Pin1 Exacerbates Non-Alcoholic Fatty Liver Disease by Enhancing Its Activity through Binding to ACC1.

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by diffuse hepatocellular steatosis due to fatty deposits in hepatocytes, excluding alcohol and other known liver injury factors. However, there are no specific drugs for the clinical treatment of NAFLD. Therefore, research on the pathogenesis of NAFLD at the cellular and molecular levels is a promising approach to finding therapeutic targets and developing targeted drugs for NAFLD. Pin1 is highly expressed during adipogenesis and contributes to adipose differentiation, but its specific mechanism of action in NAFLD is unclear. In this study, we investigated the role of Pin1 in promoting the development of NAFLD and its potential mechanisms in vitro and in vivo. First, Pin1 was verified in the NAFLD model in vitro using MCD diet-fed mice by Western Blot, RT-qPCR and immunohistochemistry (IHC) assays. In the in vitro study, we used the oleic acid (OA) stimulation-induced lipid accumulation model and examined the lipid accumulation in each group of cells by oil red O staining as well as BODIPY staining. The results showed that knockdown of Pin1 inhibited lipid accumulation in hepatocytes in an in vitro lipid accumulation model and improved lipid indices and liver injury levels. Moreover, in vivo, WT and Pin1-KO mice were fed a methionine-choline deficient (MCD) diet for 4 weeks to induce the NAFLD model. The effects of Pin1 on lipid accumulation, hepatic fibrosis, and oxidative stress were evaluated by biochemical analysis, glucose and insulin tolerance tests, histological analysis, IHC, RT-qPCR and Western blot assays. The results indicate that Pin1 knockdown significantly alleviated hepatic steatosis, fibrosis and inflammation in MCD-induced NAFLD mice, improved glucose tolerance and alleviated insulin resistance in mice. Further studies showed that the AMPK/ACC1 signalling pathway might take part in the process by which Pin1 regulates NAFLD, as evidenced by the inhibition of the AMPK/ACC1 pathway. In addition, immunofluorescence (IF), coimmunoprecipitation (Co-IP) and GST pull-down experiments also showed that Pin1 interacts directly with ACC1 and inhibits ACC1 phosphorylation levels. Our study suggests that Pin1 promotes NAFLD progression by inhibiting the activation of the AMPK/ACC1 signalling pathway, and it is possible that this effect is achieved by Pin1 interacting with ACC1 and inhibiting the phosphorylation of ACC1.

Disorders of the central nervous system: Insights from Notch and Nrf2 signaling.

The functional complexity of the central nervous system (CNS) is unparalleled in living organisms. It arises from neural crest-derived cells that migrate by the exact route, leading to the formation of a complex network of neurons and glial cells. Recent studies have shown that novel crosstalk exists between the Notch1 and Nrf2 pathways and is associated with many neurological diseases. The Notch1-Nrf2 axis may act on nervous system development, and the molecular mechanism has recently been reported. In this review, we summarize the essential structure and function of the CNS. The significance of interactions between signaling pathways and between developmental processes like proliferation, apoptosis and migration in ensuring the correct development of the CNS is also presented. We primarily focus on research concerning possible mechanism of interaction between Notch1 and Nrf2 and the functions of Notch1-Nrf2 in neurons. There may be a direct interaction between Notch1 and NRF2, which is closely related to the crosstalk that occurs between them. The significance and potential applications of the Notch1-Nrf2 axis in abnormal development of the nervous system are been highlighten. We also discuss the molecular mechanisms by which the Notch1-Nrf2 axis controls the apoptosis, antioxidant pathway and differentiation of neurons to modulate the development of the nervous system. This information will lead to a better understanding of Notch1-Nrf2 axis signaling pathways in the nervous system and may facilitate the development of new therapeutic strategies.

The role of peptidyl-prolyl isomerase Pin1 in neuronal signaling in epilepsy.

Epilepsy is a common symptom of many neurological disorders and can lead to neuronal damage that plays a major role in seizure-related disability. The peptidyl-prolyl isomerase Pin1 has wide-ranging influences on the occurrence and development of neurological diseases. It has also been suggested that Pin1 acts on epileptic inhibition, and the molecular mechanism has recently been reported. In this review, we primarily focus on research concerning the mechanisms and functions of Pin1 in neurons. In addition, we highlight the significance and potential applications of Pin1 in neuronal diseases, especially epilepsy. We also discuss the molecular mechanisms by which Pin1 controls synapses, ion channels and neuronal signaling pathways to modulate epileptic susceptibility. Since neurotransmitters and some neuronal signaling pathways, such as Notch1 and PI3K/Akt, are vital to the nervous system, the role of Pin1 in epilepsy is discussed in the context of the CaMKII-AMPA receptor axis, PSD-95-NMDA receptor axis, NL2/gephyrin-GABA receptor signaling, and Notch1 and PI3K/Akt pathways. The effect of Pin1 on the progression of epilepsy in animal models is discussed as well. This information will lead to a better understanding of Pin1 signaling pathways in epilepsy and may facilitate development of new therapeutic strategies.

The Pin1-CaMKII-AMPA Receptor Axis Regulates Epileptic Susceptibility.

Pin1 is a unique isomerase that regulates protein conformation and function after phosphorylation. Pin1 aberration contributes to some neurological diseases, notably Alzheimer's disease, but its role in epilepsy is not fully understood. We found that Pin1-deficient mice had significantly increased seizure susceptibility in multiple chemical inducing models and developed age-dependent spontaneous epilepsy. Electrophysiologically, Pin1 ablation enhanced excitatory synaptic transmission to prefrontal cortex (PFC) pyramidal neurons without affecting their intrinsic excitability. Biochemically, Pin1 ablation upregulated AMPA receptors and GluA1 phosphorylation by acting on phosphorylated CaMKII. Clinically, Pin1 was decreased significantly, whereas phosphorylated CaMKII and GluA1 were increased in the neocortex of patients with epilepsy. Moreover, Pin1 expression restoration in the PFC of Pin1-deficient mice using viral gene transfer significantly reduced phosphorylated CaMKII and GluA1 and effectively suppressed their seizure susceptibility. Thus, Pin1-CaMKII-AMPA receptors are a novel axis controlling epileptic susceptibility, highlighting attractive new therapeutic strategies.

[Effect of electroacupuncture on NMDAR-2 B mRNA expression in hippocampal tissue in vascular dementia rats].

OBJECTIVE: To study the underlying mechanism of electroacupuncture (EA) in improving learning-memory ability in vascular dementia (VD) rats. METHODS: SD rats were randomized into control, sham operation (sham), VD model, non-acupoint and acupoint groups, with 10 cases in each. VD model was established by occlusion of the bilateral common carotid arteries. Morris water maze test was performed to detect the rats' learning-memory ability. The expression of N-methyl-D-aspartate receptor (NMDAR)-2 B mRNA in hippocampal CA 1 region and dentate gyrus was measured by hybridization in situ. EA (2 Hz, 1-2 mA)was applied to "Baihui" (GV 20), "Dazhui" (GV 14) and bilateral "Shenshu"(BL 23) and non-acupoint (the chest-abdominal juncture between the first and the second lumbar vertebrae) for 20 min, once daily for 30 days. RESULTS: Self-comparison showed that 6 weeks after modeling, the escape latencies of control and sham groups, and the lingering duration in the 3rd quadrant of water pool of model, non-acupoint and acupoint groups decreased significantly (P < 0.05), while the escape latencies of model, non-acupoint and acupoint groups, and the lingering duration of control and sham groups increased considerably (P < 0.5). No significant differences were found between control and sham groups, and among model, non-acupoint and acupoint groups in the escape latency and the lingering duration in the 3rd quadrant (P > 0.05). On the 11th week after modeling, compared to their individual escape latencies and lingering duration on the 6th week, the escape latencies of controll sham and acupoint groups shortened obviously (P < 0.05), while the lingering duration in the 3"rd quadrant of the same 3 groups postponed significantly (P < 0.05). Compared with model group, the escape latency of acupoint group shortened obviously and the lingering duration increased significantly (P < 0.05). No significant differences were found between control and sham groups, and between model and non-acupoint groups in these two indexes (P > 0.05). Compared to control/sham group, the grey values of NMDAR-2 BmRNA expression in hippocampal CA 1 region and dentate gyrus in model and non-acupoint groups decreased significantly (P < 0.05). Compared to model group, the grey values of NMDAR-2 B mRNA expression in these two brain regions increased markedly (P < 0.05). No significant difference was found between control and sham groups, and between model and non-acupoint groups (P > 0.05). CONCLUSION: Acupoint-EA is able to improve VD rats' learning-memory ability which may be related to its effect in upregulating the expression of NMDAR-2 B mRNA in hippocampal and dentate gyrus.