although statistical significance was reached only in DPP-4i users for total mortality (OR, 0.89; 95% CI, 0.82-0.97). The sensitivity analysis confirmed the main results reaching a significant reduction for hospital admission in GLP-1 RA users and in-hospital mortality in SGLT-2i users compared with nonusers. IMPLICATIONS This study found a beneficial effect in the risk reduction of COVID-19 total mortality in DPP-4i users compared with nonusers. A positive trend was also observed in users of GLP-1 RA and SGLT-2i compared with nonusers. Randomized clinical trials are needed to confirm the effect of these drug classes as potential therapy for the treatment of COVID-19.
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Affiliation(s)
- Andreana Foresta
- Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
| | - Luisa Ojeda-Fernandez
- Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Giulia Macaluso
- Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Maria Carla Roncaglioni
- Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Mauro Tettamanti
- Laboratory of Geriatric Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Ida Fortino
- Unità Organizzativa Osservatorio Epidemiologico Regionale, Lombardy Region, Milan, Italy
| | - Olivia Leoni
- Unità Organizzativa Osservatorio Epidemiologico Regionale, Lombardy Region, Milan, Italy
| | | | - Marta Baviera
- Laboratory of Cardiovascular Prevention, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
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12
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Greco C, Pirotti T, Brigante G, Filippini T, Pacchioni C, Trenti T, Simoni M, Santi D. Glycemic control predicts SARS-CoV-2 prognosis in diabetic subjects. Acta Diabetol 2023; 60:817-825. [PMID: 36939895 PMCID: PMC10025792 DOI: 10.1007/s00592-023-02073-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/06/2023] [Indexed: 03/21/2023]
Abstract
AIM The coronavirus disease (COVID)-19 incidence was higher in diabetes mellitus (DM), although several differences should be considered on the basis of characteristics of cohorts evaluated. This study was designed to evaluate the prevalence and potential consequences of COVID-19 in a large diabetic population in Northern Italy. DESIGN Observational, longitudinal, retrospective, clinical study. METHODS Subjects with both type 1 and type 2 DM living in the Province of Modena and submitted to at least one SARS-CoV-2 swab between March 2020 and March 2021 were included. Data were extracted from the Hospital data warehouse. RESULTS 9553 diabetic subjects were enrolled (age 68.8 ± 14.1 years, diabetes duration 11.0 ± 6.9 years, glycated hemoglobin 57.2 ± 16.2 mmol/mol). COVID-19 was detected in 2302 patients (24.1%) with a death rate of 8.9%. The mean age and diabetes duration were significantly lower in infected versus non-infected patients. SARS-CoV-2 infection was more frequent in youngest people, according to quartile of age and retirement pension age of 65 years. No differences were detected considering sex. Higher HbA1c was detected in infected compared to non-infected patient. Death was predicted by diabetes duration and HbA1c. ROC analyses for death risk showed significant threshold for diabetes duration (10.9 years) and age (74.4 years). CONCLUSION In our cohort, SARS-CoV-2 infection correlates with age, diabetes duration and disease control. Diabetic patients with COVID-19 should be carefully followed when older than 74 years and with more than 10 years of DM duration.
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Affiliation(s)
- Carla Greco
- Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via Giardini 1355, 41126, Modena, Italy.
- Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria Di Modena, Ospedale Civile Di Baggiovara, Modena, Italy.
| | - Tommaso Pirotti
- Department of Laboratory Medicine and Anatomy Pathology, Azienda USL Modena, Modena, Italy
| | - Giulia Brigante
- Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via Giardini 1355, 41126, Modena, Italy
- Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria Di Modena, Ospedale Civile Di Baggiovara, Modena, Italy
| | - Tommaso Filippini
- Environmental, Genetic and Nutritional Epidemiology Research Center (CREAGEN), Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
- School of Public Health, University of California Berkeley, Berkeley, CA, USA
| | - Chiara Pacchioni
- Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria Di Modena, Ospedale Civile Di Baggiovara, Modena, Italy
| | - Tommaso Trenti
- Department of Laboratory Medicine and Anatomy Pathology, Azienda USL Modena, Modena, Italy
| | - Manuela Simoni
- Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via Giardini 1355, 41126, Modena, Italy
- Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria Di Modena, Ospedale Civile Di Baggiovara, Modena, Italy
| | - Daniele Santi
- Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via Giardini 1355, 41126, Modena, Italy
- Unit of Endocrinology, Department of Medical Specialties, Azienda Ospedaliero-Universitaria Di Modena, Ospedale Civile Di Baggiovara, Modena, Italy
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13
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Bernstein HG, Keilhoff G, Dobrowolny H, Steiner J. The many facets of CD26/dipeptidyl peptidase 4 and its inhibitors in disorders of the CNS - a critical overview. Rev Neurosci 2023; 34:1-24. [PMID: 35771831 DOI: 10.1515/revneuro-2022-0026] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/10/2022] [Indexed: 01/11/2023]
Abstract
Dipeptidyl peptidase 4 is a serine protease that cleaves X-proline or X-alanine in the penultimate position. Natural substrates of the enzyme are glucagon-like peptide-1, glucagon inhibiting peptide, glucagon, neuropeptide Y, secretin, substance P, pituitary adenylate cyclase-activating polypeptide, endorphins, endomorphins, brain natriuretic peptide, beta-melanocyte stimulating hormone and amyloid peptides as well as some cytokines and chemokines. The enzyme is involved in the maintenance of blood glucose homeostasis and regulation of the immune system. It is expressed in many organs including the brain. DPP4 activity may be effectively depressed by DPP4 inhibitors. Apart from enzyme activity, DPP4 acts as a cell surface (co)receptor, associates with adeosine deaminase, interacts with extracellular matrix, and controls cell migration and differentiation. This review aims at revealing the impact of DPP4 and DPP4 inhibitors for several brain diseases (virus infections affecting the brain, tumours of the CNS, neurological and psychiatric disorders). Special emphasis is given to a possible involvement of DPP4 expressed in the brain.While prominent contributions of extracerebral DPP4 are evident for a majority of diseases discussed herein; a possible role of "brain" DPP4 is restricted to brain cancers and Alzheimer disease. For a number of diseases (Covid-19 infection, type 2 diabetes, Alzheimer disease, vascular dementia, Parkinson disease, Huntington disease, multiple sclerosis, stroke, and epilepsy), use of DPP4 inhibitors has been shown to have a disease-mitigating effect. However, these beneficial effects should mostly be attributed to the depression of "peripheral" DPP4, since currently used DPP4 inhibitors are not able to pass through the intact blood-brain barrier.
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Affiliation(s)
- Hans-Gert Bernstein
- Department of Psychiatry and Psychotherapy, Otto v. Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany
| | - Gerburg Keilhoff
- Institute of Biochemistry and Cell Biology, Otto v. Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany
| | - Henrik Dobrowolny
- Department of Psychiatry and Psychotherapy, Otto v. Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany
| | - Johann Steiner
- Department of Psychiatry and Psychotherapy, Otto v. Guericke University Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany
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Kozsurek M, Király K, Gyimesi K, Lukácsi E, Fekete C, Gereben B, Mohácsik P, Helyes Z, Bölcskei K, Tékus V, Pap K, Szűcs E, Benyhe S, Imre T, Szabó P, Gajtkó A, Holló K, Puskár Z. Unique, Specific CART Receptor-Independent Regulatory Mechanism of CART(55-102) Peptide in Spinal Nociceptive Transmission and Its Relation to Dipeptidyl-Peptidase 4 (DDP4). Int J Mol Sci 2023; 24:ijms24020918. [PMID: 36674439 PMCID: PMC9865214 DOI: 10.3390/ijms24020918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 12/09/2022] [Accepted: 12/14/2022] [Indexed: 01/06/2023] Open
Abstract
Cocaine- and amphetamine-regulated transcript (CART) peptides are involved in several physiological and pathological processes, but their mechanism of action is unrevealed due to the lack of identified receptor(s). We provided evidence for the antihyperalgesic effect of CART(55-102) by inhibiting dipeptidyl-peptidase 4 (DPP4) in astrocytes and consequently reducing neuroinflammation in the rat spinal dorsal horn in a carrageenan-evoked inflammation model. Both naturally occurring CART(55-102) and CART(62-102) peptides are present in the spinal cord. CART(55-102) is not involved in acute nociception but regulates spinal pain transmission during peripheral inflammation. While the full-length peptide with a globular motif contributes to hyperalgesia, its N-terminal inhibits this process. Although the anti-hyperalgesic effects of CART(55-102), CART(55-76), and CART(62-76) are blocked by opioid receptor antagonists in our inflammatory models, but not in neuropathic Seltzer model, none of them bind to any opioid or G-protein coupled receptors. DPP4 interacts with Toll-like receptor 4 (TLR4) signalling in spinal astrocytes and enhances the TLR4-induced expression of interleukin-6 and tumour necrosis factor alpha contributing to inflammatory pain. Depending on the state of inflammation, CART(55-102) is processed in the spinal cord, resulting in the generation of biologically active isoleucine-proline-isoleucine (IPI) tripeptide, which inhibits DPP4, leading to significantly decreased glia-derived cytokine production and hyperalgesia.
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Affiliation(s)
- Márk Kozsurek
- Department of Anatomy, Histology and Embryology, Semmelweis University, H-1094 Budapest, Hungary
| | - Kornél Király
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1089 Budapest, Hungary
| | - Klára Gyimesi
- Department of Anatomy, Histology and Embryology, Semmelweis University, H-1094 Budapest, Hungary
- Department of Anaesthesiology, Uzsoki Hospital, H-1145 Budapest, Hungary
| | - Erika Lukácsi
- Department of Anatomy, Histology and Embryology, Semmelweis University, H-1094 Budapest, Hungary
| | - Csaba Fekete
- Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Eötvös Loránd Research Network, H-1083 Budapest, Hungary
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Tupper Research Institute, Tufts Medical Center, Boston, MA 02111, USA
| | - Balázs Gereben
- Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Eötvös Loránd Research Network, H-1083 Budapest, Hungary
| | - Petra Mohácsik
- Laboratory of Integrative Neuroendocrinology, Institute of Experimental Medicine, Eötvös Loránd Research Network, H-1083 Budapest, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, University of Pécs, H-7624 Pécs, Hungary
- National Laboratory for Drug Research and Development, H-1117 Budapest, Hungary
- Chronic Pain Research Group, Eötvös Loránd Research Network, H-7624 Pécs, Hungary
| | - Kata Bölcskei
- Department of Pharmacology and Pharmacotherapy, University of Pécs, H-7624 Pécs, Hungary
| | - Valéria Tékus
- Department of Pharmacology and Pharmacotherapy, University of Pécs, H-7624 Pécs, Hungary
- National Laboratory for Drug Research and Development, H-1117 Budapest, Hungary
| | - Károly Pap
- Department of Orthopaedics and Traumatology, Uzsoki Hospital, H-1145 Budapest, Hungary
| | - Edina Szűcs
- Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network, H-6726 Szeged, Hungary
| | - Sándor Benyhe
- Institute of Biochemistry, Biological Research Centre, Eötvös Loránd Research Network, H-6726 Szeged, Hungary
| | - Tímea Imre
- MS Metabolomics Laboratory, Instrumentation Centre, Research Centre for Natural Sciences, Eötvös Loránd Research Network, H-1117 Budapest, Hungary
| | - Pál Szabó
- MS Metabolomics Laboratory, Instrumentation Centre, Research Centre for Natural Sciences, Eötvös Loránd Research Network, H-1117 Budapest, Hungary
| | - Andrea Gajtkó
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Krisztina Holló
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary
| | - Zita Puskár
- Department of Anatomy, Histology and Embryology, Semmelweis University, H-1094 Budapest, Hungary
- Correspondence:
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Banik SP, Bhattacharyya M, Ghosh R, Chatterjee T, Basak P. Unveiling the prevalence and impact of diabetes on COVID-19. VIRAL, PARASITIC, BACTERIAL, AND FUNGAL INFECTIONS 2023:287-301. [DOI: 10.1016/b978-0-323-85730-7.00045-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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16
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He YF, Jiang ZG, Wu N, Bian N, Ren JL. Correlation between COVID-19 and hepatitis B: A systematic review. World J Gastroenterol 2022; 28:6599-6618. [PMID: 36569273 PMCID: PMC9782843 DOI: 10.3748/wjg.v28.i46.6599] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 10/29/2022] [Accepted: 11/19/2022] [Indexed: 12/08/2022] Open
Abstract
BACKGROUND There is growing evidence that patients with coronavirus disease 2019 (COVID-19) frequently present with liver impairment. Hepatitis B virus (HBV) remains a major public health threat in current society. Both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HBV can cause liver damage, and current findings on whether HBV infection increases disease severity in COVID-19 patients are inconsistent, and whether SARS-CoV-2 infection accelerates hepatitis B progression or leads to a worse prognosis in hepatitis B patients has not been adequately elucidated. AIM To explore the complex relationship between COVID-19 and hepatitis B in order to inform the research and management of patients co-infected with SARS-CoV-2 and HBV. METHODS An experienced information specialist searched the literature in the following online databases: PubMed, China National Knowledge Infrastructure, Google Scholar, Scopus, Wiley, Web of Science, Cochrane, and ScienceDirect. The literature published from December 2019 to September 1, 2022 was included in the search. We also searched medRxiv and bioRxiv for gray literature and manually scanned references of included articles. Articles reporting studies conducted in humans discussing hepatitis B and COVID-19 were included. We excluded duplicate publications. News reports, reports, and other gray literature were included if they contained quantifiable evidence (case reports, findings, and qualitative analysis). Some topics that included HBV or COVID-19 samples but did not have quantitative evidence were excluded from the review. RESULTS A total of 57 studies were eligible and included in this review. They were from 11 countries, of which 33 (57.9%) were from China. Forty-two of the 57 studies reported abnormalities in liver enzymes, three mainly reported abnormalities in blood parameters, four indicated no significant liver function alterations, and another eight studies did not provide data on changes in liver function. Fifty-seven studies were retrospective and the total number of co-infections was 1932, the largest sample size was 7723, and the largest number of co-infections was 353. Most of the studies suggested an interaction between hepatitis B and COVID-19, while 12 studies clearly indicated no interaction between hepatitis B and COVID-19. Six of the 57 studies clearly reported HBV activation. Six studies were related to liver transplant patients. CONCLUSION There is some association between COVID-19 and hepatitis B. Future high-quality randomized trials are needed to further elucidate the interaction between COVID-19 and hepatitis B.
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Affiliation(s)
- Yan-Fei He
- Health Management Center, The Sixth Medical Center, Chinese PLA General Hospital, Beijing 100048, China
| | - Zhi-Gang Jiang
- Department of Statistics, Zunyi Medical University, Guizhou 563006, Guizhou Province, China
| | - Ni Wu
- Health Management Center, The Sixth Medical Center, Chinese PLA General Hospital, Beijing 100048, China
| | - Ning Bian
- Health Management Center, The Sixth Medical Center, Chinese PLA General Hospital, Beijing 100048, China
| | - Jun-Lin Ren
- Department of Infection Control, The Sixth Medical Center, Chinese PLA General Hospital, Beijing 100048, China
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17
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Achom A, Das R, Pakray P. An improved Fuzzy based GWO algorithm for predicting the potential host receptor of COVID-19 infection. Comput Biol Med 2022; 151:106050. [PMID: 36334362 PMCID: PMC9404081 DOI: 10.1016/j.compbiomed.2022.106050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 08/12/2022] [Accepted: 08/20/2022] [Indexed: 12/27/2022]
Abstract
Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has infected millions worldwide. SARS-CoV-2 spike protein uses Angiotensin-converting enzyme 2 (ACE2) and Transmembrane serine protease 2 (TMPRSS2) for entering and fusing the host cell membrane. However, interaction with spike protein receptors and protease processing are not the only factors determining coronaviruses' entry. Several proteases mediate the entry of SARS-CoV-2 virus into the host cell. Identifying receptor factors helps understand tropism, transmission, and pathogenesis of COVID-19 infection in humans. The paper aims to identify novel viral receptor or membrane proteins that are transcriptionally and biologically similar to ACE2 and TMPRSS2 through a fuzzy clustering technique that employs the Grey wolf optimizer (GWO) algorithm for finding the optimal cluster center. The exploratory and exploitation capability of GWO algorithm is improved by hybridizing mutation and crossover operators of the evolutionary algorithm. Also, the genetic diversity of the grey wolf population is enhanced by eliminating weak individuals from the population. The proposed clustering algorithm's effectiveness is shown by detecting novel viral receptors and membrane proteins associated with the pathogenesis of SARS-CoV-2 infection. The expression profiles of ACE2 protein and its co-receptor factor are analyzed and compared with single-cell transcriptomics profiling using the Seurat R toolkit, mass spectrometry (MS), and immunohistochemistry (IHC). Our advanced clustering method infers that cell that expresses high ACE2 level are more affected by SARS-CoV-infection. So, SARS-CoV-2 virus affects lung, intestine, testis, heart, kidney, and liver more severely than brain, bone marrow, skin, spleen, etc. We have identified 58 novel viral receptors and 816 membrane proteins, and their role in the pathogenicity mechanism of SARS-CoV-2 infection has been studied. Besides, our study confirmed that Neuropilins (NRP1), G protein-coupled receptor 78 (GPR78), C-type lectin domain family 4 member M (CLEC4M), Kringle containing transmembrane protein 1 (KREMEN1), Asialoglycoprotein receptor 1 (ASGR1), A Disintegrin and metalloprotease 17 (ADAM17), Furin, Neuregulin-1,(NRG1), Basigin or CD147 and Poliovirus receptor (PVR) are the potential co-receptors of SARS-CoV-2 virus. A significant finding is that heparin derivative glycosaminoglycans could block the replication of SARS-CoV-2 virus inside the host cytoplasm. The membrane protein N-Deacetylase/N-Sulfotransferase-2 (NDST2), Extostosin protein (EXT1, EXT2, and EXT3), Glucuronic acid epimerase (GLCE), and Xylosyltransferase I, II (XYLT1, XYLT2) could act as the therapeutic target for inhibiting the spread of SARS-CoV-2 infection. Drugs such as carboplatin and gemcitabine are effective in such situations.
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Affiliation(s)
- Amika Achom
- Department of Computer Science and Engineering, National Institute of Technology, Mizoram, Aizwal, 796001, Mizoram, India.
| | - Ranjita Das
- Department of Computer Science and Engineering, National Institute of Technology, Mizoram, Aizwal, 796001, Mizoram, India.
| | - Partha Pakray
- Department of Computer Science and Engineering, National Institute of Technology, Silchar, Silchar, 788003, Assam, India.
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Bramante CT, Johnson SG, Garcia V, Evans MD, Harper J, Wilkins KJ, Huling JD, Mehta H, Alexander C, Tronieri J, Hong S, Kahkoska A, Alamgir J, Koraishy F, Hartman K, Yang K, Abrahamsen T, Stürmer T, Buse JB. Diabetes medications and associations with Covid-19 outcomes in the N3C database: A national retrospective cohort study. PLoS One 2022; 17:e0271574. [PMID: 36395143 PMCID: PMC9671347 DOI: 10.1371/journal.pone.0271574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 07/04/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND While vaccination is the most important way to combat the SARS-CoV-2 pandemic, there may still be a need for early outpatient treatment that is safe, inexpensive, and currently widely available in parts of the world that do not have access to the vaccine. There are in-silico, in-vitro, and in-tissue data suggesting that metformin inhibits the viral life cycle, as well as observational data suggesting that metformin use before infection with SARS-CoV2 is associated with less severe COVID-19. Previous observational analyses from single-center cohorts have been limited by size. METHODS Conducted a retrospective cohort analysis in adults with type 2 diabetes (T2DM) for associations between metformin use and COVID-19 outcomes with an active comparator design of prevalent users of therapeutically equivalent diabetes monotherapy: metformin versus dipeptidyl-peptidase-4-inhibitors (DPP4i) and sulfonylureas (SU). This took place in the National COVID Cohort Collaborative (N3C) longitudinal U.S. cohort of adults with +SARS-CoV-2 result between January 1 2020 to June 1 2021. Findings included hospitalization or ventilation or mortality from COVID-19. Back pain was assessed as a negative control outcome. RESULTS 6,626 adults with T2DM and +SARS-CoV-2 from 36 sites. Mean age was 60.7 +/- 12.0 years; 48.7% male; 56.7% White, 21.9% Black, 3.5% Asian, and 16.7% Latinx. Mean BMI was 34.1 +/- 7.8kg/m2. Overall 14.5% of the sample was hospitalized; 1.5% received mechanical ventilation; and 1.8% died. In adjusted outcomes, compared to DPP4i, metformin had non-significant associations with reduced need for ventilation (RR 0.68, 0.32-1.44), and mortality (RR 0.82, 0.41-1.64). Compared to SU, metformin was associated with a lower risk of ventilation (RR 0.5, 95% CI 0.28-0.98, p = 0.044) and mortality (RR 0.56, 95%CI 0.33-0.97, p = 0.037). There was no difference in unadjusted or adjusted results of the negative control. CONCLUSIONS There were clinically significant associations between metformin use and less severe COVID-19 compared to SU, but not compared to DPP4i. New-user studies and randomized trials are needed to assess early outpatient treatment and post-exposure prophylaxis with therapeutics that are safe in adults, children, pregnancy and available worldwide.
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Affiliation(s)
- Carolyn T. Bramante
- Division of General Internal Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Steven G. Johnson
- Institute for Health Informatics, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Victor Garcia
- Department of Biomedical Informatics, Stony Brook University Hospital, Stony Brook, New York, United States of America
| | - Michael D. Evans
- Biostatistical Design and Analysis Center, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Jeremy Harper
- Owl HealthWorks, Indianapolis, IN, United States of America
| | - Kenneth J. Wilkins
- Biostatistics Program, Office of the Director, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, Maryland, United States of America
| | - Jared D. Huling
- Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, Minnesota, United States of America
| | - Hemalkumar Mehta
- Division of Epidemiology and Methodology, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America
| | - Caleb Alexander
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Jena Tronieri
- Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Stephenie Hong
- Division of Epidemiology and Methodology, Johns Hopkins School of Public Health, Baltimore, Maryland, United States of America
| | - Anna Kahkoska
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Joy Alamgir
- ARIScience, Boston, Massachusetts, United States of America
| | - Farrukh Koraishy
- Division of Nephrology, Stony Brook University Hospital, Stony Brook, New York, United States of America
| | - Katrina Hartman
- Division of General Internal Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America
| | - Kaifeng Yang
- Division of Biostatistics, University of Minnesota School of Public Health, Minneapolis, Minnesota, United States of America
| | | | - Til Stürmer
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - John B. Buse
- Division of Endocrinology, Department of Medicine, University of North Carolina Medical School, Chapel Hill, North Carolina, United States of America
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Cao JF, Yang X, Xiong L, Wu M, Chen S, Xiong C, He P, Zong Y, Zhang L, Fu H, Qi Y, Ying X, Liu D, Hu X, Zhang X. Mechanism of N-0385 blocking SARS-CoV-2 to treat COVID-19 based on molecular docking and molecular dynamics. Front Microbiol 2022; 13:1013911. [PMID: 36329841 PMCID: PMC9622768 DOI: 10.3389/fmicb.2022.1013911] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/26/2022] [Indexed: 11/21/2023] Open
Abstract
PURPOSE 2019 Coronavirus disease (COVID-19) has caused millions of confirmed cases and deaths worldwide. TMPRSS2-mediated hydrolysis and maturation of spike protein is essential for SARS-CoV-2 infection in vivo. The latest research found that a TMPRSS2 inhibitor called N-0385 could effectively prevent the infection of the SARS-CoV-2 and its variants. However, it is not clear about the mechanism of N-0385 treatment COVID-19. Therefore, this study used computer simulations to investigate the mechanism of N-0385 treatment COVID-19 by impeding SARS-CoV-2 infection. METHODS The GeneCards database was used to search disease gene targets, core targets were analyzed by PPI, GO and KEGG. Molecular docking and molecular dynamics were used to validate and analyze the binding stability of small molecule N-0385 to target proteins. The supercomputer platform was used to simulate and analyze the number of hydrogen bonds, binding free energy, stability of protein targets at the residue level, radius of gyration and solvent accessible surface area. RESULTS There were 4,600 COVID-19 gene targets from GeneCards database. PPI, GO and KEGG analysis indicated that signaling pathways of immune response and inflammation played crucial roles in COVID-19. Molecular docking showed that N-0385 could block SARS-CoV-2 infection and treat COVID-19 by acting on ACE2, TMPRSS2 and NLRP3. Molecular dynamics was used to demonstrate that the small molecule N-0385 could form very stable bindings with TMPRSS2 and TLR7. CONCLUSION The mechanism of N-0385 treatment COVID-19 was investigated by molecular docking and molecular dynamics simulation. We speculated that N-0385 may not only inhibit SARS-CoV-2 invasion directly by acting on TMPRSS2, ACE2 and DPP4, but also inhibit the immune recognition process and inflammatory response by regulating TLR7, NLRP3 and IL-10 to prevent SARS-CoV-2 invasion. Therefore, these results suggested that N-0385 may act through multiple targets to reduce SARS-CoV-2 infection and damage caused by inflammatory responses.
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Affiliation(s)
- Jun-Feng Cao
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Xingyu Yang
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Li Xiong
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Mei Wu
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Shengyan Chen
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Chenyang Xiong
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Peiyong He
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | | | - Lixin Zhang
- Yunnan Academy of Forestry Sciences, Kunming, Yunnan, China
| | - Hongjiao Fu
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Yue Qi
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Xiran Ying
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Dengxin Liu
- Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Xiaosong Hu
- Chengdu Medical College of Basic Medical Sciences, Chengdu, China
| | - Xiao Zhang
- Chengdu Medical College of Basic Medical Sciences, Chengdu, China
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20
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Bolla AM, Loretelli C, Montefusco L, Finzi G, Abdi R, Ben Nasr M, Lunati ME, Pastore I, Bonventre JV, Nebuloni M, Rusconi S, Santus P, Zuccotti G, Galli M, D’Addio F, Fiorina P. Inflammation and vascular dysfunction: The negative synergistic combination of diabetes and COVID-19. Diabetes Metab Res Rev 2022; 38:e3565. [PMID: 35830597 PMCID: PMC9349661 DOI: 10.1002/dmrr.3565] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 01/08/2023]
Abstract
AIMS Several reports indicate that diabetes determines an increased mortality risk in patients with coronavirus disease 19 (COVID-19) and a good glycaemic control appears to be associated with more favourable outcomes. Evidence also supports that COVID-19 pneumonia only accounts for a part of COVID-19 related deaths. This disease is indeed characterised by abnormal inflammatory response and vascular dysfunction, leading to the involvement and failure of different systems, including severe acute respiratory distress syndrome, coagulopathy, myocardial damage and renal failure. Inflammation and vascular dysfunction are also well-known features of hyperglycemia and diabetes, making up the ground for a detrimental synergistic combination that could explain the increased mortality observed in hyperglycaemic patients. MATERIALS AND METHODS In this work, we conduct a narrative review on this intriguing connection. Together with this, we also present the clinical characteristics, outcomes, laboratory and histopathological findings related to this topic of a cohort of nearly 1000 subjects with COVID-19 admitted to a third-level Hospital in Milan. RESULTS We found an increased mortality in subjects with COVID-19 and diabetes, together with an altered inflammatory profile. CONCLUSIONS This may support the hypothesis that diabetes and COVID-19 meet at the crossroads of inflammation and vascular dysfunction. (ClinicalTrials.gov NCT04463849 and NCT04382794).
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Affiliation(s)
| | - Cristian Loretelli
- International Center for T1DPediatric Clinical Research Center Romeo ed Enrica InvernizziDepartment of Biomedical and Clinical Science L. SaccoUniversity of MilanMilanItaly
| | | | | | - Reza Abdi
- Nephrology DivisionBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | - Moufida Ben Nasr
- International Center for T1DPediatric Clinical Research Center Romeo ed Enrica InvernizziDepartment of Biomedical and Clinical Science L. SaccoUniversity of MilanMilanItaly
- Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | | | - Ida Pastore
- Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
| | - Joseph V. Bonventre
- Nephrology DivisionBrigham and Women's HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | - Manuela Nebuloni
- Pathology UnitASST Fatebenefratelli‐SaccoMilanItaly
- Department of Biomedical and Clinical Sciences L. SaccoUniversity of MilanMilanItaly
| | - Stefano Rusconi
- Department of Biomedical and Clinical Sciences L. SaccoUniversity of MilanMilanItaly
| | - Pierachille Santus
- Department of Biomedical and Clinical Sciences L. SaccoUniversity of MilanMilanItaly
- Division of Respiratory DiseasesASST Fatebenefratelli‐SaccoMilanItaly
| | - Gianvincenzo Zuccotti
- Pediatric Clinical Research Center Romeo ed Enrica InvernizziDepartment of Biomedical and Clinical Science L. SaccoUniversity of MilanMilanItaly
- Department of Pediatrics“V. Buzzi” Children's HospitalMilanItaly
| | - Massimo Galli
- Department of Biomedical and Clinical Sciences L. SaccoUniversity of MilanMilanItaly
- III Division of Infectious DiseasesLuigi Sacco HospitalASST Fatebenefratelli‐SaccoMilanItaly
| | - Francesca D’Addio
- Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
- International Center for T1DPediatric Clinical Research Center Romeo ed Enrica InvernizziDepartment of Biomedical and Clinical Science L. SaccoUniversity of MilanMilanItaly
| | - Paolo Fiorina
- Division of EndocrinologyASST Fatebenefratelli‐SaccoMilanItaly
- International Center for T1DPediatric Clinical Research Center Romeo ed Enrica InvernizziDepartment of Biomedical and Clinical Science L. SaccoUniversity of MilanMilanItaly
- Nephrology DivisionBoston Children's HospitalHarvard Medical SchoolBostonMassachusettsUSA
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21
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Role of Dipeptidyl Peptidase-4 (DPP4) on COVID-19 Physiopathology. Biomedicines 2022; 10:biomedicines10082026. [PMID: 36009573 PMCID: PMC9406088 DOI: 10.3390/biomedicines10082026] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 11/17/2022] Open
Abstract
DPP4/CD26 is a single-pass transmembrane protein with multiple functions on glycemic control, cell migration and proliferation, and the immune system, among others. It has recently acquired an especial relevance due to the possibility to act as a receptor or co-receptor for SARS-CoV-2, as it has been already demonstrated for other coronaviruses. In this review, we analyze the evidence for the role of DPP4 on COVID-19 risk and clinical outcome, and its contribution to COVID-19 physiopathology. Due to the pathogenetic links between COVID-19 and diabetes mellitus and the hyperinflammatory response, with the hallmark cytokine storm developed very often during the disease, we dive deep into the functions of DPP4 on carbohydrate metabolism and immune system regulation. We show that the broad spectrum of functions regulated by DPP4 is performed both as a protease enzyme, as well as an interacting partner of other molecules on the cell surface. In addition, we provide an update of the DPP4 inhibitors approved by the EMA and/or the FDA, together with the newfangled approval of generic drugs (in 2021 and 2022). This review will also cover the effects of DPP4 inhibitors (i.e., gliptins) on the progression of SARS-CoV-2 infection, showing the role of DPP4 in this disturbing disease.
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22
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Mikhael EM, Ong SC, Sheikh Ghadzi SM. Efficacy and Safety of Sitagliptin in the Treatment of COVID-19. J Pharm Pract 2022:8971900221102119. [PMID: 35581701 PMCID: PMC9121144 DOI: 10.1177/08971900221102119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Background: Coronavirus disease 2019 (COVID-19) is associated with a high risk of mortality especially among diabetes mellitus (DM) patients. Effective treatments against COVID-19 can complement the vaccination effort worldwide. Many review articles studied the effects of the dipeptidyl peptidase 4 (DPP-4) inhibitors among COVID-19 patients and found conflicting results. This heterogeneity may be due to different systemic pleiotropic effects of different DPP-4 inhibitors. Sitagliptin appears to be one of the good DPP-4 inhibitors that have antiinflammatory and antithrombotic effect. Therefore, this review assessed the benefits and safety of sitagliptin in the treatment of COVID-19. Methods: A detailed literature review using the electronic databases of Pubmed and Google Scholar was conducted during July and August 2021 to find out studies that published in English language and discussed the role of sitagliptin for COVID-19 patients. Results: 14 articles were eligible and thus included in this narrative review. Nine of these articles agreed to the benefit of sitagliptin in the treatment of COVID-19, while 3 studies considered sitagliptin as non useful or even risky, and one study was neutral in its conclusion towards the usage of sitagliptin in COVID-19. Only one study focused on the safety of sitagliptin and found that it is safe. Conclusion: Sitagliptin has anti-inflammatory, antifibrotic and antiapoptotic properties; such effects may be beneficial in reducing risks of COVID-19. Sitagliptin has good safety and fair benefits to reduce mortality among DM patients with COVID-19. Further randomized clinical trials are needed to confirm these benefits especially among patients without DM.
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Affiliation(s)
- Ehab Mudher Mikhael
- School of Pharmaceutical Sciences, 26689Universiti Sains Malaysia, Penang, Malaysia.,Clinical Pharmacy Department - College of Pharmacy, 108491University of Baghdad, Baghdad, Iraq
| | - Siew Chin Ong
- School of Pharmaceutical Sciences, 26689Universiti Sains Malaysia, Penang, Malaysia
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23
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Hu S, Buser E, Arredondo J, Relyea D, Santos Rocha C, Dandekar S. Altered Expression of ACE2 and Co-receptors of SARS-CoV-2 in the Gut Mucosa of the SIV Model of HIV/AIDS. Front Microbiol 2022; 13:879152. [PMID: 35495669 PMCID: PMC9048205 DOI: 10.3389/fmicb.2022.879152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 03/15/2022] [Indexed: 12/02/2022] Open
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of the COVID-19 pandemic, is initiated by its binding to the ACE2 receptor and other co-receptors on mucosal epithelial cells. Variable outcomes of the infection and disease severity can be influenced by pre-existing risk factors. Human immunodeficiency virus (HIV), the cause of AIDS, targets the gut mucosal immune system and impairs epithelial barriers and mucosal immunity. We sought to determine the impact and mechanisms of pre-existing HIV infection increasing mucosal vulnerability to SARS-CoV-2 infection and disease. We investigated changes in the expression of ACE2 and other SARS-CoV-2 receptors and related pathways in virally inflamed gut by using the SIV infected rhesus macaque model of HIV/AIDS. Immunohistochemical analysis showed sustained/enhanced ACE2 expression in the gut epithelium of SIV infected animals compared to uninfected controls. Gut mucosal transcriptomic analysis demonstrated enhanced expression of host factors that support SARS-CoV-2 entry, replication, and infection. Metabolomic analysis of gut luminal contents revealed the impact of SIV infection as demonstrated by impaired mitochondrial function and decreased immune response, which render the host more vulnerable to other pathogens. In summary, SIV infection resulted in sustained or increased ACE2 expression in an inflamed and immune-impaired gut mucosal microenvironment. Collectively, these mucosal changes increase the susceptibility to SARS-CoV-2 infection and disease severity and result in ineffective viral clearance. Our study highlights the use of the SIV model of AIDS to fill the knowledge gap of the enteric mechanisms of co-infections as risk factors for poor disease outcomes, generation of new viral variants and immune escape in COVID-19.
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Affiliation(s)
- Shuang Hu
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Elise Buser
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Juan Arredondo
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Dylan Relyea
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Clarissa Santos Rocha
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Satya Dandekar
- Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, CA, United States
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24
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Naigaonkar A, Patil K, Joseph S, Hinduja I, Mukherjee S. Ovarian granulosa cells from women with PCOS express low levels of SARS-CoV-2 receptors and co-factors. Arch Gynecol Obstet 2022; 306:547-555. [PMID: 35477803 PMCID: PMC9045021 DOI: 10.1007/s00404-022-06567-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 04/06/2022] [Indexed: 11/24/2022]
Abstract
Purpose Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is global pandemic with more than 5 million deaths so far. Female reproductive tract organs express coronavirus-associated receptors and factors (SCARFs), suggesting they may be susceptible to SARS-CoV-2 infection; however, the susceptibility of ovary/follicle/oocyte to the same is still elusive. Co-morbidities like obesity, type-2 diabetes mellitus, cardiovascular disease, etc. increase the risk of SARS-CoV-2 infection. These features are common in women with polycystic ovary syndrome (PCOS), warranting further scope to study SCARFs expression in ovary of these women. Materials and methods SCARFs expression in ovary and ovarian tissues of women with PCOS and healthy women was explored by analyzing publically available microarray datasets. Transcript expressions of SCARFs were investigated in mural and cumulus granulosa cells (MGCs and CGCs) from control and PCOS women undergoing in vitro fertilization (IVF). Results Microarray data revealed that ovary expresses all genes necessary for SARS-CoV-2 infection. PCOS women mostly showed down-regulated/unchanged levels of SCARFs. MGCs and CGCs from PCOS women showed lower expression of receptors ACE2, BSG and DPP4 and protease CTSB than in controls. MGCs showed lower expression of protease CTSL in PCOS than in controls. Expression of TMPRSS2 was not detected in both cell types. Conclusion Human ovarian follicle may be susceptible to SARS-CoV-2 infection. Lower expression of SCARFs in PCOS indicates that the risk of SARS-CoV-2 infection to the ovary may be lesser in these women than controls. This knowledge may help in safe practices at IVF settings in the current pandemic. Supplementary Information The online version contains supplementary material available at 10.1007/s00404-022-06567-4.
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Affiliation(s)
- Aalaap Naigaonkar
- Department of Molecular Endocrinology, National Institute for Research in Reproductive Health, Indian Council of Medical Research, J.M. Street, Parel, Mumbai, 400012, India
| | - Krutika Patil
- Department of Molecular Endocrinology, National Institute for Research in Reproductive Health, Indian Council of Medical Research, J.M. Street, Parel, Mumbai, 400012, India
| | - Shaini Joseph
- Genetic Research Centre, National Institute for Research in Reproductive Health, Indian Council of Medical Research, J.M. Street, Parel, Mumbai, 400012, India
| | - Indira Hinduja
- P. D. Hinduja National Hospital and Medical Research Centre, Mahim, Mumbai, 400016, India
| | - Srabani Mukherjee
- Department of Molecular Endocrinology, National Institute for Research in Reproductive Health, Indian Council of Medical Research, J.M. Street, Parel, Mumbai, 400012, India.
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Why was this cited? Explainable machine learning applied to COVID-19 research literature. Scientometrics 2022; 127:2313-2349. [PMID: 35431364 PMCID: PMC8993675 DOI: 10.1007/s11192-022-04314-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 02/03/2022] [Indexed: 11/06/2022]
Abstract
Multiple studies have investigated bibliometric factors predictive of the citation count a research article will receive. In this article, we go beyond bibliometric data by using a range of machine learning techniques to find patterns predictive of citation count using both article content and available metadata. As the input collection, we use the CORD-19 corpus containing research articles—mostly from biology and medicine—applicable to the COVID-19 crisis. Our study employs a combination of state-of-the-art machine learning techniques for text understanding, including embeddings-based language model BERT, several systems for detection and semantic expansion of entities: ConceptNet, Pubtator and ScispaCy. To interpret the resulting models, we use several explanation algorithms: random forest feature importance, LIME, and Shapley values. We compare the performance and comprehensibility of models obtained by “black-box” machine learning algorithms (neural networks and random forests) with models built with rule learning (CORELS, CBA), which are intrinsically explainable. Multiple rules were discovered, which referred to biomedical entities of potential interest. Of the rules with the highest lift measure, several rules pointed to dipeptidyl peptidase4 (DPP4), a known MERS-CoV receptor and a critical determinant of camel to human transmission of the camel coronavirus (MERS-CoV). Some other interesting patterns related to the type of animal investigated were found. Articles referring to bats and camels tend to draw citations, while articles referring to most other animal species related to coronavirus are lowly cited. Bat coronavirus is the only other virus from a non-human species in the betaB clade along with the SARS-CoV and SARS-CoV-2 viruses. MERS-CoV is in a sister betaC clade, also close to human SARS coronaviruses. Thus both species linked to high citation counts harbor coronaviruses which are more phylogenetically similar to human SARS viruses. On the other hand, feline (FIPV, FCOV) and canine coronaviruses (CCOV) are in the alpha coronavirus clade and more distant from the betaB clade with human SARS viruses. Other results include detection of apparent citation bias favouring authors with western sounding names. Equal performance of TF-IDF weights and binary word incidence matrix was observed, with the latter resulting in better interpretability. The best predictive performance was obtained with a “black-box” method—neural network. The rule-based models led to most insights, especially when coupled with text representation using semantic entity detection methods. Follow-up work should focus on the analysis of citation patterns in the context of phylogenetic trees, as well on patterns referring to DPP4, which is currently considered as a SARS-Cov-2 therapeutic target.
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26
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Eslami N, Aghbash PS, Shamekh A, Entezari-Maleki T, Nahand JS, Sales AJ, Baghi HB. SARS-CoV-2: Receptor and Co-receptor Tropism Probability. Curr Microbiol 2022; 79:133. [PMID: 35292865 PMCID: PMC8923825 DOI: 10.1007/s00284-022-02807-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 02/09/2022] [Indexed: 02/07/2023]
Abstract
The recent pandemic which arose from China, is caused by a pathogenic virus named "severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2)". Its rapid global expansion has inflicted an extreme public health concern. The attachment of receptor-binding domains (RBD) of the spike proteins (S) to the host cell's membrane, with or without the help of other cellular components such as proteases and especially co-receptors, is required for the first stage of its pathogenesis. In addition to humans, angiotensin-converting enzyme 2 (ACE2) is found on a wide range of vertebrate host's cellular surface. SARS-CoV-2 has a broad spectrum of tropism; thus, it can infect a vast range of tissues, organs, and hosts; even though the surface amino acids of the spike protein conflict in the receptor-binding region. Due to the heterogeneous ACE2 distribution and the presence of different domains on the SARS-CoV-2 spike protein for binding, the virus entry into diverse host cell types may depend on the host cells' receptor presentation with or without co-receptors. This review investigates multiple current types of receptor and co-receptor tropisms, with other molecular factors alongside their respective mechanisms, which facilitate the binding and entry of SARS-CoV-2 into the cells, extending the severity of the coronavirus disease 2019 (COVID-19). Understanding the pathogenesis of COVID-19 from this perspective can effectively help prevent this disease and provide more potent treatment strategies, particularly in vulnerable people with various cellular-level susceptibilities.
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Affiliation(s)
- Narges Eslami
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, 5166/15731, Tabriz, Iran
| | - Parisa Shiri Aghbash
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Drug Applied Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Shamekh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Taher Entezari-Maleki
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abolfazl Jafari Sales
- Department of Microbiology School of Basic Sciences, Islamic Azad University, Kazerun BranchKazerun, Iran
| | - Hossein Bannazadeh Baghi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, 5166/15731, Tabriz, Iran.
- Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Carbohydrate Ligands for COVID-19 Spike Proteins. Viruses 2022; 14:v14020330. [PMID: 35215921 PMCID: PMC8880561 DOI: 10.3390/v14020330] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 01/25/2022] [Accepted: 02/03/2022] [Indexed: 02/04/2023] Open
Abstract
An outbreak of SARS-CoV-2 coronavirus (COVID-19) first detected in Wuhan, China, has created a public health emergency all over the world. The pandemic has caused more than 340 million confirmed cases and 5.57 million deaths as of 23 January 2022. Although carbohydrates have been found to play a role in coronavirus binding and infection, the role of cell surface glycans in SARS-CoV-2 infection and pathogenesis is still not understood. Herein, we report that the SARS-CoV-2 spike protein S1 subunit binds specifically to blood group A and B antigens, and that the spike protein S2 subunit has a binding preference for Lea antigens. Further examination of the binding preference for different types of red blood cells (RBCs) indicated that the spike protein S1 subunit preferentially binds with blood group A RBCs, whereas the spike protein S2 subunit prefers to interact with blood group Lea RBCs. Angiotensin converting enzyme 2 (ACE2), a known target of SARS-CoV-2 spike proteins, was identified to be a blood group A antigen-containing glycoprotein. Additionally, 6-sulfo N-acetyllactosamine was found to inhibit the binding of the spike protein S1 subunit with blood group A RBCs and reduce the interaction between the spike protein S1 subunit and ACE2.
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Ballarini S, Ardusso L, Ortega Martell JA, Sacco O, Feleszko W, Rossi GA. Can bacterial lysates be useful in prevention of viral respiratory infections in childhood? The results of experimental OM-85 studies. Front Pediatr 2022; 10:1051079. [PMID: 36479289 PMCID: PMC9720385 DOI: 10.3389/fped.2022.1051079] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/24/2022] [Indexed: 11/22/2022] Open
Abstract
Respiratory tract infections (RTI) are mainly viral in origin and among the leading cause of childhood morbidity globally. Associated wheezing illness and asthma are still a clear unmet medical need. Despite the continuous progress in understanding the processes involved in their pathogenesis, preventive measures and treatments failed to demonstrate any significant disease-modifying effect. However, in the last decades it was understood that early-life exposure to microbes, may reduce the risk of infectious and allergic disorders, increasing the immune response efficacy. These results suggested that treatment with bacterial lysates (BLs) acting on gut microbiota, could promote a heterologous immunomodulation useful in the prevention of recurrent RTIs and of wheezing inception and persistence. This hypothesis has been supported by clinical and experimental studies showing the reduction of RTI frequency and severity in childhood after oral BL prophylaxis and elucidating the involved mechanisms. OM-85 is the product whose anti-viral effects have been most extensively studied in vitro, animal, and human cell studies and in translational animal infection/disease models. The results of the latter studies, describing the potential immune training-based activities of such BL, leading to the protection against respiratory viruses, will be reported. In response to human rhinovirus, influenza virus, respiratory syncytial virus and severe acute respiratory coronavirus-2, OM-85 was effective in modulating the structure and the functions of a large numbers of airways epithelial and immune cells, when administered both orally and intranasally.
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Affiliation(s)
| | - Ledit Ardusso
- Allergy and Immunology Department, Rosario School of Medicine, National University of Rosario, Rosario, Argentina
| | | | - Oliviero Sacco
- Department of Pediatrics, Pulmonary and Allergy Disease Unit, G. Gaslini University Hospital, Genoa, Italy
| | - Wojciech Feleszko
- Department of Pediatric Pulmonology and Allergy, The Medical University Children's Hospital, Warszawa, Poland
| | - Giovanni A Rossi
- Department of Pediatrics, Unit of Pediatrics Pulmonology and Respiratory Endoscopy, G. Gaslini Hospital, Genoa, Italy
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Alshanwani A, Kashour T, Badr A. Anti-Diabetic Drugs GLP-1 Agonists and DPP-4 Inhibitors may Represent Potential Therapeutic Approaches for COVID-19. Endocr Metab Immune Disord Drug Targets 2022; 22:571-578. [PMID: 34370655 DOI: 10.2174/1871530321666210809153558] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 01/08/2023]
Abstract
The fast spread of coronavirus 2019 (COVID-19) calls for immediate action to counter the associated significant loss of human life and deep economic impact. Certain patient populations like those with obesity and diabetes are at higher risk for acquiring severe COVID-19 disease and have a higher risk of COVID-19 associated mortality. In the absence of an effective and safe vaccine, the only immediate promising approach is to repurpose an existing approved drug. Several drugs have been proposed and tested as adjunctive therapy for COVID-19. Among these drugs are the glucagon-like peptide-1 (GLP-1) 2 agonists and the dipeptidylpeptidase-4 (DPP-4) inhibitors. Beyond their glucose-lowering effects, these drugs have several pleiotropic protective properties, which include cardioprotective effects, anti-inflammatory and immunomodulatory activities, antifibrotic effects, antithrombotic effects, and vascular endothelial protective properties. This narrative review discusses these protective properties and addresses their scientific plausibility for their potential use as adjunctive therapy for COVID-19 disease.
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Affiliation(s)
- Aliah Alshanwani
- College of Medicine, Physiology Department, King Saud University, Riyadh, Saudi Arabia
| | - Tarek Kashour
- King Fahd Cardiac Centre, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Amira Badr
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Advances in Targeting ACE2 for Developing COVID-19 Therapeutics. Ann Biomed Eng 2022; 50:1734-1749. [PMID: 36261668 PMCID: PMC9581451 DOI: 10.1007/s10439-022-03094-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/29/2022] [Indexed: 01/01/2023]
Abstract
Since the onset of the coronavirus pandemic in December 2019, the SARS-CoV-2 virus has accounted for over 6.3 million lives resulting in the demand to develop novel therapeutic approaches to target and treat SARS-CoV-2. Improved understanding of viral entry and infection mechanisms has led to identifying different target receptors to mitigate infection in the host. Researchers have been working on identifying and targeting potential therapeutic target receptors utilizing different candidate drugs. Angiotensin-converting enzyme-2 (ACE2) has been known to perform critical functions in maintaining healthy cardiorespiratory function. However, ACE2 also functions as the binding site for the spike protein of SARS-CoV-2, allowing the virus to enter the cells and ensue infection. Therefore, drugs targeting ACE2 receptors can be considered as therapeutic candidates. Strategies targeting the level of ACE2 expression have been investigated and compared to other potential therapeutic targets, such as TMPRSS2, RdRp, and DPP4. This mini review discusses the key therapeutic approaches that target the ACE2 receptor, which is critical to the cellular entry and propagation of the novel SARS-CoV-2. In addition, we summarize the main advantages of ACE2 targeting against alternative approaches for the treatment of COVID-19.
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Pelle MC, Zaffina I, Provenzano M, Moirano G, Arturi F. COVID-19 and diabetes-Two giants colliding: From pathophysiology to management. Front Endocrinol (Lausanne) 2022; 13:974540. [PMID: 36060943 PMCID: PMC9437522 DOI: 10.3389/fendo.2022.974540] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/01/2022] [Indexed: 01/08/2023] Open
Abstract
Since December 2019, a new coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread around the world, causing the coronavirus 2019 (COVID-19) pandemic. From the beginning, SARS-CoV-2 has put a strain on the health system. In fact, many patients have had severe forms of the disease with the need for hospitalization due to respiratory failure. To contain the pandemic, the most widely used approach has been lockdowns. Social restrictions have been reduced thanks to the development of vaccines and targeted therapies. However, fatal events still occur among people at high risk of serious infection, such as patients with concomitant diabetes. Different mechanisms have been proposed to explain the poor prognosis of patients with diabetes and COVID-19, but the specific cause is unclear. It is now known that insulin resistance, inflammation, and cytokine storm are involved. Moreover, SARS-CoV-2 uses the angiotensin-converting enzyme 2 receptors to enter cells. This receptor is expressed on pancreatic beta cells and, during infection, it appears that receptor involvement may induce hyperglycemia in patients with or without diabetes. In this study, we discuss the mechanisms underlying the poor prognosis in people with COVID-19 and diabetes and what may improve the outcome in these patients.
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Affiliation(s)
- Maria Chiara Pelle
- Department of Medical and Surgical Sciences, University ‘Magna Graecia’ of Catanzaro, Catanzaro, Italy
| | - Isabella Zaffina
- Department of Medical and Surgical Sciences, University ‘Magna Graecia’ of Catanzaro, Catanzaro, Italy
| | - Michele Provenzano
- Nephrology, Dialysis and Transplantation Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES) Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Giovenale Moirano
- Department of Medical Sciences, University of Turin, CPO-Piemonte, Turin, Italy
| | - Franco Arturi
- Department of Medical and Surgical Sciences, University ‘Magna Graecia’ of Catanzaro, Catanzaro, Italy
- Research Center for the Prevention and Treatment of Metabolic Diseases (CR METDIS), University ‘Magna Graecia’ of Catanzaro, Catanzaro, Italy
- *Correspondence: Franco Arturi,
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Beranová L, Joachimiak MP, Kliegr T, Rabby G, Sklenák V. Why was this cited? Explainable machine learning applied to COVID-19 research literature. Scientometrics 2022; 127. [PMID: 35431364 PMCID: PMC8993675 DOI: 10.1007/s11192-022-04314-9 10.1007/s11192-022-04314-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Multiple studies have investigated bibliometric factors predictive of the citation count a research article will receive. In this article, we go beyond bibliometric data by using a range of machine learning techniques to find patterns predictive of citation count using both article content and available metadata. As the input collection, we use the CORD-19 corpus containing research articles-mostly from biology and medicine-applicable to the COVID-19 crisis. Our study employs a combination of state-of-the-art machine learning techniques for text understanding, including embeddings-based language model BERT, several systems for detection and semantic expansion of entities: ConceptNet, Pubtator and ScispaCy. To interpret the resulting models, we use several explanation algorithms: random forest feature importance, LIME, and Shapley values. We compare the performance and comprehensibility of models obtained by "black-box" machine learning algorithms (neural networks and random forests) with models built with rule learning (CORELS, CBA), which are intrinsically explainable. Multiple rules were discovered, which referred to biomedical entities of potential interest. Of the rules with the highest lift measure, several rules pointed to dipeptidyl peptidase4 (DPP4), a known MERS-CoV receptor and a critical determinant of camel to human transmission of the camel coronavirus (MERS-CoV). Some other interesting patterns related to the type of animal investigated were found. Articles referring to bats and camels tend to draw citations, while articles referring to most other animal species related to coronavirus are lowly cited. Bat coronavirus is the only other virus from a non-human species in the betaB clade along with the SARS-CoV and SARS-CoV-2 viruses. MERS-CoV is in a sister betaC clade, also close to human SARS coronaviruses. Thus both species linked to high citation counts harbor coronaviruses which are more phylogenetically similar to human SARS viruses. On the other hand, feline (FIPV, FCOV) and canine coronaviruses (CCOV) are in the alpha coronavirus clade and more distant from the betaB clade with human SARS viruses. Other results include detection of apparent citation bias favouring authors with western sounding names. Equal performance of TF-IDF weights and binary word incidence matrix was observed, with the latter resulting in better interpretability. The best predictive performance was obtained with a "black-box" method-neural network. The rule-based models led to most insights, especially when coupled with text representation using semantic entity detection methods. Follow-up work should focus on the analysis of citation patterns in the context of phylogenetic trees, as well on patterns referring to DPP4, which is currently considered as a SARS-Cov-2 therapeutic target.
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Affiliation(s)
- Lucie Beranová
- Department of Econometrics, Faculty of Informatics and Statistics, VSE Praha, W Churchill sq. 4, Prague, Czech Republic
| | - Marcin P. Joachimiak
- Environmental Genomics and Systems Biology Division at Lawrence Berkeley National Laboratory, Berkeley, USA
| | - Tomáš Kliegr
- Department of Information and Knowledge Engineering, VSE Praha, Prague, Czech Republic
| | - Gollam Rabby
- Department of Information and Knowledge Engineering, VSE Praha, Prague, Czech Republic
| | - Vilém Sklenák
- Centre of Information and Library Services, VSE Praha, Prague, Czech Republic ,Department of Information and Knowledge Engineering, VSE Praha, Prague, Czech Republic
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Jeevanandam J, Paramasivam E, Palanisamy A, Ragavendran S, Thangavel SN. Molecular Insights on Bioactive Compounds against Covid-19: A Network Pharmacological and Computational Study. Curr Comput Aided Drug Des 2022; 18:425-439. [PMID: 36111763 DOI: 10.2174/1573409918666220914092145] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/04/2022] [Accepted: 07/20/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Network pharmacology based identification of phytochemicals in the form of cocktails against off-targets can play a significant role in the inhibition of SARS_CoV2 viral entry and its propagation. This study includes network pharmacology, virtual screening, docking and molecular dynamics to investigate the distinct antiviral mechanisms of effective phytochemicals against SARS_CoV2. METHODS SARS_CoV2 human-protein interaction network was explored from the BioGRID database and analysed using Cytoscape. Further analysis was performed to explore biological function, proteinphytochemical/ drugs network and up-down regulation of pathological host target proteins. This led to understand the antiviral mechanism of phytochemicals against SARS_CoV2. The network was explored through g: Profiler, EnrichR, CTD, SwissTarget, STITCH, DrugBank, BindingDB, STRING and SuperPred. Virtual screening of phytochemicals against potential antiviral targets such as M-Pro, NSP1, Receptor binding domain, RNA binding domain, and ACE2 discloses the effective interaction between them. Further, the binding energy calculations through simulation of the docked complex explain the efficiency and stability of the interactions. RESULTS The network analysis identified quercetin, genistein, luteolin, eugenol, berberine, isorhamnetin and cinnamaldehyde to be interacting with host proteins ACE2, DPP4, COMT, TUBGCP3, CENPF, BRD2 and HMOX1 which are involved in antiviral mechanisms such as viral entry, viral replication, host immune response, and antioxidant activity, thus indicating that herbal cocktails can effectively tackle the viral hijacking of the crucial biological functions of a human host. Further exploration through virtual screening, docking and molecular dynamics recognizes the effective interaction of phytochemicals such as punicalagin, scutellarin, and solamargine with their respective potential targets. CONCLUSION This work illustrates a probable strategy for the identification of phytochemical-based cocktails and off-targets which are effective against SARS_CoV 2.
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Affiliation(s)
- Jayanth Jeevanandam
- Molecular Biophysics lab, School of Chemical and Biotechnology, SASTRA Deemed to- be University, Thanjavur-613401, Tamilnadu, India
| | - Esackimuthu Paramasivam
- Molecular Biophysics lab, School of Chemical and Biotechnology, SASTRA Deemed to- be University, Thanjavur-613401, Tamilnadu, India
| | | | - Srikanth Ragavendran
- TATA-Realty Data science lab, School of Humanity and Science, SASTRA Deemed to-be University, Thanjavur-613401, Tamilnadu, India
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Farheen S, Agrawal S, Zubair S, Agrawal A, Jamal F, Altaf I, Kashif Anwar A, Umair SM, Owais M. Patho-Physiology of Aging and Immune-Senescence: Possible Correlates With Comorbidity and Mortality in Middle-Aged and Old COVID-19 Patients. FRONTIERS IN AGING 2021; 2:748591. [PMID: 35822018 PMCID: PMC9261314 DOI: 10.3389/fragi.2021.748591] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 11/30/2021] [Indexed: 01/08/2023]
Abstract
During the last 2 years, the entire world has been severely devastated by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (COVID-19) as it resulted in several million deaths across the globe. While the virus infects people indiscriminately, the casualty risk is higher mainly in old, and middle-aged COVID-19 patients. The incidences of COVID-19 associated co-morbidity and mortality have a great deal of correlation with the weakened and malfunctioning immune systems of elderly people. Presumably, due to the physiological changes associated with aging and because of possible comorbidities such as diabetes, hypertension, obesity, cardiovascular, and lung diseases, which are more common in elderly people, may be considered as the reason making the elderly vulnerable to the infection on one hand, and COVID-19 associated complications on the other. The accretion of senescent immune cells not only contributes to the deterioration of host defense, but also results in elevated inflammatory phenotype persuaded immune dysfunction. In the present review, we envisage to correlate functioning of the immune defense of older COVID-19 patients with secondary/super infection, increased susceptibility or aggravation against already existing cancer, infectious, autoimmune, and other chronic inflammatory diseases. Moreover, we have discussed how age-linked modulations in the immune system affect therapeutic response against administered drugs as well as immunological response to various prophylactic measures including vaccination in the elderly host. The present review also provides an insight into the intricate pathophysiology of the aging and the overall immune response of the host to SARS-CoV-2 infection. A better understanding of age-related immune dysfunction is likely to help us in the development of targeted preemptive strategies for deadly COVID-19 in elderly patients.
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Affiliation(s)
- Saba Farheen
- Interdisciplinary Biotechnology Unit, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
| | - Sudhanshu Agrawal
- Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA, United States
| | - Swaleha Zubair
- Department of Computer Science, Aligarh Muslim University, Aligarh, India
| | - Anshu Agrawal
- Division of Basic and Clinical Immunology, Department of Medicine, University of California, Irvine, Irvine, CA, United States
| | - Fauzia Jamal
- Interdisciplinary Biotechnology Unit, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
| | - Ishrat Altaf
- Interdisciplinary Biotechnology Unit, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
| | - Abu Kashif Anwar
- Department of Anatomy, HSZH Gov, Unani Medical College, Bhopal, India
| | | | - Mohammad Owais
- Interdisciplinary Biotechnology Unit, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, India
- *Correspondence: Mohammad Owais,
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Sharifi Y, Payab M, Mohammadi-Vajari E, Aghili SMM, Sharifi F, Mehrdad N, Kashani E, Shadman Z, Larijani B, Ebrahimpur M. Association between cardiometabolic risk factors and COVID-19 susceptibility, severity and mortality: a review. J Diabetes Metab Disord 2021; 20:1743-1765. [PMID: 34222055 PMCID: PMC8233632 DOI: 10.1007/s40200-021-00822-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/23/2021] [Indexed: 02/08/2023]
Abstract
The novel coronavirus, which began spreading from China Wuhan and gradually spreaded to most countries, led to the announcement by the World Health Organization on March 11, 2020, as a new pandemic. The most important point presented by the World Health Organization about this disease is to better understand the risk factors that exacerbate the course of the disease and worsen its prognosis. Due to the high majority of cardio metabolic risk factors like obesity, hypertension, diabetes, and dyslipidemia among the population over 60 years old and higher, these cardio metabolic risk factors along with the age of these people could worsen the prognosis of the coronavirus disease of 2019 (COVID-19) and its mortality. In this study, we aimed to review the articles from the beginning of the pandemic on the impression of cardio metabolic risk factors on COVID-19 and the effectiveness of COVID-19 on how to manage these diseases. All the factors studied in this article, including hypertension, diabetes mellitus, dyslipidemia, and obesity exacerbate the course of Covid-19 disease by different mechanisms, and the inflammatory process caused by coronavirus can also create a vicious cycle in controlling these diseases for patients.
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Affiliation(s)
- Yasaman Sharifi
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Yaas Diabetes and Metabolic Diseases Research Center, Indiana University School of Medicine, Indianapolis, IN 46202 US
| | - Moloud Payab
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Erfan Mohammadi-Vajari
- Student of Medicine, School of Medicine, Gilan University of Medical Sciences, Rasht, Iran
| | - Seyed Morsal Mosallami Aghili
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farshad Sharifi
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Mehrdad
- Diabetes Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Nursing Care Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Elham Kashani
- Department of Obstetrics and Gynecology, Golestan University of Medical Sciences, Golestan, Iran
| | - Zhaleh Shadman
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahbube Ebrahimpur
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Zhang J, Liu L. Anagliptin alleviates lipopolysaccharide-induced inflammation, apoptosis and endothelial dysfunction of lung microvascular endothelial cells. Exp Ther Med 2021; 22:1472. [PMID: 34737812 PMCID: PMC8561766 DOI: 10.3892/etm.2021.10907] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 09/07/2021] [Indexed: 12/17/2022] Open
Abstract
It has been reported that dipeptidyl peptidase-4 (DPP4) inhibition protects against acute lung injury (ALI). Anagliptin is a novel selective inhibitor of DPP4 but its role in ALI has not been studied. The present study aimed to investigate the effects of anagliptin on lipopolysaccharide (LPS)-induced human pulmonary microvascular endothelial cell (HPMVEC) injury, as well as its underlying mechanism. HPMVECs were exposed to LPS in the presence or absence of anagliptin co-treatment. MTT assay was used to evaluate cell viability and nitric oxide (NO) production was detected using a commercial kit. DPP4 and pro-inflammatory cytokine expression levels, apoptosis and migration were assessed via reverse transcription-quantitative PCR, western blotting, TUNEL staining and wound healing assay, respectively. Western blot analysis was performed to assess expression levels of proteins involved in NF-κB signaling, cell apoptosis and migration, as well as high mobility group box 1 (HMGB1)/receptor for advanced glycation end products (RAGE). LPS decreased cell viability and NO production, but elevated expression of DPP4 in HPMVECs. LPS promoted pro-inflammatory cytokine expression, NF-κB activation and cell apoptosis, but inhibited cell migration and phosphorylated-AKT/endothelial NO synthase expression. Anagliptin co-treatment significantly restored all of these effects. Mechanistically, the upregulation of HMGB1/RAGE expression induced by LPS was markedly blocked by anagliptin. In conclusion, anagliptin alleviated inflammation, apoptosis and endothelial dysfunction in LPS-induced HPMVECs via modulating HMGB1/RAGE expression. These data provide a basis for use of anagliptin in ALI treatment.
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Affiliation(s)
- Jingli Zhang
- Department of Pharmacy, Taihe County People's Hospital, Fuyang, Anhui 236600, P.R. China
| | - Lixia Liu
- Department of Respiration, No. 984 Hospital, Joint Logistics Support Force of Chinese People's Liberation Army, Beijing 100094, P.R. China
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Katsiki N, Gómez‐Huelgas R, Mikhailidis DP, Pérez‐Martínez P. Narrative review on clinical considerations for patients with diabetes and COVID-19: More questions than answers. Int J Clin Pract 2021; 75:e14833. [PMID: 34510676 PMCID: PMC8646329 DOI: 10.1111/ijcp.14833] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 09/09/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND-AIM Diabetes, obesity and hypertension are common comorbidities associated with increased severity and mortality rates from Corona Virus Disease (COVID)-19. METHODS In this narrative review (using the PubMed database), we discuss epidemiological data and pathophysiological links between diabetes and COVID-19. The potential effects of glycaemic control and antidiabetic drugs on the prevalence and outcomes of COVID-19 are also reviewed, as well as the role of telemedicine and diabetes self-management in the post-COVID-19 era. RESULTS Diabetes has been linked to COVID-19 morbidity and mortality, although further research is needed to elucidate this association. In the meantime, physicians should be aware of the potential rise in the prevalence of diabetes (due to unhealthy lifestyle changes during the pandemic), its severity and complications and focus on achieving optimal diabetes prevention and management. Telemedicine and diabetes self-management may help towards this direction. Dipeptidyl-peptidase 4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose transporter 2 (SGLT2) inhibitors may affect viral entry and infection, and thus COVID-19 outcomes, as shown in observational studies. CONCLUSION Diabetes has been associated with COVID-19 development and progression. Certain antidiabetic drugs may influence COVID-19 prevention and management. The results of ongoing randomized clinical trials will shed more light on this field.
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Affiliation(s)
- Niki Katsiki
- First Department of Internal MedicineDiabetes CenterDivision of Endocrinology and MetabolismAHEPA University HospitalThessalonikiGreece
| | - Ricardo Gómez‐Huelgas
- Internal Medicine DepartmentRegional University Hospital of MálagaInstituto de Investigación Biomédica de Málaga (IBIMA)Universidad de MalagaMalagaSpain
- CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN)Instituto de Salud Carlos IIIMadridSpain
| | - Dimitri P. Mikhailidis
- Department of Clinical BiochemistryRoyal Free Hospital CampusUniversity College London Medical SchoolUniversity College London (UCL)LondonUK
| | - Pablo Pérez‐Martínez
- CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN)Instituto de Salud Carlos IIIMadridSpain
- Lipids and Atherosclerosis UnitDepartment of MedicineIMIBIC/Hospital Universitario Reina Sofía/Universidad de CordobaCordobaSpain
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Investigating diseases and chemicals in COVID-19 literature with text mining. INTERNATIONAL JOURNAL OF INFORMATION MANAGEMENT DATA INSIGHTS 2021. [PMCID: PMC8126089 DOI: 10.1016/j.jjimei.2021.100016] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Given the rapidly unfolding nature of the COVID-19 pandemic, there is an urgent need to streamline the literature synthesis of the growing scientific research to elucidate targeted solutions. Traditional systematic literature review studies have restrictions, including analyzing a limited number of papers, having various biases, being time-consuming and labor-intensive, focusing on a few topics, and lack of data-driven tools. This research has collected 9298 papers representing COVID-19 research published through May 5, 2020. We used frequency analysis to find highly frequent manifestations and therapeutic chemicals, representing the importance of the two biomedical concepts. This study also applied topic modeling that provided 25 categories showing associations between the two overarching categories. This study is beneficial to researchers for obtaining a macro-level picture of literature, to educators for knowing the scope of literature, and to policymakers and funding agencies for creating scientific strategic plans regarding COVID-19.
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Luk AOY, Yip TCF, Zhang X, Kong APS, Wong VWS, Ma RCW, Wong GLH. Glucose-lowering drugs and outcome from COVID-19 among patients with type 2 diabetes mellitus: a population-wide analysis in Hong Kong. BMJ Open 2021; 11:e052310. [PMID: 34670765 PMCID: PMC8529616 DOI: 10.1136/bmjopen-2021-052310] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES To investigate the association between baseline use of glucose-lowering drugs and serious clinical outcome among patients with type 2 diabetes. DESIGN Territory-wide retrospective cohort of confirmed cases of COVID-19 between January 2020 and February 2021. SETTING All public health facilities in Hong Kong. PARTICIPANTS 1220 patients with diabetes who were admitted for confirmed COVID-19. PRIMARY AND SECONDARY OUTCOME MEASURES Composite clinical endpoint of intensive care unit admission, requirement of invasive mechanical ventilation and/or in-hospital death. RESULTS In this cohort (median age 65.3 years, 54.3% men), 737 (60.4%) patients were treated with metformin, 385 (31.6%) with sulphonylureas, 199 (16.3%) with dipeptidyl peptidase-4 (DPP-4) inhibitors and 273 (22.4%) with insulin prior to admission. In multivariate Cox regression, use of metformin and DPP-4 inhibitors was associated with reduced incidence of the composite endpoint relative to non-use, with respective HRs of 0.51 (95% CI 0.34 to 0.77, p=0.001) and 0.46 (95% CI 0.29 to 0.71, p<0.001), adjusted for age, sex, diabetes duration, glycated haemoglobin (HbA1c), smoking, comorbidities and drugs. Use of sulphonylureas (HR 1.55, 95% CI 1.07 to 2.24, p=0.022) and insulin (HR 6.34, 95% CI 3.72 to 10.78, p<0.001) were both associated with increased hazards of the composite endpoint. CONCLUSIONS Users of metformin and DPP-4 inhibitors had fewer adverse outcomes from COVID-19 compared with non-users, whereas insulin and sulphonylurea might predict a worse prognosis.
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Affiliation(s)
- Andrea On Yan Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong Faculty of Medicine, Hong Kong Special Administrative Region, People's Republic of China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
| | - Terry C F Yip
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong Faculty of Medicine, Hong Kong Special Administrative Region, People's Republic of China
| | - Xinge Zhang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong Faculty of Medicine, Hong Kong Special Administrative Region, People's Republic of China
| | - Alice Pik Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong Faculty of Medicine, Hong Kong Special Administrative Region, People's Republic of China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong Faculty of Medicine, Hong Kong Special Administrative Region, People's Republic of China
| | - Ronald Ching Wan Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong Faculty of Medicine, Hong Kong Special Administrative Region, People's Republic of China
- Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong Faculty of Medicine, Hong Kong Special Administrative Region, People's Republic of China
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SARS-CoV-2 and diabetes: A potential therapeutic effect of dipeptidyl peptidase 4 inhibitors in diabetic patients diagnosed with COVID-19. Metabol Open 2021; 12:100134. [PMID: 34661092 PMCID: PMC8511553 DOI: 10.1016/j.metop.2021.100134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 10/10/2021] [Indexed: 01/08/2023] Open
Abstract
COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 and has become an urgent economic and health challenge. Dipeptidyl peptidase 4 (DPP4), also mentioned as a cluster of differentiation 26 (CD26) is a serine exopeptidase found in two arrangements: a soluble form (sDPP-4) and a plasma membrane-bound form. Because other coronaviruses enter the cells by binding to DPP-4, it has been speculated that DPP-4 inhibitors may exert activity against COVID-19. Therefore, this review aimed to summarize the potential therapeutic effect of dipeptidyl peptidase 4 inhibitors in diabetic patients diagnosed with COVID-19. To include different studies, publications related to Dipeptidyl peptidase-4 inhibitor use and clinical outcomes from COVID-19 were searched from the databases such as Web of Science, PubMed, Medline, Elsevier, Google Scholar, and SCOPUS, via English key terms. A direct engrossment of DPP4 in COVID-19 needs to be elucidated, there is also evidence confirming that DPP4 inhibitors exert anti-fibrotic and modulate inflammation activity. Thus, the use of DPP-4 inhibitors could reduce mortality due to COVID-19 or improve the progression of COVID-19; this evidence may support the management of diabetic patients diagnosed with COVID-19; however more well-designed investigation is urgently required.
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Elibol A, Eren D, Erdoğan MD, Elmaağaç M, Dizdar OS, Çelik İ, Günal Aİ. Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus. Prim Care Diabetes 2021; 15:806-812. [PMID: 34376379 PMCID: PMC8332925 DOI: 10.1016/j.pcd.2021.08.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/24/2021] [Accepted: 08/01/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Diabetes mellitus (DM) increases mortality and morbidity in patients with coronavirus disease (COVID-19). In this study, it was aimed to assess factors influencing on COVID-19 pneumonia in hospitalized patients with diabetes and association with oral anti-diabetic drugs. MATERIALS AND METHODS This cross-sectional study included 432 patients with type 2 diabetes mellitus diagnosed with COVID-19. Data regarding clinical characteristics, demographic characteristics, intensive care unit (ICU) rate in patients admitted to ICU, laboratory results on day 1 and 7, thoracic computed tomography (CT) findings and oral anti-diabetic drugs used were extracted from medical records. In all patients, 75-days mortality was recorded. Data were assessed independently. RESULTS There was pneumonia in 386 (89.4%) of 432 patients with diabetes. The risk for pneumonia was markedly higher in patients on DPP-4 inhibitors; however, there was no significant among other oral anti-diabetic groups and subgroups. In addition, elevated CRP was linked to the increased risk for pneumonia. Only patients in the pneumonia group had SGLT-2 inhibitor use. During follow-up, 91 patients died. In Cox regression analysis, low Glasgow Coma Scale score, and increased lactate dehydrogenase levels were identified as significant independent risk factors for mortality. CONCLUSION The study indicated that DPP-4 inhibitor used and elevated CRP level were associated with pneumonia development. Only patients in the pneumonia group had SGLT-2 inhibitor use. No oral anti-diabetics was found to be associated with COVID-19 related death.
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Affiliation(s)
- Ayça Elibol
- University of Health Sciences Kayseri City Training and Research Hospital, Department of Internal Medicine, Kayseri, Turkey
| | - Didem Eren
- University of Health Sciences Kayseri City Training and Research Hospital, Department of Internal Medicine, Kayseri, Turkey
| | - Macide Deniz Erdoğan
- University of Health Sciences Kayseri City Training and Research Hospital, Department of Internal Medicine, Kayseri, Turkey
| | - Merve Elmaağaç
- University of Health Sciences Kayseri City Training and Research Hospital, Department of Internal Medicine, Kayseri, Turkey
| | - Oguzhan Sıtkı Dizdar
- University of Health Sciences Kayseri City Training and Research Hospital, Department of Internal Medicine, Kayseri, Turkey.
| | - İlhami Çelik
- University of Health Sciences Kayseri City Training and Research Hospital, Department of Infectious Diseases and Clinical Microbiology, Kayseri, Turkey
| | - Ali İhsan Günal
- University of Health Sciences Kayseri City Training and Research Hospital, Department of Nephrology, Kayseri, Turkey
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Al-Kuraishy HM, Al-Gareeb AI, Qusty N, Alexiou A, Batiha GES. Impact of Sitagliptin in Non-Diabetic Covid-19 Patients. Curr Mol Pharmacol 2021; 15:683-692. [PMID: 34477540 DOI: 10.2174/1874467214666210902115650] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 04/09/2021] [Accepted: 06/14/2021] [Indexed: 12/15/2022]
Abstract
OBJECTIVE In Coronavirus disease 2019 (Covid-19), SARS-CoV-2 may use dipeptidyl peptidase 4 (DPP4) as an entry-point in different tissues expressing these receptors. DPP4 inhibitors (DPP4Is), also named gliptins like sitagliptin, have anti-inflammatory and antioxidant effects; thereby lessen inflammatory and oxidative stress in diabetic Covid-19 patients. Therefore, the present study aimed to illustrate the potential beneficial effect of sitagliptin in managing Covid-19 in non-diabetic patients. METHODS A total number of 89 patients with Covid-19 were recruited from a single-center at the time of diagnosis. The recruited patients were assigned according to the standard therapy for Covid-19 and our interventional therapy into two groups; Group A: Covid-19 patients on the standard therapy (n=40) and Group B: Covid-19 patients on the standard therapy plus sitagliptin (n=49). The duration of this interventional study was 28 days according to the guideline in management patients with Covid-19. Routine laboratory investigations, serological tests, complete blood count (CBC), C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH), and serum ferritin were measured to observed Covid-19 severity and complications. Lung computed tomography (CT) and clinical scores were evaluated. RESULTS The present study illustrated that sitagliptin add-on standard therapy improved clinical outcomes, radiological scores, and inflammatory biomarkers than standard therapy alone in non-diabetic patients with Covid-19 (P<0.01). CONCLUSIONS Sitagliptin add-on standard therapy in managing non-diabetic Covid-19 patients may have a robust beneficial effect by modulating inflammatory cytokines with subsequent good clinical outcomes.
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Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad. Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad. Iraq
| | - Naeem Qusty
- Medical Laboratories Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Mecca. Saudi Arabia
| | | | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, AlBeheira, Egypt
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Sun ZG, Yu FL, Qiu XT, Li S, Li XT, Zhu HL. The Promising Enzymes for Inhibitors Development against COVID-19. Mini Rev Med Chem 2021; 22:449-456. [PMID: 34353251 DOI: 10.2174/1389557521666210805104250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/11/2021] [Accepted: 04/12/2021] [Indexed: 01/18/2023]
Abstract
Since the outbreak of COVID-19, it has been an epidemic for nearly a year. COVID-19 has brought painful disasters to people all over the world. It not only threatens lives and health, but also induces economic crises. At present, promising methods to eradicate COVID-19 mainly include drugs and vaccines. Enzyme inhibitors have always been a reliable strategy for the treatment of related diseases. Scientists worldwide have worked together to study COVID-19, have obtained the structure of key SARS-CoV-2 associated enzymes, and reported the research of inhibitors of these enzymes. This article summarizes COVID-19-related enzyme inhibitors' recent development, mainly including 3CLpro, PLpro, TMPRSS2, and RdRp inhibitors, hoping to provide valuable weapons in the ensuing battle against COVID-19.
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Affiliation(s)
- Zhi-Gang Sun
- Central Laboratory, Linyi Central Hospital, No.17 Jiankang Road, Linyi 276400. China
| | - Feng-Ling Yu
- Pharmacy Department, Linyi Central Hospital, No.17 Jiankang Road, Linyi 276400. China
| | - Xiang-Ting Qiu
- Clinical Laboratory, Linyi Central Hospital, No.17 Jiankang Road, Linyi 276400. China
| | - Shuang Li
- Pharmacy Department, Linyi Central Hospital, No.17 Jiankang Road, Linyi 276400. China
| | - Xue-Tang Li
- Pharmacy Department, Linyi Central Hospital, No.17 Jiankang Road, Linyi 276400. China
| | - Hai-Liang Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, No.163 Xianlin Road, Nanjing 210023. China
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Boutin S, Hildebrand D, Boulant S, Kreuter M, Rüter J, Pallerla SR, Velavan TP, Nurjadi D. Host factors facilitating SARS-CoV-2 virus infection and replication in the lungs. Cell Mol Life Sci 2021; 78:5953-5976. [PMID: 34223911 PMCID: PMC8256233 DOI: 10.1007/s00018-021-03889-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 06/01/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023]
Abstract
SARS-CoV-2 is the virus causing the major pandemic facing the world today. Although, SARS-CoV-2 primarily causes lung infection, a variety of symptoms have proven a systemic impact on the body. SARS-CoV-2 has spread in the community quickly infecting humans from all age, ethnicities and gender. However, fatal outcomes have been linked to specific host factors and co-morbidities such as age, hypertension, immuno-deficiencies, chronic lung diseases or metabolic disorders. A major shift in the microbiome of patients suffering of the coronavirus disease 2019 (COVID-19) have also been observed and is linked to a worst outcome of the disease. As many co-morbidities are already known to be associated with a dysbiosis of the microbiome such as hypertension, diabetes and metabolic disorders. Host factors and microbiome changes are believed to be involved as a network in the acquisition of the infection and the development of the diseases. We will review in detail in this manuscript, the immune response toward SARS-CoV-2 infection as well as the host factors involved in the facilitation and worsening of the infection. We will also address the impact of COVID-19 on the host's microbiome and secondary infection which also worsen the disease.
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Affiliation(s)
- Sébastien Boutin
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany.
- Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
| | - Dagmar Hildebrand
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany
| | - Steeve Boulant
- Division of Cellular Polarity and Viral Infection, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Infectious Diseases, Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Michael Kreuter
- Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
- Center for Interstitial and Rare Lung Diseases, Pneumology, Thoraxklinik, University of Heidelberg, Heidelberg, Germany
| | - Jule Rüter
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Tübingen, Germany
| | | | - Thirumalaisamy P Velavan
- Institute of Tropical Medicine, Universitätsklinikum Tübingen, Tübingen, Germany
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam
| | - Dennis Nurjadi
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany
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Okai CA, Wölter M, Russ M, Koy C, Petre BA, Rath W, Pecks U, Glocker MO. Profiling of intact blood proteins by matrix-assisted laser desorption/ionization mass spectrometry without the need for freezing - Dried serum spots as future clinical tools for patient screening. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2021; 35:e9121. [PMID: 33955049 DOI: 10.1002/rcm.9121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/30/2021] [Accepted: 05/02/2021] [Indexed: 06/12/2023]
Abstract
RATIONALE To open up new ways for matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)-based patient screening, blood serum is the most preferred specimen because of its richness in patho-physiological information and due to ease of collection. To overcome deleterious freeze/thaw cycles and to reduce high costs for shipping and storage, we sought to develop a procedure which enables MALDI-MS protein profiling of blood serum proteins without the need for serum freezing. METHODS Blood sera from patients/donors were divided into portions which after pre-incubation were fast frozen. Thawed aliquots were deposited on filter paper discs and air-dried at room temperature. Intact serum proteins were eluted with acid-labile detergent-containing solutions and were desalted by employing a reversed-phase bead system. Purified protein solutions were screened by MALDI-MS using standardized instrument settings. RESULTS MALDI mass spectra from protein solutions which were eluted from filter paper discs and desalted showed on average 25 strong ion signals (mass range m/z 6000 to 10,000) from intact serum proteins (apolipoproteins, complement proteins, transthyretin and hemoglobin) and from proteolytic processing products. Semi-quantitative analysis of three ion pairs: m/z 6433 and 6631, m/z 8205 and 8916, as well as m/z 9275 and 9422, indicated that the mass spectra from either pre-incubated fast-frozen serum or pre-incubated dried serum spot eluted serum contained the same information on protein composition. CONCLUSIONS A workflow that avoids the conventional cold-chain and yet enables the investigation of intact serum proteins and/or serum proteolysis products by MALDI-MS profiling was developed. The presented protocol tremendously broadens the clinical application of MALDI-MS and simultaneously allows a reduction in the costs for storage and shipping of serum samples. This will pave the way for clinical screening of patients also in areas with limited access to health care systems, and/or specialized laboratories.
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Affiliation(s)
- Charles A Okai
- Proteome Center Rostock, Medical Faculty and Natural Science Faculty, University of Rostock, Schillingallee 69, Rostock, 18057, Germany
| | - Manja Wölter
- Proteome Center Rostock, Medical Faculty and Natural Science Faculty, University of Rostock, Schillingallee 69, Rostock, 18057, Germany
- Department of Obstetrics and Gynecology, Medical Faculty, University of Rostock, Clinic Südstadt, Rostock, 18059, Germany
| | - Manuela Russ
- Proteome Center Rostock, Medical Faculty and Natural Science Faculty, University of Rostock, Schillingallee 69, Rostock, 18057, Germany
| | - Cornelia Koy
- Proteome Center Rostock, Medical Faculty and Natural Science Faculty, University of Rostock, Schillingallee 69, Rostock, 18057, Germany
| | - Brindusa A Petre
- Department of Chemistry, Alexandru Ioan Cuza University, Bd. Carol I, No.11, Iasi, 700506, Romania
- Transcend Research Center, Regional Institute of Oncology, General Henri Mathias, No.2-4, Iasi, 700483, Romania
| | - Werner Rath
- Department of Obstetrics and Gynecology, Medical Faculty, RWTH Aachen University, Aachen, 52062, Germany
| | - Ulrich Pecks
- Department of Obstetrics and Gynecology, Medical Faculty, University of Schleswig-Holstein, Campus Kiel, Arnold-Heller-Straße 3, Kiel, 24105, Germany
| | - Michael O Glocker
- Proteome Center Rostock, Medical Faculty and Natural Science Faculty, University of Rostock, Schillingallee 69, Rostock, 18057, Germany
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Ramos-Rincón JM, Pérez-Belmonte LM, Carrasco-Sánchez FJ, Jansen-Chaparro S, De-Sousa-Baena M, Bueno-Fonseca J, Pérez-Aguilar M, Arévalo-Cañas C, Bacete Cebrian M, Méndez-Bailón M, Fiteni Mera I, González García A, Navarro Romero F, Tuñón de Almeida C, Muñiz Nicolás G, González Noya A, Hernández Milian A, García García GM, Alcalá Pedrajas JN, Herrero García V, Corral-Gudino L, Comas Casanova P, Meijide Míguez H, Casas-Rojo JM, Gómez-Huelgas R. Cardiometabolic Therapy and Mortality in Very Old Patients With Diabetes Hospitalized due to COVID-19. J Gerontol A Biol Sci Med Sci 2021; 76:e102-e109. [PMID: 33945610 PMCID: PMC8135901 DOI: 10.1093/gerona/glab124] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Indexed: 12/19/2022] Open
Abstract
Background The effects of cardiometabolic drugs on the prognosis of diabetic patients with COVID-19, especially very old patients, are not well-known. This work aims to analyze the association between preadmission cardiometabolic therapy (antidiabetic, antiaggregant, antihypertensive, and lipid-lowering drugs) and in-hospital mortality among patients ≥80 years with type 2 diabetes mellitus hospitalized for COVID-19. Methods We conducted a nationwide, multicenter, observational study in patients ≥80 years with type 2 diabetes mellitus hospitalized for COVID-19 between March 1 and May 29, 2020. The primary outcome measure was in-hospital mortality. A multivariate logistic regression analysis were performed to assess the association between preadmission cardiometabolic therapy and in-hospital mortality. Results Of the 2,763 patients ≥80 years old hospitalized due to COVID-19, 790 (28.6%) had T2DM. Of these patients, 385 (48.7%) died during admission. On the multivariate analysis, the use of dipeptidyl peptidase-4 inhibitors (AOR 0.502, 95%CI 0.309-0.815, p=0.005) and angiotensin receptor blockers (AOR 0.454, 95%CI 0.274-0.759, p=0.003) were independent protectors against in-hospital mortality whereas the use of acetylsalicylic acid was associated with higher in-hospital mortality (AOR 1.761, 95%CI 1.092-2.842, p=0.020). Other antidiabetic drugs, angiotensin-converting enzyme inhibitors and statins showed neutral association with in-hospital mortality. Conclusions We found important differences between cardiometabolic drugs and in-hospital mortality in older patients with type 2 diabetes mellitus hospitalized for COVID-19. Preadmission treatment with dipeptidyl peptidase-4 inhibitors and angiotensin receptor blockers could reduce in-hospital mortality; other antidiabetic drugs, angiotensin-converting enzyme inhibitors and statins seem to have a neutral effect; and acetylsalicylic acid could be associated with excess mortality.
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Affiliation(s)
| | - Luis M Pérez-Belmonte
- Internal Medicine Department, Regional University Hospital of Málaga, Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), Spain
| | | | - Sergio Jansen-Chaparro
- Internal Medicine Department, Regional University Hospital of Málaga, Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), Spain
| | | | - José Bueno-Fonseca
- Internal Medicine Department, Regional University Hospital of Málaga, Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), Spain
| | - Maria Pérez-Aguilar
- Internal Medicine Department, Juan Ramón Jiménez University Hospital, Huelva, Spain
| | - Coral Arévalo-Cañas
- Internal Medicine Department, 12 de Octubre University Hospital, Madrid, Spain
| | - Marta Bacete Cebrian
- Internal Medicine Department, Gregorio Marañon University Hospital, Madrid, Spain
| | - Manuel Méndez-Bailón
- Internal Medicine Department, San Carlos Clinical Hospital, Complutense University, Madrid, Spain
| | | | | | | | | | | | | | | | | | | | | | - Luis Corral-Gudino
- Internal Medicine Department, Río Hortega University Hospital, Regional Health Management of Castilla y Leon (SACYL), Valladolid University, Spain
| | | | | | | | - Ricardo Gómez-Huelgas
- Internal Medicine Department, Regional University Hospital of Málaga, Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), Spain
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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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Pinheiro MM, Fabbri A, Infante M. Cytokine storm modulation in COVID-19: a proposed role for vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i). Immunotherapy 2021; 13:753-765. [PMID: 33906375 PMCID: PMC8080872 DOI: 10.2217/imt-2020-0349] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 04/13/2021] [Indexed: 02/08/2023] Open
Abstract
A dysregulated immune response characterized by the hyperproduction of several pro-inflammatory cytokines (a.k.a. 'cytokine storm') plays a central role in the pathophysiology of severe coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this Perspective article we discuss the evidence for synergistic anti-inflammatory and immunomodulatory properties exerted by vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors, the latter being a class of antihyperglycemic agents used for the treatment of Type 2 diabetes, which have also been reported as immunomodulators. Then, we provide the rationale for investigation of vitamin D and DPP-4 inhibitor combination therapy (VIDPP-4i) as an immunomodulation strategy to ratchet down the virulence of SARS-CoV-2, prevent disease progression and modulate the cytokine storm in COVID-19.
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Affiliation(s)
| | - Andrea Fabbri
- Department of Systems Medicine, Division of Endocrinology & Diabetes, Diabetes Research Institute Federation (DRIF), CTO Hospital, University of Rome Tor Vergata, Rome, Italy
| | - Marco Infante
- Department of Systems Medicine, Division of Endocrinology & Diabetes, Diabetes Research Institute Federation (DRIF), CTO Hospital, University of Rome Tor Vergata, Rome, Italy
- UniCamillus, Saint Camillus International University of Health Sciences, Section of Endocrinology, Diabetes and Metabolism, Rome, Italy
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Rome, Italy
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Abstract
COVID-19 pandemic, which caused by the newly emerged severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2), puts the entire world in an unprecedented crisis, leaving behind huge human losses and serious socio-economical damages. The clinical spectrum of COVID-19 varies from asymptomatic to multi-organ manifestations. Diabetes mellitus (DM) is a chronic inflammatory condition, which associated with metabolic and vascular abnormalities, increases the risk for SARS-CoV-2 infection, severity and mortality. Due to global prevalence, DM effect on COVID-19 outcomes as well as the potential mechanisms by which DM modulates the host-viral interactions and host-immune responses are discussed in this review. This review also highlights the effects of anti-diabetic drugs on treatment of SARS-CoV-2 infection and vice versa.
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Stasi A, Franzin R, Fiorentino M, Squiccimarro E, Castellano G, Gesualdo L. Multifaced Roles of HDL in Sepsis and SARS-CoV-2 Infection: Renal Implications. Int J Mol Sci 2021; 22:5980. [PMID: 34205975 PMCID: PMC8197836 DOI: 10.3390/ijms22115980] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 02/06/2023] Open
Abstract
High-density lipoproteins (HDLs) are a class of blood particles, principally involved in mediating reverse cholesterol transport from peripheral tissue to liver. Omics approaches have identified crucial mediators in the HDL proteomic and lipidomic profile, which are involved in distinct pleiotropic functions. Besides their role as cholesterol transporter, HDLs display anti-inflammatory, anti-apoptotic, anti-thrombotic, and anti-infection properties. Experimental and clinical studies have unveiled significant changes in both HDL serum amount and composition that lead to dysregulated host immune response and endothelial dysfunction in the course of sepsis. Most SARS-Coronavirus-2-infected patients admitted to the intensive care unit showed common features of sepsis disease, such as the overwhelmed systemic inflammatory response and the alterations in serum lipid profile. Despite relevant advances, episodes of mild to moderate acute kidney injury (AKI), occurring during systemic inflammatory diseases, are associated with long-term complications, and high risk of mortality. The multi-faceted relationship of kidney dysfunction with dyslipidemia and inflammation encourages to deepen the clarification of the mechanisms connecting these elements. This review analyzes the multifaced roles of HDL in inflammatory diseases, the renal involvement in lipid metabolism, and the novel potential HDL-based therapies.
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Affiliation(s)
- Alessandra Stasi
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
| | - Rossana Franzin
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
| | - Marco Fiorentino
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
| | - Enrico Squiccimarro
- Department of Emergency and Organ Transplant (DETO), University of Bari, 70124 Bari, Italy;
- Cardio-Thoracic Surgery Department, Heart & Vascular Centre, Maastricht University Medical Centre (MUMC), 6229HX Maastricht, The Netherlands
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Advanced Research Center on Kidney Aging (A.R.K.A.), Department of Medical and Surgical Science, University of Foggia, 71122 Foggia, Italy;
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (R.F.); (M.F.)
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