Increased prevalence of vertebrobasilar dolichoectasia in Parkinson's disease and its effect on white matter microstructure and network.

This study aimed to investigate the prevalence of vertebrobasilar dolichoectasia (VBD) in Parkinson's disease (PD) patients and analyze its role in gray matter changes, white matter (WM) microstructure and network alterations in PD. This is a cross-sectional study including 341 PD patients. Prevalence of VBD in these PD patients was compared with general population. Diffusion tensor imaging and T1-weighted imaging analysis were performed among 174 PD patients with or without VBD. Voxel-based morphometry analysis was used to estimate gray matter volume changes. Tract-based spatial statistics and region of interest-based analysis were used to evaluate WM microstructure changes. WM network analysis was also performed. Significantly higher prevalence of VBD in PD patients was identified compared with general population. Lower fractional anisotropy and higher diffusivity, without significant gray matter involvement, were found in PD patients with VBD in widespread areas. Decreased global and local efficiency, increased hierarchy, decreased degree centrality at left Rolandic operculum, increased betweenness centrality at left postcentral gyrus and decreased average connectivity strength between and within several modules were identified in PD patients with VBD. VBD is more prevalent in PD patients than general population. Widespread impairments in WM microstructure and WM network involving various motor and nonmotor PD symptom-related areas are more prominent in PD patients with VBD compared with PD patients without VBD.

High-salt diet induces dyslipidemia through the SREBP2/PCSK9 pathway in dahl salt-sensitive rats.

A high-salt diet is known to increase serum cholesterol levels; however, the underlying mechanism of salt-induced dyslipidemia in patients with salt-sensitivity remains poorly understood. We aimed to investigate whether high-salt diet (HSD) can induce dyslipidemia and elucidate the underlying mechanism of salt-induced dyslipidemia in Dahl salt-sensitive (SS) rats. Metabolomic and biochemical analyses revealed that the consumption of an HSD (8 % NaCl) significantly increased the serum levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in SS rats. The enzyme-linked immunosorbent assay demonstrated an increase in circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels, accompanied by a decrease in hepatic low-density lipoprotein receptor (LDLR) levels due to HSD consumption. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis revealed that HSD consumption activated sterol regulatory element-binding protein-2 (SREBP2) expression in the liver and kidney, resulting in upregulation of PCSK9 at the transcriptional level in the liver and at the translational level in the kidney, ultimately increasing circulating PCSK9 levels. The combined effects of HSD on the liver and kidney contributed to the development of hypercholesterolemia. Furthermore, an in vitro assay confirmed that high-salt exposure led to an increase in the protein expression of SREBP2 and PCSK9 secretion, thereby reducing low-density lipoprotein (LDL) uptake. This study, for the first time, shows that an HSD induces dyslipidemia through activation of the SREBP2/PCSK9 pathway, providing new insights into the prevention and treatment of dyslipidemia in patients with salt sensitivity.

Cerebellar and cerebral white matter changes in Parkinson's disease with resting tremor.

PURPOSE: Cerebellum modulates the amplitude of resting tremor in Parkinson's disease (PD) via cerebello-thalamo-cortical (CTC) circuit. Tremor-related white matter alterations have been identified in PD patients by pathological studies, but in vivo evidence is limited; the influence of such cerebellar white matter alterations on tremor-related brain network, including CTC circuit, is also unclear. In this study, we investigated the cerebral and cerebellar white matter alterations in PD patients with resting tremor using diffusion tensor imaging (DTI). METHODS: In this study, 30 PD patients with resting tremor (PDWR), 26 PD patients without resting tremor (PDNR), and 30 healthy controls (HCs) from the Parkinson's Progression Markers Initiative (PPMI) cohort were included. Tract-based spatial statistics (TBSS) and region of interest-based analyses were conducted to determine white matter difference. Correlation analysis between DTI measures and clinical characteristics was also performed. RESULTS: In the whole brain, TBSS and region of interest-based analyses identified higher fractional anisotropy (FA) value, lower mean diffusivity (MD) value, and lower radial diffusivity (RD) in multiple fibers. In the cerebellum, TBSS analysis revealed significantly higher FA value, decreased RD value as well as MD value in multiple cerebellar tracts including the inferior cerebellar peduncle (ICP) and middle cerebellar peduncle (MCP) when comparing the PDWR with HC, and higher FA value in the MCP when compared with PDNR. CONCLUSION: We identified better white matter integrity in the cerebrum and cerebellum in PDWR indicating a potential association between the cerebral and cerebellar white matter and resting tremor in PD.

Study of the relationship between onset lateralization and hemispheric white matter asymmetry in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized by a lateralized onset, but its cause and mechanism are still unclear. METHODS: Obtaining diffusion tensor imaging (DTI) data from the Parkinson's Progression Markers Initiative (PPMI). Tract-based spatial statistics analysis and region-of-interest-based analysis were performed to evaluate the white matter (WM) asymmetry using original DTI parameters, Z Score normalized parameters, or the asymmetry index (AI). Hierarchical cluster analysis and least absolute shrinkage and selection operator regression were performed to construct predictive models for predicting the PD onset side. DTI data from The Second Affiliated Hospital of Chongqing Medical University were obtained for external validation of the prediction model. RESULTS: 118 PD patients and 69 healthy controls (HC) from PPMI were included. Right-onset PD patients presented more asymmetric areas than left-onset PD patients. The inferior cerebellar peduncle (ICP), superior cerebellar peduncle (SCP), external capsule (EC), cingulate gyrus (CG), superior fronto-occipital fasciculus (SFO), uncinate fasciculus (UNC), and tapetum (TAP) showed significant asymmetry in left-onset and right-onset PD patients. An onset-side-specific pattern of WM alterations exists in PD patients, and a prediction model was constructed. The predicting models based on AI and ΔZ Score presented favorable efficacy in predicting PD onset side by external validation in 26 PD patients and 16 HCs from our hospital. CONCLUSIONS: Right-onset PD patients may have more severe WM damage than left-onset PD patients. WM asymmetry in ICP, SCP, EC, CG, SFO, UNC, and TAP may predict PD onset side. Imbalances in the WM network may underlie the mechanism of lateralized onset in PD.

Effects of Anti-Parkinsonian Drugs on Verbal Fluency in Patients with Parkinson's Disease: A Network Meta-Analysis.

Verbal fluency impairment is common in patients with Parkinson's disease (PD), but the effect of drugs on verbal fluency in PD patients has not been comprehensively evaluated. We conducted a network meta-analysis based on four online databases to compare the effect of drugs on verbal fluency in PD patients. This study was performed and reported according to PRISMA-NMA guidelines. In total, 6 out of 3707 articles (three RCTS and three cross-sectional studies) covering eight drug regimens were included (five for letter fluency, five for semantic fluency). In terms of letter fluency, the ranking of the overall efficacy of included drug regimens was: levodopa, levodopa combined with pramipexole, rotigotine, cabergoline, pramipexole, pergolide, but no drug regimen presented a significant advantage over the others. In terms of semantic fluency, the ranking of the overall efficacy of included drug regimens was: rotigotine, levodopa, cabergoline, pergolide, pramipexole, among which, levodopa alone (SMD = 0.93, 95%CI: 0.28-1.59) and rotigotine alone (SMD = 1.18, 95%CI: 0.28-2.09) were statistically superior to pramipexole, while no significant difference was identified between all the other drug regimens. Levodopa and rotigotine seem to be more appropriate choices for PD patients with verbal fluency impairment. Further study is needed to illustrate the efficacy of drugs on verbal fluency in PD patients.

Mesenchymal stem cell transplantation worsens intestinal inflammation and microenvironment in PI3Kγ-knockout mice.

Considering the possible interaction between mesenchymal stem cells (MSCs) and PI3Kγ-associated drugs, we evaluated the efficacy and action mechanism of MSCs in the treatment of colitis in PI3Kγ-/- mice. Trinitro-benzene-sulfonic acid enema was used to create a colitis model, and MSCs were transplanted through the caudal vein to treat colitis in wild-type and PI3Kγ-/- mice. We sequenced microbial 16S rRNA genes in the colonic mucosa of PI3Kγ-/- and wild-type mice and quantified colonic IgA, IL-2, IL-10, IL-17A, occludin, and serum IgA. MSC transplantation led to a more serious reduction in the weight of trinitro-benzene-sulfonic acid-administered PI3Kγ-/- mice than that in wild-type mice. The disease activity index, pathological scoring, number of taxa in the colon, Berger-Parker index, I-index, proportion of Proteobacteria, and IgA level in the blood were higher in PI3Kγ-/- mice than in wild-type mice after MSC transplantation. The occludin and IL-10 levels in the colon tissues decreased before and after MSC transplantation in PI3Kγ-/- mice, whereas they were increased in wild-type mice The IL-17 level decreased in both wild-type and PI3Kγ-/- mice, with knockout mice showing a greater decrease. Therefore, MSC transplantation in PI3Kγ-/- mice led to increased numbers of exogenous pathogenic microorganisms and enhanced colitis that was difficult to relieve.

Sex Discrepancy Observed for Gestational Metabolic Syndrome Parameters and Polygenic Risk Associated With Preschoolers' BMI Growth Trajectory: The Ma'anshan Birth Cohort Study.

Background: Few studies have investigated the associations of childhood growth trajectories with the prenatal metabolic risks of mothers and their interaction with children's genetic susceptibility. Objective: To investigate the effects of gestational metabolic syndrome (GMS) risks and children's polygenic risk scores (PRSs), and their interaction effect on the BMI trajectory and obesity risk of offspring from birth to 6 years of age. Methods: A total of 2,603 mother-child pairs were recruited from the Ma'anshan birth cohort (Anhui Province of China) study. Data on maternal prepregnancy obesity, gestational weight gain (GWG), gestational diabetes mellitus (GDM), and hypertensive disorders of pregnancy (HDP) were used to evaluate maternal GMS risk. In addition, 1,482 cord blood samples were used to genotype 11 candidate single-nucleotide polymorphisms (SNPs) to calculate children's PRSs. The latent class growth model using the longitudinal BMI-for-age z scores (BMIz) was applied to validly capture the BMIz growth trajectory. Results: Maternal GMS status was associated with higher BMIz scores and with an increased risk of overweight/obesity. Positive relationships were revealed between PRS and the risk of overweight/obesity among girls. Additionally, maternal GMS significantly interacted with the child's PRS on BMIz scores and the risk of overweight/obesity among girls. Hierarchical BMI trajectory graphs by different exposure groups showed consistent findings, and both boys' and girls' BMIz trajectories were divided into three groups. Among girls, the higher the GMS risk or PRS they had, the higher the probability of being in the high BMIz trajectory group. Conclusions: Maternal GMS status increased BMIz scores and the risk of obesity in both boys and girls and elevated the child's BMI trajectory from birth to 6 years of age among girls. PRSs were significantly associated with children's BMI trajectory and the risk of obesity and modified the associations between maternal GMS status and obesity biomarkers only among girls. Thus, regarding childhood obesity, steps should be taken to decrease maternal metabolic risks before and during pregnancy, and sex discrepancies should be noted to identify high-risk populations after birth to hierarchically manage them.

A review on pathology, mechanism, and therapy for cerebellum and tremor in Parkinson's disease.

Tremor is one of the core symptoms of Parkinson's disease (PD), but its mechanism is poorly understood. The cerebellum is a growing focus in PD-related researches and is reported to play an important role in tremor in PD. The cerebellum may participate in the modulation of tremor amplitude via cerebello-thalamo-cortical circuits. The cerebellar excitatory projections to the ventral intermediate nucleus of the thalamus may be enhanced due to PD-related changes, including dopaminergic/non-dopaminergic system abnormality, white matter damage, and deep nuclei impairment, which may contribute to dysregulation and resistance to levodopa of tremor. This review summarized the pathological, structural, and functional changes of the cerebellum in PD and discussed the role of the cerebellum in PD-related tremor, aiming to provide an overview of the cerebellum-related mechanism of tremor in PD.

Sequential neural activity in sensorimotor area and mirror neural system for graded mirror therapy with imagined hand movements.

BACKGROUND: Graded motor imagery (GMI) therapy is a neural rehabilitative physiotherapy that has been shown to alleviate the severity of complex regional pain syndrome, phantom limb pain and disability. OBJECTIVE: To identify neural networks associated with the use of graded mirror therapy (MT) while imagining hand movements. METHODS: We made a block-design functional magnetic resonance imaging study of MT included three experiments: (1) immobile unimanual MT (IU-MT), in which the right hand flexed and made a fist, which then remained immobile; (2) mobilization unimanual MT (MU-MT), in which the right hand performed a flexion-extension movement; and (3) mobilization bimanual MT (MB-MT), in which both hands performed a flexion-extension movement. When subjects started their hand movements, they gazed at the mirror and imagined the same movement behind the mirror. RESULTS: We discovered that the sensorimotor area of the left brain, superior temporal gyrus/middle temporal gyrus (STG/MTG) of the right brain and visual areas were activated by IU-MT. In MU-MT, only the STG/MTG was activated. Furthermore, MB-UT mostly activated the sensorimotor area and STG of the right brain. However, there were no brain areas activated by MU-MT compared with IU-MT or MB-MT; but, MB-MT activated more motor areas than IU-MT. Importantly, we determined that the level of mirror imagery was negatively correlated with signals in the mirror neuron system (MNS) and positively related with the signals in the sensorimotor areas. CONCLUSIONS: We suggest that graded MT might be a sequential therapeutic program that can enhance the sensorimotor cortex. The MNS might have an initiating role in graded MT. Thus, there is the possibility that graded MT is a helpful treatment strategy for the rehabilitation of dysfunctional patients.

Gestational diabetes mellitus, autistic traits and ADHD symptoms in toddlers: Placental inflammatory and oxidative stress cytokines do not play an intermediary role.

OBJECTIVE: To evaluate whether gestational diabetes mellitus (GDM) is associated with increased risks of autistic traits and attention deficit/hyperactivity disorder (ADHD) among offspring and whether placental inflammatory and oxidative stress cytokines play an intermediary role. METHODS: Based on a prospective cohort study from China, namely, the Ma'anshan Birth Cohort study (MABC), 3260 mother-child pairs were included. Autistic traits and ADHD symptoms among children were assessed at 18 months and 36 months, respectively. The mRNA expression levels of fourteen placental cytokines were determined using PCR. Logistic regression analysis was used to examine the associations between GDM and the risks of autistic traits or ADHD symptoms. Mediation analysis was used to assess the potential mediation effects of certain placental inflammatory factors. RESULTS: Of the 3260 children, 419 (12.85%) were exposed to GDM. The prevalence rates of autistic traits and ADHD symptoms were 13.86% and 6.4%, respectively. A 48.6% increased risk of autistic traits was observed among offspring born to mothers with GDM [odds ratio (OR) = 1.49, 95% confidence interval (95%CI): 1.11-2.00)], while no significant association was found in terms of ADHD symptoms. There were significant positive associations between GDM and IL-10 expression and between HIF1-α and CRP mRNA expression and a significant negative association between GDM and CD206 mRNA expression. The expression of MCP-1 mRNA was negatively associated with the risk of autistic traits [adjusted OR = 0.73 (95%CI: 0.73-0.55)]. The levels of TNF-α were positively associated with the risk of ADHD symptoms [OR = 2.11 (95%CI: 1.39-3.21)], while GRP78 was inversely associated with it [OR = 0.64 (95%CI: 0.44-0.94)]. However, none of the 14 placental cytokines was involved as a key mediator. CONCLUSION: Our findings suggest that GDM may act as a risk factor for autistic traits in offspring, while the biological mechanisms may not involve the 14 placental cytokines studied. No significant association between GDM and ADHD symptoms was observed.

The role of triiodothyronine (T3) and T3/free thyroxine (fT4) in glucose metabolism during pregnancy: the Ma'anshan birth cohort study.

OBJECTIVES: Compared with other thyroid markers, fewer studies have explored the associations between triiodothyronine (T3), T3/free thyroxine (fT4) and glucose abnormality during pregnancy. Thus, we aimed to: (i) examine the associations of T3 and T3/fT4 with glucose metabolism indicators and (ii) evaluate, in the first trimester, the performance of the two markers as predictors of gestational diabetes mellitus (GDM) risk. METHODS: Longitudinal data from 2723 individuals, consisting of three repeated measurements of T3 and fT4, from the Man'anshan birth cohort study (MABC), China, were analyzed using a time-specific generalized estimating equation (GEE). The receiver operating characteristic curve (ROC) - area under the curve (AUC) and Hosmer-Lemeshow goodness of fit test was used to assess the discrimination and calibration of prediction models. RESULTS: T3 and T3/fT4 presented stable associations with the level of fasting glucose, glucose at 1h/2 h during pregnancy. T3 and T3/fT4 in both the first and second trimesters were positively associated with the risk of GDM, with the larger magnitude of association observed in the second trimester (odds ratio (OR) = 2.50, 95% CI = 1.95, 3.21 for T3; OR = 1.09, 95% CI = 1.07, 1.12 for T3/fT4). T3 ((AUC) = 0.726, 95% CI = 0.698, 0.754) and T3/fT4 (AUC = 0.724, 95% CI = 0.696, 0.753) in the first trimester could improve the performance of the prediction model; however, the overall performance is not good. CONCLUSION: Significant and stable associations of T3, T3/fT4 and glucose metabolism indicators were documented. Both T3 and T3/fT4 improve the performance of the GDM predictive model.

An adherent drug depot for retinal ganglion cell protection and regeneration in rat traumatic optic neuropathy models.

Traumatic optic neuropathy (TON) describes an injury to the optic nerve following either blunt or penetrating trauma, and remains an important cause of vision loss. No generalized treatment of TON has been established so far to restore the injured optic nerve. We developed an adherent drug-encapsulated bi-layered depot (DBP) as a dual drug vehicle for local treatment to protect the residual retinal ganglion cells (RGCs) and regenerate axons following optic nerve damage. The inner layer of the depot was prepared by co-electrospinning poly(d,l-lactide-co-glycolide acid) (PLGA: 75 : 25) and collagen (COL) with the hydrophobic corticosteroid triamcinolone acetonide (TA) loaded. The outer layer was made of PLGA and the hydrophilic neuroprotective agent Fasudil (FA). The DBP showed suitable morphology, hydrophilicity and mechanical properties, and slowly released TA and FA in vitro by undergoing time-dependent degradation and swelling. All depots showed good biocompatibility with L929 mouse fibroblasts, and DBP was helpful in maintaining the morphology of RGCs in vitro. In addition, direct implantation of DBP at the injured optic nerve in a rat model mitigated inflammation and the death of RGCs, and increased the expression of nerve growth-related protein GAP-43. Therefore, DBP maybe a promising local therapy against TON in future.

Adenoviral transfer of hemopexin gene attenuates oxidative stress and apoptosis in cultured primary cortical neuron cell exposed to blood clot.

BACKGROUND: A growing body of experimental evidence suggests that hemin released from heme is a potent oxidant and accumulates in intracranial hematomas. Hemopexin (Hpx) decreases hemin accumulation and catabolism by nerve cells. In previous study, we observed that Hpx gene knockout aggravated striatal injury and worsened behavioral deficits of mice subjected to intracerebral hemorrhage. AIM: To examine the effect of Hpx on oxidative damage and apoptosis in cultured nerve cells with blood clot. METHODS: Neuron and glial cells were transfected with adenoviral Hpx gene. Transfected primary neuron-glial cells were co-cultured with 50 µl of arterial blood clot using insert transwells. The sham group was co-coulture with 50 µl of DMEM/F12, which contained 28 µl of serum; the control group was transfected with adenoviral vector. At 12 and 24 h, the level of malonaldehyde (MDA), surperoxide dismutase (SOD) concentration, glutathione (GSH), apoptosis, expression of HO-1 and caspase-3 were detected. RESULTS: MDA level was decreased (P < 0.01) whereas SOD and GSH concentration were increased in the Hpx group (P < 0.05 and P < 0.01, respectively). Results of flow cytometry revealed no significant difference in apoptosis between the Hpx group and model group at 12 h. However, the percentage of cells undergoing apoptosis in the Hpx group was decreased at 24 h compared with the model group (P < 0.01). HO-1 expression decreased in the Hpx group at 24 h (P < 0.01) while caspase-3 expression decreased at both 12 and 24 h (P < 0.011 and P < 0.05, respectively) compared with the model group. CONCLUSION: Hpx protected nerve cells exposed to blood from injury by anti-oxidation and a decrease in the expression of HO-1 and caspase-3.

Correction to: Expression and Function of Zinc-α2-Glycoprotein.

In the original publication, the author name was incorrectly published as "Lifeng Chen".

Insulin attenuates epileptiform discharge-induced oxidative stress by increasing zinc-α2-glycoprotein in primary cultured cortical neurons.

Zinc-α2-glycoprotein (ZAG) is decreased in neurons of epilepsy patients and models. Either insulin or overexpressing ZAG suppresses seizure and epileptiform discharges. ZAG is known to influence insulin sensitivity of tissues, but whether insulin regulates ZAG is unknown. This study investigated the effect and mechanism of insulin on ZAG expression and epileptiform discharge-induced oxidative stress. Primary cultured cortical neurons were treated with insulin, AXL1717 (inhibitor of insulin-like growth factor-1 receptor), or BMS-754807 (inhibitor of both insulin receptor and insulin-like growth factor-1 receptor). Mg-free epileptiform discharge model was also made. Levels of ZAG and AZGP1 mRNAs in neurons were measured. Oxidative stress in Mg-free-treated treated neurons underwent AZGP1 knock-down, AZGP1 overexpression, or insulin treatment was determined. Insulin treatment increased ZAG expression in neurons; this insulin-induced ZAG increase was abolished by either AXL1717 or BMS-754807. Either insulin treatment or ZAG overexpression suppressed epileptiform discharge-induced oxidative stress in neurons. Knock-down of ZAG abolished the antioxidative stress effect of insulin. Insulin-induced ZAG increase in neurons was mainly related to the activation of insulin-like growth factor-1 receptors. Insulin presented its antioxidative stress effect in neuronal epileptiform discharge models by increasing ZAG.

Dual cross-linked chitosan microspheres formulated with spray-drying technique for the sustained release of levofloxacin.

OBJECTIVE: This study was aimed to develop sustained drug release from levofloxacin (LF)-loaded chitosan (CS) microspheres for treating ophthalmic infections. SIGNIFICANCE: Dual cross-linked CS microspheres developed by the spray-drying technique displays significantly higher level of sustained drug release compared with non-cross-linked CS microspheres. METHODS: LF-loaded CS microspheres were prepared using the spray-drying technique, and then solidified with tripolyphosphate and glutaraldehyde as dual cross-linking agents. The microspheres were characterized by surface morphology, size distribution, zeta potential, encapsulation efficiency, and drug release profiles in vitro. The drug quantification was verified and analyzed by high-performance liquid chromatography (HPLC). The structural interactions of the CS with LF were studied with Fourier transform infrared spectroscopy. The effect of various influencing excipients in the formulation of the dual cross-linked CS microspheres on drug encapsulation efficiency and the drug release profiles were extensively investigated. RESULT: The microspheres demonstrated high encapsulation efficiency (72.4 ∼ 98.55%) and were uniformly spherical with wrinkled surface. The mean particle size was between 1020.7 ± 101.9 and 2381.2 ± 101.6 nm. All microspheres were positively charged (zeta potential ranged from 31.1 ± 1.32 to 42.81 ± 1.55 mV). The in vitro release profiles showed a sustained release of the drug and it was remarkably influenced by the cross-linking process. CONCLUSION: This novel spray-drying technique we have developed is suitable for manufacturing LF-loaded CS microspheres, and thus could serve as a potential platform for sustained drug release for effective therapeutic application in ocular infections.

Expression and Function of Zinc-α2-Glycoprotein.

Zinc-α2-glycoprotein (ZAG), encoded by the AZGP1 gene, is a major histocompatibility complex I molecule and a lipid-mobilizing factor. ZAG has been demonstrated to promote lipid metabolism and glucose utilization, and to regulate insulin sensitivity. Apart from adipose tissue, skeletal muscle, liver, and kidney, ZAG also occurs in brain tissue, but its distribution in brain is debatable. Only a few studies have investigated ZAG in the brain. It has been found in the brains of patients with Krabbe disease and epilepsy, and in the cerebrospinal fluid of patients with Alzheimer disease, frontotemporal lobe dementia, and amyotrophic lateral sclerosis. Both ZAG protein and AZGP1 mRNA are decreased in epilepsy patients and animal models, while overexpression of ZAG suppresses seizure and epileptic discharges in animal models of epilepsy, but knowledge of the specific mechanism of ZAG in epilepsy is limited. In this review, we summarize the known roles and molecular mechanisms of ZAG in lipid metabolism and glucose metabolism, and in the regulation of insulin sensitivity, and discuss the possible mechanisms by which it suppresses epilepsy.