MYCT1 attenuates renal fibrosis and tubular injury in diabetic kidney disease.

Tubulointerstitial abnormalities contribute to the progression of diabetic kidney disease (DKD). However, the underlying mechanism of the pathobiology of tubulointerstitial disease is largely unknown. Here, we showed that MYCT1 expression was downregulated in in vitro and in vivo DKD models. Adeno-associated virus (AAV)-Myct1 significantly attenuated renal dysfunction and tubulointerstitial fibrosis in diabetic db/db mice and downregulated Sp1 transcription and TGF-ß1/SMAD3 pathway activation. In human proximal tubular epithelial cells, high glucose-induced high expression of SP1 and TGF-ß1/SMAD3 pathway activation as well as overaccumulation of extracellular matrix (ECM) were abrogated by MYCT1 overexpression. Mechanistically, the binding of VDR to the MYCT1 promoter was predicted and confirmed using dual-luciferase reporter and ChIP analysis. VDR transcriptionally upregulates MYCT1. Our data reveal MYCT1 as a new and potential therapeutic target in treating DKD.

A systematic analysis of genotype-phenotype associations with PLA2G6.

BACKGROUND: PLA2G6-associated neurodegeneration (PLAN) can be categorized into infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (aNAD), neurodegeneration with brain iron accumulation (NBIA), and early-onset parkinsonism (EOP). OBJECTIVES: To determine the genotype-phenotype association in PLAN. METHODS: "PLA2G6" or "PARK14" or "phospholipase A2 group VI" or "iPLA2ß" were searched across MEDLINE from June 23, 1997, to March 1, 2023. A total of 391 patients were identified, and 340 patients of them were finally included in the assessment. RESULTS: The loss of function (LOF) mutation ratios were significantly different (p < 0.001), highest in INAD, followed by NBIA, aNAD, and EOP. Four ensemble scores (i.e., BayesDel, VARITY, ClinPred, and MetaRNN) were assessed to predict the deleteriousness of missense mutations and demonstrated significant differences (p < 0.001). Binary logistic regression analyses demonstrated that LOF mutations were independently associated with brain iron accumulation (p = 0.006) and ataxia (p = 0.025). CONCLUSIONS: LOF or more deleterious missense mutations are more likely to promote the development of serious phenotype of PLAN, and LOF mutations are independently associated with brain iron accumulation and ataxia.

MYCT1 alters the glycogen shunt by regulating selective translation of RACK1-mediated enzymes.

MYCT1 has been shown to function as a tumor suppressor in various tumors, but its role in metabolism has never been reported. Here, we showed that global inactivation of Myct1 in mice led to progressive accumulation of glycogen in the liver, which was accompanied by aberrant changes in intermediates of the glycogen metabolic pathway. Mechanistically, MYCT1 appeared to promote translation efficiency of PGM1, UGP2 and GSK3A in hepatic cells in a RACK1-dependent manner. Consequently, upregulation of the three enzymes enhanced the glycogen shunt. Our data reveal a critical role of MYCT1 as a switch for the glycogen shunt in tumor cells.

Gadolinium enhancement of atherosclerotic plaque in the intracranial artery.

Background: Gadolinium enhancement on high resolution magnetic resonance imaging (HR-MRI) has been considered a sign of instability and inflammation of intracranial atherosclerotic plaques. Our research objective was to explore the relationship between the extent of plaque enhancement (PE), the degree of intracranial artery stenosis, and acute ischemic stroke events.Methods: HR-MRI was performed in 91 patients with intracranial vascular stenosis to determine the existence and intensity of PE.Results: Among 91 patients enrolled in the trial, there were 43 patients in the acute/subacute group (≤1 month from ischemic stroke event), 15 patients in the chronic group (>1 month from ischemic stroke event), and 33 patients in the non-culprit plaques group (no ischemic stroke event). A total of 105 intracranial atherosclerotic plaques were detected in 91 patients. 14 (13.3%) were mild-stenosis plaques, 22 (21.0%) were moderate-stenosis plaques, and 69 (65.7%) were severe-stenosis plaques. There were 12 (11.4%), 18 (17.1%), and 75 (71.4%) plaques in the non-enhanced plaque group, the mild-enhancement group, and the significant-enhancement group, respectively. The degree of PE among the acute/subacute group, the chronic group, and the non-culprit plaque group had a significant difference (P = 0.005). Enhanced plaques were more often observed in culprit plaques (acute/subacute group and chronic group) than non-culprit plaques (96.7% vs 77.3%). Non-enhanced plaques were more often observed in non-culprit plaques than culprit plaques (acute/subacute group and chronic group) (22.7% vs 3.3%). And 36.6% of the enhanced plaques were non-culprit plaques. After performing univariate and multivariate logistic regression analysis, the results showed that strong plaque enhancement (P = 0.025, odds ratio [OR] 3.700, 95% confidence interval [95% CI] 1.182-11.583) and severe stenosis (P = 0.008, OR 4.393, 95%CI 1.481-13.030) were significantly associated with acute ischemic events.Conclusion: Enhanced plaques were more often observed in culprit plaques, and non-enhanced plaques were more often observed in non-culprit plaques. Moreover, significant plaque enhancement and severe ICAS were closely associated with acute ischemic events.

Magnetic resonance imaging relaxation time in Alzheimer's disease.

The magnetic resonance imaging (MRI) relaxation time constants, T1 and T2, are sensitive to changes in brain tissue microstructure integrity. Quantitative T1 and T2 relaxation times have been proposed to serve as non-invasive biomarkers of Alzheimer's disease (AD), in which alterations are believed to not only reflect AD-related neuropathology but also cognitive impairment. In this review, we summarize the applications and key findings of MRI techniques in the context of both AD subjects and AD transgenic mouse models. Furthermore, the possible mechanisms of relaxation time alterations in AD will be discussed. Future studies could focus on relaxation time alterations in the early stage of AD, and longitudinal studies are needed to further explore relaxation time alterations during disease progression.

Potential roles of the RGMa-FAK-Ras pathway in hippocampal mossy fiber sprouting in the pentylenetetrazole kindling model.

Mossy fiber sprouting (MFS) is a unique feature of chronic epilepsy. However, the molecular signals underlying MFS are still unclear. The repulsive guidance molecule A (RGMa) appears to contribute to axon growth and axonal guidance, and may exert its biological effects by dephosphorylating focal adhesion kinase (FAK) at Tyr397, then regulating the activation of Ras. The objective of this study was to explore the expression patterns of RGMa, FAK (Tyr397) and Ras in epileptogenesis, and their correlation with MFS. The epileptic models were established by intraperitoneal pentylenetetrazole (PTZ) injection of Sprague­Dawley rats. At 3 days and at 1, 2, 4 and 6 weeks after the first PTZ injection, Timm staining was scored at different time points in the CA3 region of the hippocampus and dentate gyrus. The protein levels of RGMa, FAK (Tyr397) and Ras were analyzed at different time points in the CA3 region of the hippocampus using immunofluorescence, immunohistochemistry and western blot analysis. Compared with the control (saline­injected) group, the expression of RGMa in the CA3 area was significantly downregulated (P<0.05) from 3 days and still maintained the low expression at 6 weeks in the PTZ group. The expression of FAK (Tyr397) and Ras was upregulated (P<0.05) in the PTZ groups. The Timm score in the CA3 region was significantly higher than that in the control group at different time points and reached a peak at 4 weeks. In the CA3 region, no obvious distinction was observed at the different time points in the control group. To the best of our knowledge, these are the first results to indicate that the RGMa­FAK­Ras pathway may be involved in MFS and the development of temporal lobe epilepsy.

Dynamic expression patterns of ATF3 and p53 in the hippocampus of a pentylenetetrazole-induced kindling model.

Epilepsy is a common and often deleterious neurological condition. Emerging evidence has demonstrated the roles of innate immunity and the associated inflammatory processes in epilepsy. In a previous study, we found that Toll­like receptors (TLRs) are upregulated and promote mossy fiber sprouting (MFS) in an epileptic model. As downstream effectors of TLRs, the activating transcription factor 3 (ATF3) and p53 proteins were shown to be involved in neurite outgrowth. In the present study, we hypothesized that ATF3 and p53 participate in the process of epilepsy and can affect MFS. To investigate this hypothesis, we examined the expression of ATF3 and p53 in hippocampal tissues of rats kindled by pentylenetetrazole (PTZ) using immunofluorescence, immunohistochemistry and western blotting. MFS was evaluated by Timm staining in the hippocampus. Results from these experiments revealed that expression of ATF3 and p53 is significantly higher (p<0.05) in the CA3 area of the hippocampus in the PTZ-treated group compared to the control group. ATF3 expression gradually increased from 3 days to 4 weeks, peaked at 4 weeks and decreased slightly at 6 weeks in the PTZ group, while the expression of p53 was maintained at similar levels at different time­points following PTZ treatment. No obvious difference in the expression of these proteins was observed between the PTZ and the control group in the dentate gyrus (DG) area (p>0.05). The degree of MFS in the PTZ group peaked at 4 weeks and was maintained at a high level until 6 weeks post­PTZ treatment. In conclusion, ATF3 and p53 may be involved in the occurrence of seizure and play critical roles in MFS in the PTZ kindling model.

Expression of SOCSs and TLRs in the hippocampus of pentylenetetrazole kindling model.

BACKGROUND: Epilepsy is one of the most common neurological disorders, and approximately one-third of patients with epilepsy are resistant to anti-epileptic drugs (AEDs). Recent emerging evidence has demonstrated the roles of innate immunity and the associated inflammatory processes in epilepsy. Toll-like receptors (TLRs) are a type of pattern-recognition receptor that promote innate immune defense. The SOCS proteins as negative-feedback regulators in cytokine signaling are involved in the regulation of TLR-mediated immune responses. However, few studies investigating the role of TLRs and SOCSs in epilepsy have been reported. METHODS: To explore the role of innate immunity in the mechanism of epilepsy, the pentylenetetrazole (PTZ) kindling rat model was established using intraperitoneal injection of PTZ. The expression levels of TLR2, TLR4, and STAT molecules in rat hippocampi were analyzed using qRT-PCR and western blotting techniques. The expression levels of SOCS-1 and SOCS-3 in rat hippocampi were analyzed using qRT-PCR. RESULTS: Our data demonstrated that both the mRNA and protein expression of TLR2 and TLR4 were significantly upregulated in the rat hippocampus with PTZ injection, which was accompanied by an inhibition of SOCS-1 and SOCS-3 and an upregulation of STAT3. CONCLUSIONS: Our study suggested that SOCSs and TLRs contribute to the development of epilepsy which may lead to therapeutic interventions that limit epileptogenesis.