|
1
|
Horváth ÁI, Bölcskei K, Szentes N, Borbély É, Tékus V, Botz B, Rusznák K, Futácsi A, Czéh B, Mátyus P, Helyes Z. Novel multitarget analgesic candidate SZV-1287 demonstrates potential disease-modifying effects in the monoiodoacetate-induced osteoarthritis mouse model. Front Pharmacol 2024; 15:1377081. [PMID: 39351091 PMCID: PMC11439770 DOI: 10.3389/fphar.2024.1377081] [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: 01/26/2024] [Accepted: 08/21/2024] [Indexed: 10/04/2024] Open
Abstract
Introduction Monoiodoacetate (MIA)-induced osteoarthritis (OA) is the most commonly used rodent model for testing anti-OA drug candidates. Herein, we investigated the effects of our patented multitarget drug candidate SZV-1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl) propanal oxime) that is currently under clinical development for neuropathic pain and characterized the mouse model through complex functional, in vivo imaging, and morphological techniques. Methods Knee OA was induced by intraarticular MIA injection (0.5 and 0.8 mg). Spontaneous pain was assessed based on weight distribution, referred pain by paw mechanonociception (esthesiometry), edema by caliper, neutrophil myeloperoxidase activity by luminescence, matrix metalloproteinase activity, vascular leakage and bone remodeling by fluorescence imaging, bone morphology by micro-CT, histopathological alterations by semiquantitative scoring, and glia activation by immunohistochemistry. Then, SZV-1287 (20 mg/kg/day) or its vehicle was injected intraperitoneally over a 21-day period. Results MIA induced remarkably decreased thresholds of weight bearing and paw withdrawal, alterations in the tibial and femoral structures (reactive sclerosis, increased trabeculation, and cortical erosions), histopathological damage (disorganized cartilage structure, hypocellularity, decreased matrix staining and tidemark integrity, and increased synovial hyperplasia and osteophyte formation), and changes in the astrocyte and microglia density in the lumbar spinal cord. There were no major differences between the two MIA doses in most outcome measures. SZV-1287 inhibited MIA-induced weight bearing reduction, hyperalgesia, edema, myeloperoxidase activity, histopathological damage, and astrocyte and microglia density. Conclusion SZV-1287 may have disease-modifying potential through analgesic, anti-inflammatory, and chondroprotective effects. The MIA mouse model is valuable for investigating OA-related mechanisms and testing compounds in mice at an optimal dose of 0.5 mg.
Collapse
Affiliation(s)
- Ádám István Horváth
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- National Laboratory for Drug Research and Development, Budapest, Hungary
| | - Kata Bölcskei
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
| | - Nikolett Szentes
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- National Laboratory for Drug Research and Development, Budapest, Hungary
- Hungarian Research Network, HUN-REN-PTE Chronic Pain Research Group, Pécs, Hungary
| | - Éva Borbély
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- National Laboratory for Drug Research and Development, Budapest, Hungary
| | - Valéria Tékus
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- Hungarian Research Network, HUN-REN-PTE Chronic Pain Research Group, Pécs, Hungary
- Department of Laboratory Diagnostics, Faculty of Health Sciences, University of Pécs, Pécs, Hungary
| | - Bálint Botz
- Department of Medical Imaging, Medical School, University of Pécs, Pécs, Hungary
| | - Kitti Rusznák
- Department of Laboratory Medicine, Medical School, University of Pécs, Pécs, Hungary
- Neurobiology of Stress Research Group, János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Anett Futácsi
- Department of Laboratory Medicine, Medical School, University of Pécs, Pécs, Hungary
- Neurobiology of Stress Research Group, János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Boldizsár Czéh
- Department of Laboratory Medicine, Medical School, University of Pécs, Pécs, Hungary
- Neurobiology of Stress Research Group, János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Péter Mátyus
- National Laboratory of Infectious Animal Diseases, Antimicrobial Resistance, Veterinary Public Health and Food Chain Safety, University of Veterinary Medicine, Budapest, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary
- National Laboratory for Drug Research and Development, Budapest, Hungary
- Hungarian Research Network, HUN-REN-PTE Chronic Pain Research Group, Pécs, Hungary
- PharmInVivo Ltd., Pécs, Hungary
- ALGONIST Biotechnologies GmBH, Vienna, Austria
| |
Collapse
|
|
2
|
Guerra-Ávila PL, Guzmán TJ, Vargas-Guerrero B, Domínguez-Rosales JA, Cervantes-Garduño AB, Salazar-Montes AM, Sánchez-Orozco LV, Gurrola-Díaz CM. Comparative Screening of the Liver Gene Expression Profiles from Type 1 and Type 2 Diabetes Rat Models. Int J Mol Sci 2024; 25:4151. [PMID: 38673735 PMCID: PMC11050131 DOI: 10.3390/ijms25084151] [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: 02/26/2024] [Revised: 04/04/2024] [Accepted: 04/06/2024] [Indexed: 04/28/2024] Open
Abstract
Experimental animal models of diabetes can be useful for identifying novel targets related to disease, for understanding its physiopathology, and for evaluating emerging antidiabetic treatments. This study aimed to characterize two rat diabetes models: HFD + STZ, a high-fat diet (60% fat) combined with streptozotocin administration (STZ, 35 mg/kg BW), and a model with a single STZ dose (65 mg/kg BW) in comparison with healthy rats. HFD + STZ- induced animals demonstrated a stable hyperglycemia range (350-450 mg/dL), whereas in the STZ-induced rats, we found glucose concentration values with a greater dispersion, ranging from 270 to 510 mg/dL. Moreover, in the HFD + STZ group, the AUC value of the insulin tolerance test (ITT) was found to be remarkably augmented by 6.2-fold higher than in healthy animals (33,687.0 ± 1705.7 mg/dL/min vs. 5469.0 ± 267.6, respectively), indicating insulin resistance (IR). In contrast, a more moderate AUC value was observed in the STZ group (19,059.0 ± 3037.4 mg/dL/min) resulting in a value 2.5-fold higher than the average exhibited by the control group. After microarray experiments on liver tissue from all animals, we analyzed genes exhibiting a fold change value in gene expression <-2 or >2 (p-value <0.05). We found 27,686 differentially expressed genes (DEG), identified the top 10 DEGs and detected 849 coding genes that exhibited opposite expression patterns between both diabetes models (491 upregulated genes in the STZ model and 358 upregulated genes in HFD + STZ animals). Finally, we performed an enrichment analysis of the 849 selected genes. Whereas in the STZ model we found cellular pathways related to lipid biosynthesis and metabolism, in the HFD + STZ model we identified pathways related to immunometabolism. Some phenotypic differences observed in the models could be explained by transcriptomic results; however, further studies are needed to corroborate these findings. Our data confirm that the STZ and the HFD + STZ models are reliable experimental models for human T1D and T2D, respectively. These results also provide insight into alterations in the expression of specific liver genes and could be utilized in future studies focusing on diabetes complications associated with impaired liver function.
Collapse
Affiliation(s)
- Paloma Lucía Guerra-Ávila
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| | - Tereso J. Guzmán
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
- Department of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstraße 48, 48149 Münster, Germany
| | - Belinda Vargas-Guerrero
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| | - José Alfredo Domínguez-Rosales
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| | - Alejandra Beatriz Cervantes-Garduño
- Laboratorio de Genómica Clínica, Facultad de Odontología, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México C.P. 04510, Mexico;
| | - Adriana María Salazar-Montes
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| | - Laura Verónica Sánchez-Orozco
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| | - Carmen Magdalena Gurrola-Díaz
- Instituto de Investigación en Enfermedades Crónico-Degenerativas, Instituto Transdisciplinar de Investigación e Innovación en Salud, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud (C.U.C.S.), Universidad de Guadalajara, Guadalajara, Sierra Mojada 950, Puerta peatonal 7, Col. Independencia, Guadalajara C.P. 44350, Mexico; (P.L.G.-Á.); (T.J.G.); (B.V.-G.); (J.A.D.-R.); (A.M.S.-M.); (L.V.S.-O.)
| |
Collapse
|
|
3
|
Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications. Cells 2022; 11:cells11213362. [PMID: 36359761 PMCID: PMC9655436 DOI: 10.3390/cells11213362] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/19/2022] [Accepted: 10/20/2022] [Indexed: 11/24/2022] Open
Abstract
Diabetic retinopathy (DR), with increasing incidence, is the major cause of vision loss and blindness worldwide in working-age adults. Diabetic macular edema (DME) remains the main cause of vision impairment in diabetic patients, with its pathogenesis still not completely elucidated. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of DR and DME. Currently, intravitreal injection of anti-VEGF agents remains as the first-line therapy in DME treatment due to the superior anatomic and functional outcomes. However, some patients do not respond satisfactorily to anti-VEGF injections. More than 30% patients still exist with persistent DME even after regular intravitreal injection for at least 4 injections within 24 weeks, suggesting other pathogenic factors, beyond VEGF, might contribute to the pathogenesis of DME. Recent advances showed nearly all the retinal cells are involved in DR and DME, including breakdown of blood-retinal barrier (BRB), drainage dysfunction of Müller glia and retinal pigment epithelium (RPE), involvement of inflammation, oxidative stress, and neurodegeneration, all complicating the pathogenesis of DME. The profound understanding of the changes in proteomics and metabolomics helps improve the elucidation of the pathogenesis of DR and DME and leads to the identification of novel targets, biomarkers and potential therapeutic strategies for DME treatment. The present review aimed to summarize the current understanding of DME, the involved molecular mechanisms, and the changes in proteomics and metabolomics, thus to propose the potential therapeutic recommendations for personalized treatment of DME.
Collapse
|
|
4
|
Carpéné C, Viana P, Iffiú-Soltesz Z, Tapolcsányi P, Földi AÁ, Mátyus P, Dunkel P. Effects of Chemical Structures Interacting with Amine Oxidases on Glucose, Lipid and Hydrogen Peroxide Handling by Human Adipocytes. Molecules 2022; 27:6224. [PMID: 36234761 PMCID: PMC9571511 DOI: 10.3390/molecules27196224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/07/2022] [Accepted: 09/19/2022] [Indexed: 11/26/2022] Open
Abstract
Benzylamine is a natural molecule present in food and edible plants, capable of activating hexose uptake and inhibiting lipolysis in human fat cells. These effects are dependent on its oxidation by amine oxidases present in adipocytes, and on the subsequent hydrogen peroxide production, known to exhibit insulin-like actions. Virtually, other substrates interacting with such hydrogen peroxide-releasing enzymes potentially can modulate lipid accumulation in adipose tissue. Inhibition of such enzymes has also been reported to influence lipid deposition. We have therefore studied in human adipocytes the lipolytic and lipogenic activities of pharmacological entities designed to interact with amine oxidases highly expressed in this cell type: the semicarbazide-sensitive amine oxidase (SSAO also known as PrAO or VAP-1) and the monoamine oxidases (MAO). The results showed that SZV-2016 and SZV-2017 behaved as better substrates than benzylamine, releasing hydrogen peroxide once oxidized, and reproduced or even exceeded its insulin-like metabolic effects in fat cells. Additionally, several novel SSAO inhibitors, such as SZV-2007 and SZV-1398, have been evidenced and shown to inhibit benzylamine metabolic actions. Taken as a whole, our findings reinforce the list of molecules that influence the regulation of triacylglycerol assembly/breakdown, at least in vitro in human adipocytes. The novel compounds deserve deeper investigation of their mechanisms of interaction with SSAO or MAO, and constitute potential candidates for therapeutic use in obesity and diabetes.
Collapse
Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR1297, 31432 Toulouse, France
- Team Dinamix, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, 31432 Toulouse, France
| | - Pénélope Viana
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR1297, 31432 Toulouse, France
- Team Dinamix, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, 31432 Toulouse, France
| | - Zsuzsa Iffiú-Soltesz
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR1297, 31432 Toulouse, France
| | - Pál Tapolcsányi
- Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hungary
| | - Anna Ágota Földi
- Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hungary
| | - Péter Mátyus
- Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hungary
- E-Group ICT SOFTWARE, H-1027 Budapest, Hungary
| | - Petra Dunkel
- Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hungary
| |
Collapse
|
|
5
|
Carpéné C, Stiliyanov Atanasov K, Les F, Mercader Barcelo J. Hyperglycemia and reduced adiposity of streptozotocin-induced diabetic mice are not alleviated by oral benzylamine supplementation. World J Diabetes 2022; 13:752-764. [PMID: 36188146 PMCID: PMC9521444 DOI: 10.4239/wjd.v13.i9.752] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/13/2022] [Accepted: 08/22/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Benzylamine (Bza) oral administration delays the onset of hyperglycemia in insulin-resistant db-/- mice; a genetic model of obesity and type 2 diabetes.
AIM To extend the antihyperglycemic properties of oral benzylamine to a model of insulin-deficient type 1 diabetes.
METHODS Male Swiss mice were rendered diabetic by streptozotocin treatment (STZ) and divided in two groups: one received 0.5% Bza as drinking solution for 24 d (STZ Bza-drinking) while the other was drinking water ad libitum. Similar groups were constituted in age-matched, nondiabetic mice. Food intake, liquid intake, body weight gain and nonfasting blood glucose levels were followed during treatment. At the end of treatment, fasted glycemia, liver and white adipose tissue (WAT) mass were measured, while glucose uptake assays were performed in adipocytes.
RESULTS STZ diabetic mice presented typical features of insulin-deficient diabetes: reduced body mass and increased blood glucose levels. These altered parameters were not normalized in the Bza-drinking group in spite of restored food and water intake. Bza consumption could not reverse the severe fat depot atrophy of STZ diabetic mice. In the nondiabetic mice, no difference was found between control and Bza-drinking mice for any parameter. In isolated adipocytes, hexose uptake was partially activated by 0.1 mmol/L Bza in a manner that was obliterated in vitro by the amine oxidase inhibitor phenelzine and that remained unchanged after Bza supplementation. Oxidation of 0.1 mmol/L Bza in WAT was lower in STZ diabetic than in normoglycemic mice.
CONCLUSION Bza supplementation could not normalize the altered glucose handling of STZ diabetic mice with severe WAT atrophy. Consequently, its antidiabetic potential in obese and diabetic rodents does not apply to lipoatrophic type 1 diabetic mice.
Collapse
Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR 1297, Toulouse 31432, France
| | - Kristiyan Stiliyanov Atanasov
- Molecular Biology and One Health research group, Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma 07122, Spain
| | - Francisco Les
- Department of Pharmacy, Faculty of Health Sciences, Universidad San Jorge, Villanueva de Gállego, Zaragoza 50830, Spain
| | - Josep Mercader Barcelo
- Molecular Biology and One Health research group, Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma 07122, Spain
| |
Collapse
|
|
6
|
Ren J, Zhang S, Pan Y, Jin M, Li J, Luo Y, Sun X, Li G. Diabetic retinopathy: Involved cells, biomarkers, and treatments. Front Pharmacol 2022; 13:953691. [PMID: 36016568 PMCID: PMC9396039 DOI: 10.3389/fphar.2022.953691] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetic retinopathy (DR), a leading cause of vision loss and blindness worldwide, is caused by retinal neurovascular unit dysfunction, and its cellular pathology involves at least nine kinds of retinal cells, including photoreceptors, horizontal and bipolar cells, amacrine cells, retinal ganglion cells, glial cells (Müller cells, astrocytes, and microglia), endothelial cells, pericytes, and retinal pigment epithelial cells. Its mechanism is complicated and involves loss of cells, inflammatory factor production, neovascularization, and BRB impairment. However, the mechanism has not been completely elucidated. Drug treatment for DR has been gradually advancing recently. Research on potential drug targets relies upon clear information on pathogenesis and effective biomarkers. Therefore, we reviewed the recent literature on the cellular pathology and the diagnostic and prognostic biomarkers of DR in terms of blood, protein, and clinical and preclinical drug therapy (including synthesized molecules and natural molecules). This review may provide a theoretical basis for further DR research.
Collapse
Affiliation(s)
- Jiahui Ren
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Jinghong, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Kunming, China
| | - Shuxia Zhang
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
| | - Yunfeng Pan
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
| | - Meiqi Jin
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
| | - Jiaxin Li
- Yunnan Key Laboratory of Southern Medicine Utilization, Kunming, China
- College of Pharmacy, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yun Luo
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun , ; Guang Li,
| | - Xiaobo Sun
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Beijing, China
- *Correspondence: Yun Luo, ; Xiaobo Sun , ; Guang Li,
| | - Guang Li
- Institute of Medicinal Plant Development, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Yunnan Branch, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Jinghong, China
- Yunnan Key Laboratory of Southern Medicine Utilization, Kunming, China
- *Correspondence: Yun Luo, ; Xiaobo Sun , ; Guang Li,
| |
Collapse
|
|
7
|
Vascular adhesion protein-1 and microvascular diabetic complications. Pharmacol Rep 2022; 74:40-46. [PMID: 35001320 DOI: 10.1007/s43440-021-00343-y] [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: 07/27/2021] [Revised: 11/20/2021] [Accepted: 11/23/2021] [Indexed: 10/19/2022]
Abstract
Vascular adhesion protein-1 (VAP-1) is a bifunctional protein that has the ability to catalyze the deamination of primary amines and is involved in the production of hydrogen peroxide, aldehydes, and advanced glycation end products (AGEs). VAP-1 is usually stored in intracellular vesicles of endothelial cells, smooth muscles, and adipocytes. It is responsible for leukocyte transmigration and adhesion. Overexpression of VAP-1 exacerbates oxidative stress and modulates a variety of inflammatory mediators linked with diabetic complications. Numerous studies have suggested the association of increased insulin levels with serum VAP-1 (sVAP-1). Preclinical research evidence suggests the increased activity of sVAP-1 in type 1 and 2 diabetes. Scientific reports on VAP-1 inhibitors have shown a reduction in severity in diabetic animal models. VAP-1 is a potential target of a therapeutically effective line of treatment for diabetes and diabetic complications such as nephropathy and retinopathy. The primary focus of this review is the role of VAP-1 in diabetes and its associated microvascular complications.
Collapse
|
|
8
|
Hernandez-Castillo C, Shuck SC. Diet and Obesity-Induced Methylglyoxal Production and Links to Metabolic Disease. Chem Res Toxicol 2021; 34:2424-2440. [PMID: 34851609 DOI: 10.1021/acs.chemrestox.1c00221] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The obesity rate in the United States is 42.4% and has become a national epidemic. Obesity is a complex condition that is influenced by socioeconomic status, ethnicity, genetics, age, and diet. Increased consumption of a Western diet, one that is high in processed foods, red meat, and sugar content, is associated with elevated obesity rates. Factors that increase obesity risk, such as socioeconomic status, also increase consumption of a Western diet because of a limited access to healthier options and greater affordability of processed foods. Obesity is a public health threat because it increases the risk of several pathologies, including atherosclerosis, diabetes, and cancer. The molecular mechanisms linking obesity to disease onset and progression are not well understood, but a proposed mechanism is physiological changes caused by altered lipid peroxidation, glycolysis, and protein metabolism. These metabolic pathways give rise to reactive molecules such as the abundant electrophile methylglyoxal (MG), which covalently modifies nucleic acids and proteins. MG-adducts are associated with obesity-linked pathologies and may have potential for biomonitoring to determine the risk of disease onset and progression. MG-adducts may also play a role in disease progression because they are mutagenic and directly impact protein stability and function. In this review, we discuss how obesity drives metabolic alterations, how these alterations lead to MG production, the association of MG-adducts with disease, and the potential impact of MG-adducts on cellular function.
Collapse
Affiliation(s)
- Carlos Hernandez-Castillo
- Department of Diabetes and Cancer Metabolism, Beckman Research Institute of City of Hope, Duarte, California 91010, United States
| | - Sarah C Shuck
- Department of Diabetes and Cancer Metabolism, Beckman Research Institute of City of Hope, Duarte, California 91010, United States
| |
Collapse
|
|
9
|
Horváth ÁI, Szentes N, Tékus V, Payrits M, Szőke É, Oláh E, Garami A, Fliszár-Nyúl E, Poór M, Sár C, Kálai T, Pál S, Percze K, Scholz ÉN, Mészáros T, Tóth B, Mátyus P, Helyes Z. Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain. Biomedicines 2021; 9:biomedicines9070749. [PMID: 34209525 PMCID: PMC8301340 DOI: 10.3390/biomedicines9070749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 11/24/2022] Open
Abstract
SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate.
Collapse
Affiliation(s)
- Ádám István Horváth
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary; (Á.I.H.); (N.S.); (V.T.); (M.P.); (É.S.)
- Molecular Pharmacology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
| | - Nikolett Szentes
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary; (Á.I.H.); (N.S.); (V.T.); (M.P.); (É.S.)
- Molecular Pharmacology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
| | - Valéria Tékus
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary; (Á.I.H.); (N.S.); (V.T.); (M.P.); (É.S.)
- Molecular Pharmacology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
| | - Maja Payrits
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary; (Á.I.H.); (N.S.); (V.T.); (M.P.); (É.S.)
- Molecular Pharmacology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
| | - Éva Szőke
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary; (Á.I.H.); (N.S.); (V.T.); (M.P.); (É.S.)
- Molecular Pharmacology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
- ALGONIST Biotechnologies GmBH, 1030 Vienna, Austria
| | - Emőke Oláh
- Department of Thermophysiology, Institute for Translational Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary; (E.O.); (A.G.)
| | - András Garami
- Department of Thermophysiology, Institute for Translational Medicine, Medical School, University of Pécs, H-7624 Pécs, Hungary; (E.O.); (A.G.)
| | - Eszter Fliszár-Nyúl
- Department of Pharmacology, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary; (E.F.-N.); (M.P.)
| | - Miklós Poór
- Department of Pharmacology, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary; (E.F.-N.); (M.P.)
| | - Cecília Sár
- Institute of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary; (C.S.); (T.K.)
| | - Tamás Kálai
- Institute of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary; (C.S.); (T.K.)
| | - Szilárd Pál
- Institute of Pharmaceutical Technology and Biopharmacy, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary;
| | - Krisztina Percze
- Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Faculty of Medicine, Semmelweis University, H-1094 Budapest, Hungary; (K.P.); (É.N.S.); (T.M.)
| | - Éva Nagyné Scholz
- Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Faculty of Medicine, Semmelweis University, H-1094 Budapest, Hungary; (K.P.); (É.N.S.); (T.M.)
| | - Tamás Mészáros
- Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Faculty of Medicine, Semmelweis University, H-1094 Budapest, Hungary; (K.P.); (É.N.S.); (T.M.)
| | - Blanka Tóth
- Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, H-1111 Budapest, Hungary;
| | - Péter Mátyus
- Institute of Digital Health Sciences, Faculty of Health and Public Services, Semmelweis University, H-1094 Budapest, Hungary;
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624 Pécs, Hungary; (Á.I.H.); (N.S.); (V.T.); (M.P.); (É.S.)
- Molecular Pharmacology Research Group & Centre for Neuroscience, János Szentágothai Research Centre, University of Pécs, H-7624 Pécs, Hungary
- ALGONIST Biotechnologies GmBH, 1030 Vienna, Austria
- PharmInVivo Ltd., H-7629 Pécs, Hungary
- Correspondence:
| |
Collapse
|