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Bala C, Rusu A, Ciobanu DM, Roman G, Crăciun AE. Metabolomics in Pathogenic Pathways and Targeted Therapies for Diabetic Neuropathy: A Comprehensive Review. Metabolites 2025; 15:86. [PMID: 39997711 PMCID: PMC11857525 DOI: 10.3390/metabo15020086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/23/2025] [Accepted: 01/27/2025] [Indexed: 02/26/2025] Open
Abstract
INTRODUCTION AND OBJECTIVE This literature review aims to provide an overview of the progress in metabolomic assessment in animal and cell models and in humans with diabetic neuropathy (DN). METHODS Metabolomics has emerged as an important approach for investigating, identifying, and describing biomarkers related to DN. None has yet been validated for use in clinical practice. RESULTS DN induced significant alterations in energy metabolism and carbohydrates, lipids, amino acids, peptides, and proteins. Several treatments for DN, evaluated using metabolomics, were proved to have promising results. CONCLUSIONS The ideal metabolite or set of metabolites that could be used as biomarkers should identify patients with diabetes prone to develop DN or those prone to progress to severe forms of sensory loss, associated with risk of ulcerations and amputation. Another potential use of a metabolite might be as an indicator of treatment response in clinical trials using agents with potential disease-modifying properties.
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Affiliation(s)
| | | | - Dana Mihaela Ciobanu
- Department of Diabetes and Nutrition Diseases, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania; (C.B.); (A.R.); (G.R.); (A.E.C.)
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Wang Z, Kushibiki H, Tarusawa T, Osonoi S, Ogasawara S, Miura C, Sasaki T, Ryuzaki M, Yagihashi S, Mizukami H. Hypertension is associated with the reduction in epidermal small fibres independently of sural nerve inflammation in type 2 diabetic subjects. J Neurochem 2025; 169:e16235. [PMID: 39453752 PMCID: PMC11808456 DOI: 10.1111/jnc.16235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 10/27/2024]
Abstract
Diabetic polyneuropathy (DPN) is a multifactorial disease associated not only with hyperglycaemia but also with circulatory disturbances such as hypertension. A close interaction between the immune system and hypertension is known. It remains unclear whether the inflammatory response is associated with hypertension in the pathology of human DPN. Autopsied patients were evaluated: 7 non-diabetic patients (nDM), 11 non-diabetic patients with hypertension (nDMHT), 6 patients with diabetes (DM) and 9 patients with hypertension and diabetes (DMHT). Intraepidermal nerve fibre density (IENFD) was examined by immunofluorescent staining. Dissected sural nerve (SNs) were morphometrically quantified. Dermal and endoneurial macrophage infiltration was evaluated by double immunostaining using anti-CD68 and anti-CD206 antibodies. IENFD was significantly decreased in DM compared to nDM (p < 0.05) and was further decreased in DMHT (p < 0.05). Myelinated nerve fibre density (MNFD) in the SN was significantly decreased in DM compared with nDM (p < 0.05) and further decreased in DMHT (p < 0.01 vs. DM). The infiltration of CD206-/CD68+ proinflammatory macrophages in the SN was significantly increased in DM compared to nDM (p < 0.05), whilst the number of CD206+/CD68+ anti-inflammatory macrophages was decreased in DM (p < 0.05). Hypertension had no impact on macrophage infiltration. The ratio of CD206- and CD206+ macrophage was negatively correlated with MNFD (r = 0.42, p < 0.05) but not IENFD (r = 0.30, p = 0.09). Dermal CD206+ macrophage infiltration was similar amongst all groups. Diabetes complicated by hypertension significantly increased the total diffusion barrier thickness (p < 0.01 vs. DM). Total diffusion barrier thickness was inversely correlated with both IENFD (r = -0.59, p < 0.01) and MNFD (r =-0.62, p < 0.01). Our results suggest that vascular factors and inflammation might be synergistically involved in pathological changes in human diabetic patients through different mechanisms.
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Affiliation(s)
- Zhenchao Wang
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiJapan
| | - Hanae Kushibiki
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiJapan
| | - Takefusa Tarusawa
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiJapan
| | - Sho Osonoi
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiJapan
| | - Saori Ogasawara
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiJapan
| | - Chinatsu Miura
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiJapan
| | - Takanori Sasaki
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiJapan
| | - Masaki Ryuzaki
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiJapan
| | - Soroku Yagihashi
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiJapan
| | - Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiJapan
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Sango K, Yako H, Niimi N, Takaku S. Immortalized Schwann cell lines as useful tools for pathogenesis-based therapeutic approaches to diabetic peripheral neuropathy. Front Endocrinol (Lausanne) 2025; 15:1531209. [PMID: 39906036 PMCID: PMC11790431 DOI: 10.3389/fendo.2024.1531209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 12/24/2024] [Indexed: 02/06/2025] Open
Abstract
Growing evidence suggests that hyperglycemia-related abnormalities in Schwann cells play a pivotal role in the development and progression of diabetic peripheral neuropathy (DPN). Several immortalized Schwann cell lines have been established in our laboratory and utilized for the study of DPN; IMS32 from normal ICR mice, 1970C3 from normal C57BL/6 mice, IWARS1 and IKARS1 from wild-type and aldose reductase-deficient C57BL/6 mice, and IFRS1 from normal Fischer 344 rats. These cell lines retain biological features of Schwann cells and display high proliferative activities that enable us to perform molecular and biochemical analyses. In addition, these cells have exhibited metabolic alterations under exposure to diabetes-associated conditions, such as hyperglycemia, dyslipidemia, glycative and oxidative stress load. Herein, recent studies with these cell lines regarding the pathogenic factors of DPN (augmentation of the polyol and other collateral glycolysis pathways, glycative and oxidative stress-induced cell injury, autophagic and proteostatic disturbances, etc.) and therapeutic strategies targeting these factors are introduced.
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Affiliation(s)
- Kazunori Sango
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Hideji Yako
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
- Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Naoko Niimi
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Shizuka Takaku
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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Bernardoni BL, D'Agostino I, Scianò F, La Motta C. The challenging inhibition of Aldose Reductase for the treatment of diabetic complications: a 2019-2023 update of the patent literature. Expert Opin Ther Pat 2024; 34:1085-1103. [PMID: 39365044 DOI: 10.1080/13543776.2024.2412573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/12/2024] [Accepted: 09/11/2024] [Indexed: 10/05/2024]
Abstract
INTRODUCTION Aldose reductase (AKR1B1, EC: 1.1.1.21) is a recognized target for the treatment of long-term diabetic complications since its activation in hyperglycemia and role in the polyol pathway. In particular, the tissue-specificity of AKR1B1 expression makes the design of the traditional Aldose Reductase Inhibitors (ARIs) and the more recent Aldose Reductase Differential Inhibitors (ARDIs) exploitable strategies to treat pathologies resulting from diabetic conditions. AREAS COVERED A brief overview of the roles and functions of AKR1B1 along with known ARIs and ARDIs was provided. Then, the design of the latest inhibitors in the scientific scenario was discussed, aiming at introducing the research achievement in the field of intellectual properties. Patents dealing with AKR1B1 and diabetes filed in the 2019-2023 period were collected and analyzed. Reaxys, Espacenet, SciFindern, and Google Patents were surveyed, using 'aldose reductase' and 'inhibitor' as the reference keywords. The search results were then filtered by PRISMA protocol, thus obtaining 16 records to review. EXPERT OPINION Although fewer in number than in the early 2000s, patent applications are still being filed in the field of ARIs, with a large number of Chinese inventors reporting new synthetic ARIs in favor of the repositioning approach.
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Affiliation(s)
| | | | - Fabio Scianò
- Department of Pharmacy, University of Pisa, Pisa, Italy
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Yako H, Niimi N, Takaku S, Kato A, Kato K, Sango K. Role of Exogenous Pyruvate in Maintaining Adenosine Triphosphate Production under High-Glucose Conditions through PARP-Dependent Glycolysis and PARP-Independent Tricarboxylic Acid Cycle. Int J Mol Sci 2024; 25:11089. [PMID: 39456870 PMCID: PMC11508270 DOI: 10.3390/ijms252011089] [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: 08/28/2024] [Revised: 09/26/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024] Open
Abstract
Pyruvate serves as a key metabolite in energy production and as an anti-oxidant. In our previous study, exogenous pyruvate starvation under high-glucose conditions induced IMS32 Schwann cell death because of the reduced glycolysis-tricarboxylic acid (TCA) cycle flux and adenosine triphosphate (ATP) production. Thus, this study focused on poly-(ADP-ribose) polymerase (PARP) to investigate the detailed molecular mechanism of cell death. Rucaparib, a PARP inhibitor, protected Schwann cells against cell death and decreased glycolysis but not against an impaired TCA cycle under high-glucose conditions in the absence of pyruvate. Under such conditions, reduced pyruvate dehydrogenase (PDH) activity and glycolytic and mitochondrial ATP production were observed but not oxidative phosphorylation or the electric transfer chain. In addition, rucaparib supplementation restored glycolytic ATP production but not PDH activity and mitochondrial ATP production. No differences in the increased activity of caspase 3/7 and the localization of apoptosis-inducing factor were found among the experimental conditions. These results indicate that Schwann cells undergo necrosis rather than apoptosis or parthanatos under the aforementioned conditions. Exogenous pyruvate plays a pivotal role in maintaining the flux in PARP-dependent glycolysis and the PARP-independent TCA cycle in Schwann cells under high-glucose conditions.
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Affiliation(s)
- Hideji Yako
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; (N.N.); (S.T.)
| | - Naoko Niimi
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; (N.N.); (S.T.)
| | - Shizuka Takaku
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; (N.N.); (S.T.)
| | - Ayako Kato
- Laboratory of Medicine, Aichi Gakuin University School of Pharmacy, Nagoya 464-8650, Japan; (A.K.); (K.K.)
| | - Koichi Kato
- Laboratory of Medicine, Aichi Gakuin University School of Pharmacy, Nagoya 464-8650, Japan; (A.K.); (K.K.)
| | - Kazunori Sango
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan; (N.N.); (S.T.)
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Mizukami H. Pathological evaluation of the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy. Pathol Int 2024; 74:438-453. [PMID: 38888200 PMCID: PMC11551828 DOI: 10.1111/pin.13458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/29/2024] [Accepted: 06/02/2024] [Indexed: 06/20/2024]
Abstract
Currently, there are more than 10 million patients with diabetes mellitus in Japan. Therefore, the need to explore the pathogenesis of diabetes and the complications leading to its cure is becoming increasingly urgent. Pathological examination of pancreatic tissues from patients with type 2 diabetes reveals a decrease in the volume of beta cells because of a combination of various stresses. In human type 2 diabetes, islet amyloid deposition is a unique pathological change characterized by proinflammatory macrophage (M1) infiltration into the islets. The pathological changes in the pancreas with islet amyloid were different according to clinical factors, which suggests that type 2 diabetes can be further subclassified based on islet pathology. On the other hand, diabetic peripheral neuropathy is the most frequent diabetic complication. In early diabetic peripheral neuropathy, M1 infiltration in the sciatic nerve evokes oxidative stress or attenuates retrograde axonal transport, as clearly demonstrated by in vitro live imaging. Furthermore, islet parasympathetic nerve density and beta cell volume were inversely correlated in type 2 diabetic Goto-Kakizaki rats, suggesting that diabetic peripheral neuropathy itself may contribute to the decrease in beta cell volume. These findings suggest that the pathogenesis of diabetes mellitus and diabetic peripheral neuropathy may be interrelated.
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Affiliation(s)
- Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Biomedical Research CenterHirosaki University Graduate School of MedicineHirosakiAomoriJapan
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Kushibiki H, Mizukami H, Osonoi S, Takeuchi Y, Sasaki T, Ogasawara S, Wada K, Midorikawa S, Ryuzaki M, Wang Z, Yamada T, Yamazaki K, Tarusawa T, Tanba T, Mikami T, Matsubara A, Ishibashi Y, Hakamada K, Nakaji S. Tryptophan metabolism and small fibre neuropathy: a correlation study. Brain Commun 2024; 6:fcae103. [PMID: 38618209 PMCID: PMC11010654 DOI: 10.1093/braincomms/fcae103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 01/10/2024] [Accepted: 03/24/2024] [Indexed: 04/16/2024] Open
Abstract
Small nerve fibres located in the epidermis sense pain. Dysfunction of these fibres decreases the pain threshold known as small fibre neuropathy. Diabetes mellitus is accompanied by metabolic changes other than glucose, synergistically eliciting small fibre neuropathy. These findings suggest that various metabolic changes may be involved in small fibre neuropathy. Herein, we explored the correlation between pain sensation and changes in plasma metabolites in healthy Japanese subjects. The pain threshold evaluated from the intraepidermal electrical stimulation was used to quantify pain sensation in a total of 1021 individuals in the 2017 Iwaki Health Promotion Project. Participants with a pain threshold evaluated from the intraepidermal electrical stimulation index <0.20 mA were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-low group (n = 751); otherwise, they were categorized into the pain threshold evaluated from the intraepidermal electrical stimulation index-high group (n = 270). Metabolome analysis of plasma was conducted using capillary electrophoresis time-of-flight mass spectrometry. The metabolite set enrichment analysis revealed that the metabolism of tryptophan was significantly correlated with the pain threshold evaluated from the intraepidermal electrical stimulation index in all participants (P < 0.05). The normalized level of tryptophan was significantly decreased in participants with a high pain threshold evaluated from the intraepidermal electrical stimulation index. In addition to univariate linear regression analyses, the correlation between tryptophan concentration and the pain threshold evaluated from the intraepidermal electrical stimulation index remained significant after adjustment for multiple factors (β = -0.07615, P < 0.05). These findings indicate that specific metabolic changes are involved in the deterioration of pain thresholds. Here, we show that abnormal tryptophan metabolism is significantly correlated with an elevated pain threshold evaluated from the intraepidermal electrical stimulation index in the Japanese population. This correlation provides insight into the pathology and clinical application of small fibre neuropathy.
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Affiliation(s)
- Hanae Kushibiki
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Sho Osonoi
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Yuki Takeuchi
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Takanori Sasaki
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Saori Ogasawara
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Kanichiro Wada
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Shin Midorikawa
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Otorhinolaryngology-Head and Neck Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Masaki Ryuzaki
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Zhenchao Wang
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Takahiro Yamada
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Keisuke Yamazaki
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Takefusa Tarusawa
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Taiyo Tanba
- Department of Pathology and Molecular Medicine, Biomedical Research Center, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Tatsuya Mikami
- Innovation Center for Health Promotion, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Atsushi Matsubara
- Department of Otorhinolaryngology-Head and Neck Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Yasuyuki Ishibashi
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
| | - Shigeyuki Nakaji
- Department of Social Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan
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Li J, Zhu N, Wang Y, Bao Y, Xu F, Liu F, Zhou X. Application of Metabolomics and Traditional Chinese Medicine for Type 2 Diabetes Mellitus Treatment. Diabetes Metab Syndr Obes 2023; 16:4269-4282. [PMID: 38164418 PMCID: PMC10758184 DOI: 10.2147/dmso.s441399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/21/2023] [Indexed: 01/03/2024] Open
Abstract
Diabetes is a major global public health problem with high incidence and case fatality rates. Traditional Chinese medicine (TCM) is used to help manage Type 2 Diabetes Mellitus (T2DM) and has steadily gained international acceptance. Despite being generally accepted in daily practice, the TCM methods and hypotheses for understanding diseases lack applicability in the current scientific characterization systems. To date, there is no systematic evaluation system for TCM in preventing and treating T2DM. Metabonomics is a powerful tool to predict the level of metabolites in vivo, reveal the potential mechanism, and diagnose the physiological state of patients in time to guide the follow-up intervention of T2DM. Notably, metabolomics is also effective in promoting TCM modernization and advancement in personalized medicine. This review provides updated knowledge on applying metabolomics to TCM syndrome differentiation, diagnosis, biomarker discovery, and treatment of T2DM by TCM. Its application in diabetic complications is discussed. The combination of multi-omics and microbiome to fully elucidate the use of TCM to treat T2DM is further envisioned.
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Affiliation(s)
- Jing Li
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, People’s Republic of China
| | - Na Zhu
- Clinical Trial Research Center, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Central Hospital, Qingdao, People’s Republic of China
| | - Yaqiong Wang
- Clinical Trial Research Center, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Central Hospital, Qingdao, People’s Republic of China
| | - Yanlei Bao
- Department of Pharmacy, Liaoyuan People’s Hospital, Liaoyuan, People’s Republic of China
| | - Feng Xu
- Clinical Trial Research Center, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Central Hospital, Qingdao, People’s Republic of China
| | - Fengjuan Liu
- Clinical Trial Research Center, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Central Hospital, Qingdao, People’s Republic of China
| | - Xuefeng Zhou
- Clinical Trial Research Center, Affiliated Qingdao Central Hospital of Qingdao University, Qingdao Central Hospital, Qingdao, People’s Republic of China
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Yako H, Niimi N, Takaku S, Sango K. Advantages of omics approaches for elucidating metabolic changes in diabetic peripheral neuropathy. Front Endocrinol (Lausanne) 2023; 14:1208441. [PMID: 38089620 PMCID: PMC10715313 DOI: 10.3389/fendo.2023.1208441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 11/15/2023] [Indexed: 12/18/2023] Open
Abstract
Various animal and cell culture models of diabetes mellitus (DM) have been established and utilized to study diabetic peripheral neuropathy (DPN). The divergence of metabolic abnormalities among these models makes their etiology complicated despite some similarities regarding the pathological and neurological features of DPN. Thus, this study aimed to review the omics approaches toward DPN, especially on the metabolic states in diabetic rats and mice induced by chemicals (streptozotocin and alloxan) as type 1 DM models and by genetic mutations (MKR, db/db and ob/ob) and high-fat diet as type 2 DM models. Omics approaches revealed that the pathways associated with lipid metabolism and inflammation in dorsal root ganglia and sciatic nerves were enriched and controlled in the levels of gene expression among these animal models. Additionally, these pathways were conserved in human DPN, indicating the pivotal pathogeneses of DPN. Omics approaches are beneficial tools to better understand the association of metabolic changes with morphological and functional abnormalities in DPN.
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Affiliation(s)
- Hideji Yako
- Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
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Xu J, Chen Q, Cai M, Han X, Lu H. Ultra-high performance liquid chromatography coupled to tandem mass spectrometry-based metabolomics study of diabetic distal symmetric polyneuropathy. J Diabetes Investig 2023; 14:1110-1120. [PMID: 37347226 PMCID: PMC10445193 DOI: 10.1111/jdi.14041] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 05/17/2023] [Accepted: 05/29/2023] [Indexed: 06/23/2023] Open
Abstract
AIMS/INTRODUCTION Distal symmetric polyneuropathy (DSPN) is a common complication of type 2 diabetes mellitus, but the underlining mechanisms have not yet been elucidated. The current study was designed to screen the feature metabolites classified as potential biomarkers, and to provide deeper insights into the underlying distinctive metabolic changes during disease progression. MATERIALS AND METHODS Plasma metabolite profiles were obtained by the ultra-high liquid chromatography coupled to tandem mass spectrometry method from healthy control participants, patients with type 2 diabetes mellitus and patients with DSPN. Potential biomarkers were selected through comprehensive analysis of statistically significant differences between groups. RESULTS Overall, 938 metabolites were identified. Among them, 12 metabolites (dimethylarginine, N6-acetyllysine, N-acetylhistidine, N,N,N-trimethyl-alanylproline betaine, cysteine, 7-methylguanine, N6-carbamoylthreonyladenosine, pseudouridine, 5-methylthioadenosine, N2,N2-dimethylguanosine, aconitate and C-glycosyl tryptophan) were identified as the specific biomarkers. The content of 12 metabolites were significantly higher in the DSPN group compared with the other two groups. Additionally, they showed good performance to discriminate the DSPN state. Correlation analyses showed that the levels of 12 metabolites might be more closely related to the glucose metabolic changes, followed by the levels of lipid metabolism. CONCLUSIONS The finding of the 12 signature metabolites might provide a novel perspective for the pathogenesis of DSPN. Future studies are required to test this observation further.
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Affiliation(s)
- Jiahui Xu
- Department of EndocrinologyShuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Qingguang Chen
- Department of EndocrinologyShuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Mengjie Cai
- Department of EndocrinologyShuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Xu Han
- Department of EndocrinologyShuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
| | - Hao Lu
- Department of EndocrinologyShuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina
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Zhang T, Wu J, Yao X, Zhang Y, Wang Y, Han Y, Wu Y, Xu Z, Lan J, Han S, Zou H, Sun Q, Wang D, Zhang J, Wang G. The Aldose Reductase Inhibitor Epalrestat Maintains Blood-Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia. Mol Neurobiol 2023; 60:3741-3757. [PMID: 36940077 DOI: 10.1007/s12035-023-03304-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 03/08/2023] [Indexed: 03/21/2023]
Abstract
Excessive activation of aldose reductase (AR) in the brain is a risk factor for aggravating cerebral ischemia injury. Epalrestat is the only AR inhibitor with proven safety and efficacy, which is used in the clinical treatment of diabetic neuropathy. However, the molecular mechanisms underlying the neuroprotection of epalrestat remain unknown in the ischemic brain. Recent studies have found that blood-brain barrier (BBB) damage was mainly caused by increased apoptosis and autophagy of brain microvascular endothelial cells (BMVECs) and decreased expression of tight junction proteins. Thus, we hypothesized that the protective effect of epalrestat is mainly related to regulating the survival of BMVECs and tight junction protein levels after cerebral ischemia. To test this hypothesis, a mouse model of cerebral ischemia was established by permanent middle cerebral artery ligation (pMCAL), and the mice were treated with epalrestat or saline as a control. Epalrestat reduced the ischemic volume, enhanced BBB function, and improved the neurobehavior after cerebral ischemia. In vitro studies revealed that epalrestat increased the expression of tight junction proteins, and reduced the levels of cleaved-caspase3 and LC3 proteins in mouse BMVECs (bEnd.3 cells) exposed to oxygen-glucose deprivation (OGD). In addition, bicalutamide (an AKT inhibitor) and rapamycin (an mTOR inhibitor) increased the epalrestat-induced reduction in apoptosis and autophagy related protein levels in bEnd.3 cells with OGD treatment. Our findings suggest that epalrestat improves BBB function, which may be accomplished by reducing AR activation, promoting tight junction proteins expression, and upregulating AKT/mTOR signaling pathway to inhibit apoptosis and autophagy in BMVECs.
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Affiliation(s)
- Tongshuai Zhang
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Jinrong Wu
- Department of Anaesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Xinmin Yao
- Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang, China
| | - Yao Zhang
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Yue Wang
- Department of Anesthesiology, Second Affiliated Hospital of Air Force Medical University, Xi'an, 710032, Shaanxi, China
| | - Yang Han
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Yun Wu
- The Medical Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China
| | - Zhenyu Xu
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Jing Lan
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Siyu Han
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Haifeng Zou
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China
| | - Qixu Sun
- Department of Gastroenterology, Penglai People's Hospital, Yantai, 264117, Shandong, China
| | - Dandan Wang
- Wu Lian De Memorial Hospital, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
| | - Jingyu Zhang
- The Medical Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
| | - Guangyou Wang
- Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China.
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12
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Osonoi S, Mizukami H, Takeuchi Y, Sugawa H, Ogasawara S, Takaku S, Sasaki T, Kudoh K, Ito K, Sango K, Nagai R, Yamamoto Y, Daimon M, Yamamoto H, Yagihashi S. RAGE activation in macrophages and development of experimental diabetic polyneuropathy. JCI Insight 2022; 7:160555. [PMID: 36477360 PMCID: PMC9746912 DOI: 10.1172/jci.insight.160555] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 10/19/2022] [Indexed: 12/12/2022] Open
Abstract
It is suggested that activation of receptor for advanced glycation end products (RAGE) induces proinflammatory response in diabetic nerve tissues. Macrophage infiltration is invoked in the pathogenesis of diabetic polyneuropathy (DPN), while the association between macrophage and RAGE activation and the downstream effects of macrophages remain to be fully clarified in DPN. This study explored the role of RAGE in the pathogenesis of DPN through the modified macrophages. Infiltrating proinflammatory macrophages impaired insulin sensitivity, atrophied the neurons in dorsal root ganglion, and slowed retrograde axonal transport (RAT) in the sciatic nerve of type 1 diabetic mice. RAGE-null mice showed an increase in the population of antiinflammatory macrophages, accompanied by intact insulin sensitivity, normalized ganglion cells, and RAT. BM transplantation from RAGE-null mice to diabetic mice protected the peripheral nerve deficits, suggesting that RAGE is a major determinant for the polarity of macrophages in DPN. In vitro coculture analyses revealed proinflammatory macrophage-elicited insulin resistance in the primary neuronal cells isolated from dorsal root ganglia. Applying time-lapse recording disclosed a direct impact of proinflammatory macrophage and insulin resistance on the RAT deficits in primary neuronal cultures. These results provide a potentially novel insight into the development of RAGE-related DPN.
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Affiliation(s)
- Sho Osonoi
- Department of Pathology and Molecular Medicine and,Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | | | - Yuki Takeuchi
- Department of Pathology and Molecular Medicine and,Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hikari Sugawa
- Laboratory of Food and Regulation Biology, Department of Bioscience, School of Agriculture, Tokai University, Higashi-ku, Kumamoto, Japan
| | | | - Shizuka Takaku
- Diabetic Neuropathy Project, Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan
| | | | | | - Koichi Ito
- Department of Bioscience and Laboratory Medicine, Hirosaki University Graduate School of Health Sciences, Hirosaki, Japan
| | - Kazunori Sango
- Diabetic Neuropathy Project, Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo, Japan
| | - Ryoji Nagai
- Laboratory of Food and Regulation Biology, Department of Bioscience, School of Agriculture, Tokai University, Higashi-ku, Kumamoto, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Makoto Daimon
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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13
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Song L, Han R, Yin H, Li J, Zhang Y, Wang J, Yang Z, Bai J, Guo M. Sphingolipid metabolism plays a key role in diabetic peripheral neuropathy. Metabolomics 2022; 18:32. [PMID: 35596842 DOI: 10.1007/s11306-022-01879-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/07/2022] [Indexed: 10/18/2022]
Abstract
INTRODUCTION As the most common chronic complication of diabetes mellitus (DM), diabetic peripheral neuropathy (DPN) seriously affects the quality of life of DM patients. So, it is of great significance for the diagnosis and treatment of DPN. In recent years, there have been numerous studies on pathogenesis and biomarkers of DM, but there are few studies on the biomarkers of DPN. OBJECTIVES This research is intended to identify abnormal metabolic pathways, search for potential biomarkers of DPN, and provide a metabolic basis for the diagnosis and mechanism of DPN. METHODS Serum samples from 23 healthy controls (HC), 42 DM patients and 30 DPN patients and urine samples from 42 HC, 40 DM patients, and 30 DPN patients were collected. UPLC-Q-TOF/MS was used to analyze the samples. Potential biomarkers were screened from principal component analysis (PCA) to orthogonal partial least squares discriminant analysis (OPLS-DA) and further evaluated by receiver operating characteristic analysis (ROC). The biomarkers were then enriched and pathway analyzed. RESULTS 12 potential DPN biomarkers were identified from patient's serum. 11 potential DPN biomarkers were identified from the patient's urine. Among them, the diagnostic ability of gluconic acid, lipoic acid, sphinganine, bilirubin, sphingosine and 4-hydroxybenzoic acid was increased by ROC analysis. Potential biomarkers suggest that the disorder of DPN metabolism may be linked to sphingolipid metabolism. CONCLUSIONS This research laid a theoretical foundation for the diagnosis and pathogenesis of DPN.
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Affiliation(s)
- Lili Song
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., 301617, Tianjin, People's Republic of China
| | - Rui Han
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., 301617, Tianjin, People's Republic of China
| | - Hongqing Yin
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., 301617, Tianjin, People's Republic of China
| | - Jingfang Li
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., 301617, Tianjin, People's Republic of China
| | - Yue Zhang
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., 301617, Tianjin, People's Republic of China
| | - Jiayi Wang
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., 301617, Tianjin, People's Republic of China
| | - Zhen Yang
- School of Traditional Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist., 301617, Tianjin, People's Republic of China
| | - Junwei Bai
- Tianjin Nankai Hospital of Traditional Chinese Medicine, 28 Guangkaixin Street, Nankai District, 300102, Tianjin, People's Republic of China.
| | - Maojuan Guo
- Department of Pathology, School of integrative Medicine, Tianjin University of Traditional Chinese Medicine, Jian Kang Chan Ye Yuan, Jinghai Dist, 301617, Tianjin, People's Republic of China.
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14
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James CF, Tripathi S, Karampatou K, Gladston DV, Pappachan JM. Pharmacotherapy of Painful Diabetic Neuropathy: A Clinical Update. SISLI ETFAL HASTANESI TIP BULTENI 2022; 56:1-20. [PMID: 35515975 PMCID: PMC9040305 DOI: 10.14744/semb.2021.54670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 12/30/2021] [Indexed: 02/08/2023]
Abstract
The rising prevalence of diabetes mellitus (DM) leads on to an increase in chronic diabetic complications. Diabetic peripheral neuropathies (DPNs) are common chronic complications of diabetes. Distal symmetric polyneuropathy is the most prevalent form. Most patients with DPN will remain pain-free; however, painful DPN (PDPN) occurs in 6-34% of all DM patients and is associated with reduced health-related-quality-of-life and substantial economic burden. Symptomatic treatment of PDPN and diabetic autonomic neuropathy is the key treatment goals. Using certain patient related characteristics, subjects with PDPN can be stratified and assigned targeted therapies to produce better pain outcomes. The aim of this review is to discuss the various pathogenetic mechanisms of DPN with special reference to the mechanisms leading to PDPN and the various pharmacological and non-pharmacological therapies available for its management. Recommended pharmacological therapies include anticonvulsants, antidepressants, opioid analgesics, and topical medications.
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Affiliation(s)
- Cornelius Fernandez James
- Department of Endocrinology & Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, United Kingdom
| | - Shiva Tripathi
- Department of Anaesthesia & Pain Management, Lancashire Teaching Hospitals NHS Trust, United Kingdom
| | - Kyriaki Karampatou
- Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, United Kingdom
| | - Divya V Gladston
- Department of Anaesthesiology, Regional Cancer Centre, Thiruvananthapuram, India
| | - Joseph M Pappachan
- Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, United Kingdom; The University of Manchester, Manchester, UK; Manchester Metropolitan University, Manchester, UK
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15
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Singh M, Kapoor A, Bhatnagar A. Physiological and Pathological Roles of Aldose Reductase. Metabolites 2021; 11:655. [PMID: 34677370 PMCID: PMC8541668 DOI: 10.3390/metabo11100655] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/17/2021] [Accepted: 09/17/2021] [Indexed: 12/15/2022] Open
Abstract
Aldose reductase (AR) is an aldo-keto reductase that catalyzes the first step in the polyol pathway which converts glucose to sorbitol. Under normal glucose homeostasis the pathway represents a minor route of glucose metabolism that operates in parallel with glycolysis. However, during hyperglycemia the flux of glucose via the polyol pathway increases significantly, leading to excessive formation of sorbitol. The polyol pathway-driven accumulation of osmotically active sorbitol has been implicated in the development of secondary diabetic complications such as retinopathy, nephropathy, and neuropathy. Based on the notion that inhibition of AR could prevent these complications a range of AR inhibitors have been developed and tested; however, their clinical efficacy has been found to be marginal at best. Moreover, recent work has shown that AR participates in the detoxification of aldehydes that are derived from lipid peroxidation and their glutathione conjugates. Although in some contexts this antioxidant function of AR helps protect against tissue injury and dysfunction, the metabolic transformation of the glutathione conjugates of lipid peroxidation-derived aldehydes could also lead to the generation of reactive metabolites that can stimulate mitogenic or inflammatory signaling events. Thus, inhibition of AR could have both salutary and injurious outcomes. Nevertheless, accumulating evidence suggests that inhibition of AR could modify the effects of cardiovascular disease, asthma, neuropathy, sepsis, and cancer; therefore, additional work is required to selectively target AR inhibitors to specific disease states. Despite past challenges, we opine that a more gainful consideration of therapeutic modulation of AR activity awaits clearer identification of the specific role(s) of the AR enzyme in health and disease.
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Affiliation(s)
- Mahavir Singh
- Eye and Vision Science Laboratory, Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Aniruddh Kapoor
- Internal Medicine—Critical Care, School of Medicine, Saint Louis University, St. Louis, MO 63141, USA;
| | - Aruni Bhatnagar
- Christina Lee Brown Envirome Institute, School of Medicine, University of Louisville, Louisville, KY 40202, USA;
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16
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Zhu Z, Liu Q, Sun J, Bao Z, Wang W. Silencing of PFKFB3 protects podocytes against high glucose‑induced injury by inducing autophagy. Mol Med Rep 2021; 24:765. [PMID: 34490476 PMCID: PMC8430303 DOI: 10.3892/mmr.2021.12405] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 05/19/2021] [Indexed: 12/28/2022] Open
Abstract
Diabetic nephropathy (DN) is a diabetic complication that threatens the health of patients with diabetes. In addition, podocyte injury can lead to the occurrence of DN. The protein 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) may be associated with diabetes; however, the effects of PFKFB3 knockdown by small interfering (si)RNA on the growth of podocytes remains unknown. To investigate the mechanism by which PFKFB3 mediates podocyte injury, MPC5 mouse podocyte cells were treated with high-glucose (HG), and cell viability and apoptosis were examined by Cell Counting Kit-8 assay and flow cytometry, respectively. In addition, the expression of autophagy-related proteins were measured using western blot analysis and immunofluorescence staining. Cell migration was investigated using a Transwell assay and phalloidin staining was performed to observe the cytoskeleton. The results revealed that silencing of PFKFB3 significantly promoted MPC5 cell viability and inhibited apoptosis. In addition, the migration of the MPC5 cells was notably downregulated by siPFKFB3. Moreover, PFKFB3 silencing notably reversed the HG-induced decrease in oxygen consumption rate, and the HG-induced increase in extracellular acidification rate was rescued by PFKFB3 siRNA. Furthermore, silencing of PFKFB3 induced autophagy in HG-treated podocytes through inactivating phosphorylated (p-)mTOR, p-AMPKα, LC3 and sirtuin 1, and activating p62. In conclusion, silencing of PFKFB3 may protect podocytes from HG-induced injury by inducing autophagy. Therefore, PFKFB3 may serve as a potential target for treatment of DN.
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Affiliation(s)
- Zhengming Zhu
- Department of Nephrology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310007, P.R. China
| | - Qingsheng Liu
- Department of Geriatrics, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310007, P.R. China
| | - Jianshi Sun
- Department of Nephrology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China
| | - Ziyang Bao
- Department of Nephrology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310007, P.R. China
| | - Weiwei Wang
- Department of Nephrology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310007, P.R. China
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17
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Zglejc-Waszak K, Mukherjee K, Juranek JK. The cross-talk between RAGE and DIAPH1 in neurological complications of diabetes: A review. Eur J Neurosci 2021; 54:5982-5999. [PMID: 34449932 DOI: 10.1111/ejn.15433] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 01/10/2023]
Abstract
Neuropathy, or dysfunction of peripheral nerve, is one of the most common neurological manifestation in patients with diabetes mellitus (DM). DM is typically associated with a hyperglycaemic milieu, which promotes non-enzymatic glycation of proteins. Proteins with advanced glycation are known to engage a cell-surface receptor called the receptor for advanced glycation end products (RAGE). Thus, it is reasonable to assume that RAGE and its associated molecule-mediated cellular signalling may contribute to DM-induced symmetrical axonal (length-dependent) neuropathy. Of particular interest is diaphanous related formin 1 (DIAPH1), a cytoskeletal organizing molecule, which interacts with the cytosolic domain of RAGE and whose dysfunction may precipitate axonopathy/neuropathy. Indeed, it has been demonstrated that both RAGE and DIAPH1 are expressed in the motor and sensory fibres of nerve harvested from DM animal models. Although the detailed molecular role of RAGE and DIAPH1 in diabetic neurological complications remains unclear, here we will discuss available evidence of their involvement in peripheral diabetic neuropathy. Specifically, we will discuss how a hyperglycaemic environment is not only likely to elevate advanced glycation end products (ligands of RAGE) and induce a pro-inflammatory environment but also alter signalling via RAGE and DIAPH1. Further, hyperglycaemia may regulate epigenetic mechanisms that interacts with RAGE signalling. We suggest the cumulative effect of hyperglycaemia on RAGE-DIAPH1-mediated signalling may be disruptive to axonal cytoskeletal organization and transport and is therefore likely to play a key role in pathogenesis of diabetic symmetrical axonal neuropathy.
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Affiliation(s)
- Kamila Zglejc-Waszak
- Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Konark Mukherjee
- Fralin Biomedical Research Institute at VTC, Virginia Tech Roanoke, Roanoke, Virginia, USA
| | - Judyta Karolina Juranek
- Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
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18
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Takahashi K, Mizukami H, Osonoi S, Ogasawara S, Hara Y, Kudoh K, Takeuchi Y, Sasaki T, Daimon M, Yagihashi S. Inhibitory effects of xanthine oxidase inhibitor, topiroxostat, on development of neuropathy in db/db mice. Neurobiol Dis 2021; 155:105392. [PMID: 34000416 DOI: 10.1016/j.nbd.2021.105392] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/03/2021] [Accepted: 05/10/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammation and oxidative stress contribute to the pathophysiology of diabetic neuropathy. According to recent evidence, the modulation of macrophage polarization in peripheral nerves represents a potential therapeutic target for diabetic neuropathy. Xanthine oxidase, which is a form of xanthin oxidoreductase, is the rate-limiting enzyme that catalyzes the degradation of hypoxanthine and xanthine into uric acid. Activation of xanthine oxidase promotes oxidative stress and macrophage activation. A preclinical study reported the beneficial effects of xanthine oxidase inhibitors on peripheral nerve dysfunction in experimental models of diabetes. However, the detailed mechanisms remain unknown. In this study, we examined the effect of the xanthine oxidase inhibitor topiroxostat on macrophage polarization and peripheral neuropathy in an obese diabetic model, db/db mice. First, the effects of xanthine oxidase inhibitors on cultured macrophages and dorsal root ganglion neurons exposed to xanthine oxidase were assessed. Furthermore, five-week-old db/db mice were administered the xanthine oxidase inhibitors topiroxostat [1 mg/kg/day (dbT1) or 2 mg/kg/day (dbT2)] or febuxostat [1 mg/kg (dbF)]. Glucose metabolism and body weight were evaluated during the experimental period. At 4 and 8 weeks of treatment, peripheral nerve functions such as nerve conduction velocities, thermal thresholds and pathology of skin and sciatic nerves were evaluated. The mRNA expression of molecules related to inflammation and oxidative stress was also measured in sciatic nerves. Untreated db/db mice and the nondiabetic db strain (db/m) were studied for comparison. An in vitro study showed that topiroxostat suppressed macrophage activation and proinflammatory but not anti-inflammatory polarization, and prevented the reduction in neurite outgrowth from neurons exposed to xanthine oxidase. Neuropathic changes exemplified by delayed nerve conduction and reduced intraepidermal nerve fiber density developed in db/db mice. These deficits were significantly prevented in the treated group, most potently in dbT2. Protective effects were associated with the suppression of macrophage infiltration, cytokine expression, and oxidative stress in the sciatic nerve and decreased plasma xanthine oxidoreductase activity. Our results revealed the beneficial effects of the xanthine oxidase inhibitor topiroxostat on neuropathy development in a mouse model of type 2 diabetes. The suppression of proinflammatory macrophage activation and oxidative stress-induced damage were suggested to be involved in this process.
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Affiliation(s)
- Kazuhisa Takahashi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan.
| | - Sho Osonoi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Saori Ogasawara
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Yutaro Hara
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; Department of Gastroenterological Surgery and Pediatric Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Kazuhiro Kudoh
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Yuki Takeuchi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Takanori Sasaki
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Makoto Daimon
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
| | - Soroku Yagihashi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
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19
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Rajbhandari J, Fernandez CJ, Agarwal M, Yeap BXY, Pappachan JM. Diabetic heart disease: A clinical update. World J Diabetes 2021; 12:383-406. [PMID: 33889286 PMCID: PMC8040078 DOI: 10.4239/wjd.v12.i4.383] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/27/2021] [Accepted: 03/13/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus (DM) significantly increases the risk of heart disease, and DM-related healthcare expenditure is predominantly for the management of cardiovascular complications. Diabetic heart disease is a conglomeration of coronary artery disease (CAD), cardiac autonomic neuropathy (CAN), and diabetic cardiomyopathy (DCM). The Framingham study clearly showed a 2 to 4-fold excess risk of CAD in patients with DM. Pathogenic mechanisms, clinical presentation, and management options for DM-associated CAD are somewhat different from CAD among nondiabetics. Higher prevalence at a lower age and more aggressive disease in DM-associated CAD make diabetic individuals more vulnerable to premature death. Although common among diabetic individuals, CAN and DCM are often under-recognised and undiagnosed cardiac complications. Structural and functional alterations in the myocardial innervation related to uncontrolled diabetes result in damage to cardiac autonomic nerves, causing CAN. Similarly, damage to the cardiomyocytes from complex pathophysiological processes of uncontrolled DM results in DCM, a form of cardiomyopathy diagnosed in the absence of other causes for structural heart disease. Though optimal management of DM from early stages of the disease can reduce the risk of diabetic heart disease, it is often impractical in the real world due to many reasons. Therefore, it is imperative for every clinician involved in diabetes care to have a good understanding of the pathophysiology, clinical picture, diagnostic methods, and management of diabetes-related cardiac illness, to reduce morbidity and mortality among patients. This clinical review is to empower the global scientific fraternity with up-to-date knowledge on diabetic heart disease.
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Affiliation(s)
- Jake Rajbhandari
- College of Medical and Dental Sciences, University of Birmingham Medical School, Birmingham B15 2TH, United Kingdom
| | | | - Mayuri Agarwal
- Department of Endocrinology and Metabolism, Pilgrim Hospital, Boston PE21 9QS, United Kingdom
| | - Beverly Xin Yi Yeap
- Department of Medicine, The University of Manchester Medical School, Manchester M13 9PL, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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20
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Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems. Int J Mol Sci 2021; 22:ijms22031031. [PMID: 33494154 PMCID: PMC7864348 DOI: 10.3390/ijms22031031] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/13/2021] [Accepted: 01/19/2021] [Indexed: 12/13/2022] Open
Abstract
Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.
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Mizukami H, Osonoi S. Pathogenesis and Molecular Treatment Strategies of Diabetic Neuropathy Collateral Glucose-Utilizing Pathways in Diabetic Polyneuropathy. Int J Mol Sci 2020; 22:ijms22010094. [PMID: 33374137 PMCID: PMC7796340 DOI: 10.3390/ijms22010094] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/16/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
Diabetic polyneuropathy (DPN) is the most common neuropathy manifested in diabetes. Symptoms include allodynia, pain, paralysis, and ulcer formation. There is currently no established radical treatment, although new mechanisms of DPN are being vigorously explored. A pathophysiological feature of DPN is abnormal glucose metabolism induced by chronic hyperglycemia in the peripheral nerves. Particularly, activation of collateral glucose-utilizing pathways such as the polyol pathway, protein kinase C, advanced glycation end-product formation, hexosamine biosynthetic pathway, pentose phosphate pathway, and anaerobic glycolytic pathway are reported to contribute to the onset and progression of DPN. Inhibitors of aldose reductase, a rate-limiting enzyme involved in the polyol pathway, are the only compounds clinically permitted for DPN treatment in Japan, although their efficacies are limited. This may indicate that multiple pathways can contribute to the pathophysiology of DPN. Comprehensive metabolic analysis may help to elucidate global changes in the collateral glucose-utilizing pathways during the development of DPN, and highlight therapeutic targets in these pathways.
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Affiliation(s)
- Hiroki Mizukami
- Department Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;
- Correspondence: ; Tel.: +81-172-39-5025
| | - Sho Osonoi
- Department Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
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Osonoi S, Mizukami H, Itabashi C, Wada K, Kudoh K, Igawa A, Ogasawara S, Ishibashi Y, Daimon M, Yagihashi S, Nakaji S. Increased Oxidative Stress Underlies Abnormal Pain Threshold in a Normoglycemic Japanese Population. Int J Mol Sci 2020; 21:E8306. [PMID: 33167536 PMCID: PMC7663937 DOI: 10.3390/ijms21218306] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 01/13/2023] Open
Abstract
Normal-high HbA1c levels are a risk factor for attenuated pain sensation in normoglycemic subjects. It is unclear, however, what mechanisms underlie the pathogenesis of attenuated pain sensation in such a population. We, therefore, explored the relationship between oxidative stress (OS) and pain sensation in a rural Japanese population. A population-based study of 894 individuals (average age 53.8 ± 0.5 years) and 55 subjects with impaired fasting glucose (IFG) were enrolled in this study. Individuals with diabetes were excluded. Relationships between pain threshold induced by intraepidermal electrical stimulation (PINT) and clinico-hematological parameters associated with OS were evaluated. Univariate linear regression analyses revealed age, BMI, HbA1c, the OS biomarker urine 8-hydroxy-2'-deoxyguanosine (8-OHdG), systolic blood pressure, and decreased Achilles tendon reflex on the PINT scores. Adjustments for age, gender, and multiple clinical measures confirmed a positive correlation between PINT scores and urine 8-OHdG (β = 0.09, p < 0.01). Urine 8-OHdG correlated positively with higher HbA1c levels and age in the normoglycemic population. Unlike in the normoglycemic population, both inflammation and OS were correlated with elevated PINT scores in IFG subjects. OS may be a major contributing factor to elevated PINT scores in a healthy Japanese population.
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Affiliation(s)
- Sho Osonoi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;
| | - Hiroki Mizukami
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
| | - Chieko Itabashi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
| | - Kanichiro Wada
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (K.W.); (Y.I.)
| | - Kazuhiro Kudoh
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
| | - Akiko Igawa
- Department of Gastroenterological Surgery and Pediatric Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;
| | - Saori Ogasawara
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
| | - Yasuyuki Ishibashi
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (K.W.); (Y.I.)
| | - Makoto Daimon
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;
| | - Soroku Yagihashi
- Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan; (S.O.); (C.I.); (K.K.); (S.O.); (S.Y.)
| | - Shigeyuki Nakaji
- Department of Social Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan;
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