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      Dapagliflozin Activates Neurons in the Central Nervous System and Regulates Cardiovascular Activity by Inhibiting SGLT-2 in Mice

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          Abstract

          Purpose

          This study investigates the possible effect and central mechanism of novel antidiabetic medication sodium glucose transporter-2 (SGLT-2i) on the cardiovascular activity.

          Material and Methods

          Thirty-four normal male C57BL/6 mice were randomly assigned to 2 groups to receive single Dapagliflozin (1.52mg/kg) dose via intragastric gavage or a comparable dose of saline. Glycemic level (BG), blood pressure (BP) and heart rate (HR) were measured 2 hours after administration of the respective treatments. Immunohistochemical tests were performed to determine the effect of SGLT-2i on neural localization of SGLT-2 and c-Fos, a neural activator. The distributional relationships of SGLT-2 and c-Fos were examined by immunofluorescence.

          Results

          Administration of SGLT-2i significantly decreased BP but did not affect the HR. There was no difference in BG between the two groups. Results showed that SGLT-2 was localized to specific regions involved in autonomic control. Expression of c-Fos was significantly higher in major critical nuclei in the aforementioned regions in groups treated with Dapagliflozin.

          Conclusion

          This study demonstrates that SGLT-2 is expressed in CNS tissues involved in autonomic control and possibly influence cardiovascular function. Dapagliflozin influences central autonomic activity via unidentified pathways by inhibiting central or peripheral SGLT-2. These results provide a new concept that sympathetic inhibition by SGLT-2i can be mediated by central autonomic system, a mechanism that explains how SGLT-2i improves the cardiovascular function.

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          Most cited references59

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          Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications.

          Sodium-glucose cotransporter-2 (SGLT2) inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic therapies. Because of their unique glycosuric mechanism, SGLT2 inhibitors also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg, respectively, which may underlie cardiovascular and kidney benefits. SGLT2 inhibition also is associated with an acute, dose-dependent reduction in estimated glomerular filtration rate by ≈5 mL·min(-1)·1.73 m(-2) and ≈30% to 40% reduction in albuminuria. These effects mirror preclinical observations suggesting that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (estimated glomerular filtration rate 30% reductions in cardiovascular mortality, overall mortality, and heart failure hospitalizations associated with empagliflozin, even though, by design, the hemoglobin A1c difference between the randomized groups was marginal. Aside from an increased risk of mycotic genital infections, empagliflozin-treated patients had fewer serious adverse events, including a lower risk of acute kidney injury. In light of the EMPA-REG OUTCOME results, some diabetes clinical practice guidelines now recommend that SGLT2 inhibitors with proven cardiovascular benefit be prioritized in patients with type 2 diabetes mellitus who have not achieved glycemic targets and who have prevalent atherosclerotic cardiovascular disease. With additional cardiorenal protection trials underway, sodium-related physiological effects of SGLT2 inhibitors and clinical correlates of natriuresis, such as the impact on blood pressure, heart failure, kidney protection, and mortality, will be a major management focus.
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            Circadian rhythm disruption and mental health

            Circadian rhythms are internal manifestations of the solar day that permit adaptations to predictable environmental temporal changes. These ~24-h rhythms are controlled by molecular clockworks within the brain that are reset daily to precisely 24 h by exposure to the light–dark cycle. Information from the master clock in the mammalian hypothalamus conveys temporal information to the entire body via humoral and neural communication. A bidirectional relationship exists between mood disorders and circadian rhythms. Mood disorders are often associated with disrupted circadian clock-controlled responses, such as sleep and cortisol secretion, whereas disruption of circadian rhythms via jet lag, night-shift work, or exposure to artificial light at night, can precipitate or exacerbate affective symptoms in susceptible individuals. Evidence suggests strong associations between circadian rhythms and mental health, but only recently have studies begun to discover the direct interactions between the circadian system and mood regulation. This review provides an overview of disrupted circadian rhythms and the relationship to behavioral health and psychiatry. The focus of this review is delineating the role of disruption of circadian rhythms on mood disorders using human night shift studies, as well as jet lag studies to identify links. We also review animal models of disrupted circadian rhythms on affective responses. Lastly, we propose low-cost behavioral and lifestyle changes to improve circadian rhythms and presumably behavioral health.
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              The Fos family of transcription factors and their role in tumourigenesis.

              Members of the Fos family (c-Fos, FosB and its smaller splice variants, Fra-1 and Fra-2) dimerise with Jun proteins to form the AP-1 transcription factor complex. Based on the rapidly growing amount of data from experimental studies, animal models and investigations on clinical tumour samples, this review summarises the current knowledge about the role of these proteins in carcinogenesis. In addition to c-Fos, which has oncogenic activity and is frequently overexpressed in tumour cells, Fra-1 seems to play a role in the progression of many carcinomas. The results obtained from various studies show different implications for these transcription factors according to tumour type, i.e., Fra-1 overexpression enhances the motility and invasion of breast and colorectal cancer cells, but inhibits the tumourigenicity of cervical carcinoma cell lines. Knowledge about regulation of invasion and metastasis in different malignant tumours in vivo might open promising perspectives to targeted therapeutic approaches.
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                Author and article information

                Journal
                Diabetes Metab Syndr Obes
                Diabetes Metab Syndr Obes
                DMSO
                dmso
                Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy
                Dove
                1178-7007
                05 August 2020
                2020
                : 13
                : 2781-2799
                Affiliations
                [1 ]Department of Endocrinology, Shanghai Pudong Hospital, Fudan University , Shanghai 201399, People’s Republic of China
                Author notes
                Correspondence: Ligang Zhou Department of Endocrinology, Shanghai Pudong Hospital, Fudan University , Shanghai201399, People’s Republic of ChinaTel +86 13611927616 Email zhouligang@yahoo.com
                [*]

                These authors contributed equally to this work

                Article
                258593
                10.2147/DMSO.S258593
                7425107
                32848437
                4b857903-6945-414f-8b64-854463d103c0
                © 2020 Nguyen et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 28 April 2020
                : 10 July 2020
                Page count
                Figures: 6, Tables: 5, References: 65, Pages: 19
                Funding
                Funded by: Special Department Fund of the Pudong, New Area Health Planning Commission
                Funded by: Integrative Medicine special fund of Shanghai Municipal Health Planning Committee
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Funded by: Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai
                Funded by: Outstanding Clinical Discipline Project of Shanghai Pudong
                Funded by: Natural Science Foundation of China 10.13039/501100001809
                Funded by: Shanghai Natural Science Foundation 10.13039/100007219
                This work was supported by Special Department Fund of the Pudong, New Area Health Planning Commission (PWZzk2017-03), and Integrative Medicine special fund of Shanghai Municipal Health Planning Committee (ZHYY-ZXYJHZX-2-201712), National Natural Science Foundation of China (81370932), Outstanding Leaders Training Program of Pudong Health Bureau of Shanghai (PWR12014-06), the Outstanding Clinical Discipline Project of Shanghai Pudong (PWYgy-2018-08), the Natural Science Foundation of China (21675034), Shanghai Natural Science Foundation (19ZR1447500).
                Categories
                Original Research

                Endocrinology & Diabetes
                sodium glucose co-transporter-2,dapagliflozin,c-fos,cardiovascular activity,brain nuclei

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