Larysa V Natrus, Yulia S Osadchuk, Olha O Lisakovska, Dmytro O Labudzinskyi, Yulia G Klys, Yuri B Chaikovsky
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Western blotting, RT-PCR, transmission electron microscopy, and immunohistochemical staining were performed.</p><p><strong>Results: </strong>We found T2DM-associated enlargement of ER cisterns, while drug administration slightly improved VMH ultrastructural signs of damage. GRP78 level was 2.1-fold lower in T2DM vs. control. Metformin restored GRP78 to control, while PA increased it by 2.56-fold and metformin+PA-by 3.28-fold vs. T2DM. PERK was elevated by 3.61-fold in T2DM, after metformin-by 4.98-fold, PA-5.64-fold, and metformin+PA-3.01-fold vs. control. A 2.45-fold increase in ATF6 was observed in T2DM. Metformin decreased ATF6 content vs. T2DM. Interestingly, PA exerted a more pronounced lowering effect on ATF6, while combined treatment restored ATF6 to control. IRE1 increased in T2DM (2.4-fold), metformin (1.99-fold), and PA (1.45-fold) groups vs. control, while metformin+PA fully normalized its content. The Iba1 level was upregulated in T2DM (5.44-fold) and metformin groups (6.88-fold). Despite PA treatment leading to a further 8.9-fold Iba1 elevation, PA+metformin caused the Iba1 decline vs. metformin and PA treatment. GFAP level did not change in T2DM but rose in metformin and PA groups vs. control. PA+metformin administration diminished GFAP vs. PA. T2DM-induced changes were associated with dramatically decreased ZO-1 levels, while PA treatment increased it almost to control values.</p><p><strong>Conclusions: </strong>T2DM-induced UPR imbalance, activation of microglia, and impairments in cell integrity may trigger VMH dysfunction. Drug administration slightly improved ultrastructural changes in VMH, normalized UPR, and caused an astrocyte activation. PA and metformin exerted beneficial effects for counteracting diabetes-induced ER stress in VMH.</p>","PeriodicalId":51299,"journal":{"name":"Neural Plasticity","volume":null,"pages":null},"PeriodicalIF":3.0000,"publicationDate":"2022-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8800605/pdf/","citationCount":"10","resultStr":"{\"title\":\"Effect of Propionic Acid on Diabetes-Induced Impairment of Unfolded Protein Response Signaling and Astrocyte/Microglia Crosstalk in Rat Ventromedial Nucleus of the Hypothalamus.\",\"authors\":\"Larysa V Natrus, Yulia S Osadchuk, Olha O Lisakovska, Dmytro O Labudzinskyi, Yulia G Klys, Yuri B Chaikovsky\",\"doi\":\"10.1155/2022/6404964\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The aim was to investigate the influence of propionic acid (PA) on the endoplasmic reticulum (ER), unfolded protein response (UPR) state, and astrocyte/microglia markers in rat ventromedial hypothalamus (VMH) after type 2 diabetes mellitus (T2DM).</p><p><strong>Methods: </strong>Male Wistar rats were divided: (1) control, (2) T2DM, and groups that received the following (14 days, orally): (3) metformin (60 mg/kg), (4) PA (60 mg/kg), and (5) PA+metformin. Western blotting, RT-PCR, transmission electron microscopy, and immunohistochemical staining were performed.</p><p><strong>Results: </strong>We found T2DM-associated enlargement of ER cisterns, while drug administration slightly improved VMH ultrastructural signs of damage. GRP78 level was 2.1-fold lower in T2DM vs. control. Metformin restored GRP78 to control, while PA increased it by 2.56-fold and metformin+PA-by 3.28-fold vs. T2DM. PERK was elevated by 3.61-fold in T2DM, after metformin-by 4.98-fold, PA-5.64-fold, and metformin+PA-3.01-fold vs. control. A 2.45-fold increase in ATF6 was observed in T2DM. Metformin decreased ATF6 content vs. T2DM. Interestingly, PA exerted a more pronounced lowering effect on ATF6, while combined treatment restored ATF6 to control. IRE1 increased in T2DM (2.4-fold), metformin (1.99-fold), and PA (1.45-fold) groups vs. control, while metformin+PA fully normalized its content. The Iba1 level was upregulated in T2DM (5.44-fold) and metformin groups (6.88-fold). Despite PA treatment leading to a further 8.9-fold Iba1 elevation, PA+metformin caused the Iba1 decline vs. metformin and PA treatment. GFAP level did not change in T2DM but rose in metformin and PA groups vs. control. PA+metformin administration diminished GFAP vs. PA. T2DM-induced changes were associated with dramatically decreased ZO-1 levels, while PA treatment increased it almost to control values.</p><p><strong>Conclusions: </strong>T2DM-induced UPR imbalance, activation of microglia, and impairments in cell integrity may trigger VMH dysfunction. Drug administration slightly improved ultrastructural changes in VMH, normalized UPR, and caused an astrocyte activation. 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引用次数: 10
摘要
背景:目的探讨丙酸(PA)对2型糖尿病(T2DM)大鼠下丘脑腹内侧(VMH)内质网(ER)、未折叠蛋白反应(UPR)状态和星形胶质细胞/小胶质细胞标志物的影响。方法:雄性Wistar大鼠分为:(1)对照组，(2)T2DM组和(14 d，口服):(3)二甲双胍(60 mg/kg)， (4) PA (60 mg/kg)， (5) PA+二甲双胍组。Western blotting, RT-PCR，透射电镜，免疫组织化学染色。结果:我们发现t2dm相关的内质网池增大，而给药可轻微改善VMH超微结构损伤征象。T2DM组GRP78水平比对照组低2.1倍。与T2DM相比，二甲双胍使GRP78恢复到控制水平，而PA使GRP78增加2.56倍，二甲双胍+PA使GRP78增加3.28倍。与对照组相比，T2DM患者PERK升高3.61倍，二甲双胍升高4.98倍，pa -5.64倍，二甲双胍+ pa -3.01倍。T2DM患者ATF6升高2.45倍。与T2DM相比，二甲双胍降低ATF6含量。有趣的是，PA对ATF6有更明显的降低作用，而联合治疗使ATF6恢复到控制状态。T2DM组IRE1升高(2.4倍)，二甲双胍组升高(1.99倍)，PA组升高(1.45倍)，而二甲双胍+PA组IRE1含量完全正常化。T2DM组(5.44倍)和二甲双胍组(6.88倍)Iba1水平上调。尽管PA治疗导致Iba1进一步升高8.9倍，但与二甲双胍和PA治疗相比，PA+二甲双胍导致Iba1下降。T2DM患者GFAP水平没有变化，但与对照组相比，二甲双胍组和PA组GFAP水平升高。与PA相比，PA+二甲双胍可降低GFAP。t2dm诱导的改变与ZO-1水平显著降低相关，而PA治疗使ZO-1水平几乎升高到控制值。结论:t2dm诱导的UPR失衡、小胶质细胞激活和细胞完整性受损可能引发VMH功能障碍。给药可轻微改善VMH超微结构变化，使UPR正常化，并引起星形胶质细胞活化。PA和二甲双胍对糖尿病引起的VMH内质网应激有有益的抑制作用。
Effect of Propionic Acid on Diabetes-Induced Impairment of Unfolded Protein Response Signaling and Astrocyte/Microglia Crosstalk in Rat Ventromedial Nucleus of the Hypothalamus.
Background: The aim was to investigate the influence of propionic acid (PA) on the endoplasmic reticulum (ER), unfolded protein response (UPR) state, and astrocyte/microglia markers in rat ventromedial hypothalamus (VMH) after type 2 diabetes mellitus (T2DM).
Methods: Male Wistar rats were divided: (1) control, (2) T2DM, and groups that received the following (14 days, orally): (3) metformin (60 mg/kg), (4) PA (60 mg/kg), and (5) PA+metformin. Western blotting, RT-PCR, transmission electron microscopy, and immunohistochemical staining were performed.
Results: We found T2DM-associated enlargement of ER cisterns, while drug administration slightly improved VMH ultrastructural signs of damage. GRP78 level was 2.1-fold lower in T2DM vs. control. Metformin restored GRP78 to control, while PA increased it by 2.56-fold and metformin+PA-by 3.28-fold vs. T2DM. PERK was elevated by 3.61-fold in T2DM, after metformin-by 4.98-fold, PA-5.64-fold, and metformin+PA-3.01-fold vs. control. A 2.45-fold increase in ATF6 was observed in T2DM. Metformin decreased ATF6 content vs. T2DM. Interestingly, PA exerted a more pronounced lowering effect on ATF6, while combined treatment restored ATF6 to control. IRE1 increased in T2DM (2.4-fold), metformin (1.99-fold), and PA (1.45-fold) groups vs. control, while metformin+PA fully normalized its content. The Iba1 level was upregulated in T2DM (5.44-fold) and metformin groups (6.88-fold). Despite PA treatment leading to a further 8.9-fold Iba1 elevation, PA+metformin caused the Iba1 decline vs. metformin and PA treatment. GFAP level did not change in T2DM but rose in metformin and PA groups vs. control. PA+metformin administration diminished GFAP vs. PA. T2DM-induced changes were associated with dramatically decreased ZO-1 levels, while PA treatment increased it almost to control values.
Conclusions: T2DM-induced UPR imbalance, activation of microglia, and impairments in cell integrity may trigger VMH dysfunction. Drug administration slightly improved ultrastructural changes in VMH, normalized UPR, and caused an astrocyte activation. PA and metformin exerted beneficial effects for counteracting diabetes-induced ER stress in VMH.
期刊介绍：
Neural Plasticity is an international, interdisciplinary journal dedicated to the publication of articles related to all aspects of neural plasticity, with special emphasis on its functional significance as reflected in behavior and in psychopathology. Neural Plasticity publishes research and review articles from the entire range of relevant disciplines, including basic neuroscience, behavioral neuroscience, cognitive neuroscience, biological psychology, and biological psychiatry.
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