Zi Shen Wan Fang regulates kynurenine metabolism to alleviate diabetes-associated cognitive impairment via activating the skeletal muscle PGC1α-PPARα signaling

Yin, Qingsheng; Zhang, Lin; Han, Xu; Zhang, Hanyu; Wang, Fang; Qin, Xiuping; Zhuang, Pengwei; Zhang, Yanjun

doi:10.1016/j.phymed.2022.154000

Cited by 11 publications

(4 citation statements)

References 38 publications

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“…Previous cumulative studies confirmed that gut microbiota plays an important role in regulating tryptophan-kynurenine metabolism (Kennedy et al, 2017;Agus et al, 2018;Deng et al, 2021), and several studies also found that tryptophankynurenine metabolism is involved in the regulation of glutamate neurotransmitters and synaptic excitability, which is crucial for the protection of cognitive function (Oxenkrug, 2007;Forrest et al, 2015;Tanaka et al, 2020;Bakker et al, 2021). More notably, our previous study found abnormal kynurenine metabolism in DCI mice, and ZSWF treatment could improve kynurenine metabolism in DCI mice (Yin et al, 2022). These studies suggest that regulation of tryptophan-kynurenine metabolic pathway may be the mechanism by which ZSWF improves cognitive function by maintaining intestinal microbiome homeostasis in DCI mice.…”

Section: Discussionmentioning

confidence: 61%

Zi Shen Wan Fang Attenuates Neuroinflammation and Cognitive Function Via Remodeling the Gut Microbiota in Diabetes-Induced Cognitive Impairment Mice

et al. 2022

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Background: Cognitive dysfunction is a critical complication of diabetes mellitus, and there are still no clinically approved drugs. Zi Shen Wan Fang (ZSWF) is an optimized prescription composed of Anemarrhenae Rhizoma, Phellodendri Chinensis Cortex, and Cistanches Herba. The purpose of this study is to investigate the effect of ZSWF on DCI and explore its mechanism from the perspective of maintaining intestinal microbial homeostasis in order to find an effective prescription for treating DCI.Methods: The diabetes model was established by a high-fat diet combined with intraperitoneal injections of streptozotocin (STZ, 120 mg/kg) and the DCI model was screened by Morris water maze (MWM) after 8 weeks of continuous hyperglycemic stimulation. The DCI mice were randomly divided into the model group (DCI), the low- and high-ZSWF–dose groups (9.63 g/kg, 18.72 g/kg), the mixed antibiotic group (ABs), and the ZSWF combined with mixed antibiotic group (ZSWF + ABs). ZSWF was administered orally once a day for 8 weeks. Then, cognitive function was assessed using MWM, neuroinflammation and systemic inflammation were analyzed by enzyme-linked immunosorbent assay kits, intestinal barrier integrity was assessed by hematoxylin-eosin (HE) staining and Western blot and high performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Furthermore, the alteration to intestinal flora was monitored by 16S rDNA sequencing.Results: ZSWF restored cognitive function in DCI mice and reduced levels of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α. Moreover, ZSWF protected the integrity of the intestinal barrier by increasing intestinal ZO-1 and occludin protein expression and decreasing urinary lactulose to mannitol ratio. In addition, ZSWF reshaped the imbalanced gut microbiota in DCI mice by reversing the abundance changes of a wide range of intestinal bacteria at the phyla and genus levels. In contrast, removing gut microbiota with antibiotics partially eliminated the effects of ZSWF on improving cognitive function and reducing inflammation, confirming the essential role of gut microbiota in the improvement of DCI by ZSWF.Conclusion: ZSWF can reverse cognitive impairment in DCI mice by remolding the structure of destructed gut microbiota community, which is a potential Chinese medicine prescription for DCI treatment.

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Section: Discussionmentioning

confidence: 61%

Zi Shen Wan Fang Attenuates Neuroinflammation and Cognitive Function Via Remodeling the Gut Microbiota in Diabetes-Induced Cognitive Impairment Mice

et al. 2022

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“…Furthermore, the current study demonstrated that T2DM simultaneously decreased the PGC1α levels in the skeletal muscle and hippocampus, which reduced the biosynthesis of the enzyme kynurenine (KYN) aminotransferase (KAT). KAT converts neurotoxic KYN into neuroprotective KYN acid, thus inhibiting toxic accumulation in the brain in T2DM mice [ 39 ]. Therefore, enhanced energy expenditure in peripheral tissue can induce hepatokines and myokines that might partially contribute to improving neurogenesis in T2DM.…”

Section: Discussionmentioning

confidence: 99%

The Potential Role of Myokines/Hepatokines in the Progression of Neuronal Damage in Streptozotocin and High-Fat Diet-Induced Type 2 Diabetes Mellitus Mice

Lee

Lim

2022

Biomedicines

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Background: Diabetes is highly prevalent, and the number of patients with diabetic sarcopenia and cognitive impairment has grown, leading to decreased quality of life. Although the exact mechanisms between sarcopenia and cognitive impairment have not been elucidated, it is speculated that muscle and liver-derived mediators might contribute to brain function. This study examined the molecular mechanisms associated with muscle-brain interaction accompanied by insulin resistance (IR) caused by aberrant energy metabolism via myokines/hepatokines in type 2 diabetes mellitus (T2DM) mice. Methods: T2DM was induced by a high-fat diet and streptozotocin injection. Behavior tests were conducted to analyze grip strength and cognitive function. Histopathological changes in skeletal muscle and brain tissue were examined by hematoxylin and eosin staining and the protein levels of biomarkers related to energy metabolism via myokines/hepatokines were measured by western blot. Results: T2DM caused peripheral and central IR. Furthermore, T2DM led to aberrant energy metabolism through the reduced fibroblast growth factor 21 dependent AMP-activated kinase (AMPK)/surtuin1/proliferator-activated receptor γ coactivator-1α pathway in T2DM. Subsequently, reduced circulating myokines/hepatokines were in accordance with their levels with hippocampal neuronal markers in T2DM mice. Accordingly, skeletal muscle (muscle strength: 2.83 ± 0.39 vs. 2.187 ± 0.51, p = 0.004) and brain function (PAT: 38.5 ± 57.91 vs. 11.556 ± 12.03, p = 0.02) impairment and morphological changes (muscle cross-sectional area: 872.43 ± 242.87 vs. 743.68 ± 169.31, p = 0.01; density of neurons in hippocampus: 145 ± 15.13 vs. 77 ± 35.51, p = 0.05; density of neurons in cortex: 138.333 ± 6.66 vs. 78 ± 17.35, p = 0.05) were shown in T2DM mice. In addition, the working ability demonstrated by Y-maze was positively correlated with % lean mass (p = 0.046, R = 0.3426). Conclusions: T2DM led to aberrant energy in skeletal muscle and brain via myokines/hepatokines. This study suggested that myokines and hepatokines might have potential roles in skeletal muscle and central metabolic functions which can mediate cognitive function in T2DM mice.

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“…Notably, HIIT activates the KYN pathway to product KYNA more effectively than MICT in patients with MS (Joisten et al, 2021). In addition to exercise, drug administration or a ketogenic diet can increase the production of KYNA, and activates the PGC1α/PPARα signaling in skeletal muscle in normal or model mice (Pathak et al, 2022;Yin et al, 2022; Table 3).…”

Section: Effects Of Muscle Dynamics On Circulation and Central Kyna L...mentioning

confidence: 99%

The function of previously unappreciated exerkines secreted by muscle in regulation of neurodegenerative diseases

Bian,

Wang,

Wang

et al. 2024

Front. Mol. Neurosci.

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The initiation and progression of neurodegenerative diseases (NDs), distinguished by compromised nervous system integrity, profoundly disrupt the quality of life of patients, concurrently exerting a considerable strain on both the economy and the social healthcare infrastructure. Exercise has demonstrated its potential as both an effective preventive intervention and a rehabilitation approach among the emerging therapeutics targeting NDs. As the largest secretory organ, skeletal muscle possesses the capacity to secrete myokines, and these myokines can partially improve the prognosis of NDs by mediating the muscle-brain axis. Besides the well-studied exerkines, which are secreted by skeletal muscle during exercise that pivotally exert their beneficial function, the physiological function of novel exerkines, e.g., apelin, kynurenic acid (KYNA), and lactate have been underappreciated previously. Herein, this review discusses the roles of these novel exerkines and their mechanisms in regulating the progression and improvement of NDs, especially the significance of their functions in improving NDs’ prognoses through exercise. Furthermore, several myokines with potential implications in ameliorating ND progression are proposed as the future direction for investigation. Elucidation of the function of exerkines secreted by skeletal muscle in the regulation of NDs advances the understanding of its pathogenesis and facilitates the development of therapeutics that intervene in these processes to cure NDs.

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Zi Shen Wan Fang regulates kynurenine metabolism to alleviate diabetes-associated cognitive impairment via activating the skeletal muscle PGC1α-PPARα signaling

Cited by 11 publications

References 38 publications

Zi Shen Wan Fang Attenuates Neuroinflammation and Cognitive Function Via Remodeling the Gut Microbiota in Diabetes-Induced Cognitive Impairment Mice

Zi Shen Wan Fang Attenuates Neuroinflammation and Cognitive Function Via Remodeling the Gut Microbiota in Diabetes-Induced Cognitive Impairment Mice

The Potential Role of Myokines/Hepatokines in the Progression of Neuronal Damage in Streptozotocin and High-Fat Diet-Induced Type 2 Diabetes Mellitus Mice

The function of previously unappreciated exerkines secreted by muscle in regulation of neurodegenerative diseases

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