Cognitive dysfunction in schizophrenia patients caused by down-regulation of γ-aminobutyric acid receptor subunits.

BACKGROUND: The expression pattern of gamma aminobutyric acid (GABA) receptor subunits are commonly altered in patients with schizophrenia, which may lead to nerve excitation/inhibition problems, affecting cognition, emotion, and behavior. AIM: To explore GABA receptor expression and its relationship with schizophrenia and to provide insights into more effective treatments. METHODS: This case-control study enrolled 126 patients with schizophrenia treated at our hospital and 126 healthy volunteers who underwent physical examinations at our hospital during the same period. The expression levels of the GABA receptor subunits were detected using 1H-magnetic resonance spectroscopy. The recognized cognitive battery tool, the MATRICS Consensus Cognitive Battery, was used to evaluate the scores for various dimensions of cognitive function. The correlation between GABA receptor subunit downregulation and schizophrenia was also analyzed. RESULTS: Significant differences in GABA receptor subunit levels were found between the case and control groups (P < 0.05). A significant difference was also found between the case and control groups in terms of cognitive function measures, including attention/alertness and learning ability (P < 0.05). Specifically, as the expression levels of GABRA1 (α1 subunit gene), GABRB2 (ß2 subunit gene), GABRD (δ subunit), and GABRE (ε subunit) decreased, the severity of the patients' condition increased gradually, indicating a positive correlation between the downregulation of these 4 receptor subunits and schizophrenia (P < 0.05). However, the expression levels of GABRA5 (α5 subunit gene) and GABRA6 (α6 subunit gene) showed no significant correlation with schizophrenia (P > 0.05). CONCLUSION: Downregulation of the GABA receptor subunits is positively correlated with schizophrenia. In other words, when GABA receptor subunits are downregulated in patients, cognitive impairment becomes more severe.

IRAK-M Ablation Promotes Status Epilepticus-Induced Neuroinflammation via Activating M1 Microglia and Impairing Excitatory Synaptic Function.

Epilepsy is one of the most common neurological disorders. The pro-epileptic and antiepileptic roles of microglia have recently garnered significant attention. Interleukin-1 receptor-associated kinase (IRAK)-M, an important kinase in the innate immune response, is mainly expressed in microglia and acts as a negative regulator of the TLR4 signaling pathway that mediates the anti-inflammatory effect. However, whether IRAK-M exerts a protective role in epileptogenesis as well as the molecular and cellular mechanisms underlying these processes are yet to be elucidated. An epilepsy mouse model induced by pilocarpine was used in this study. Real-time quantitative polymerase chain reaction and western blot analysis were used to analyze mRNA and protein expression levels, respectively. Whole-cell voltage-clamp recordings were employed to evaluate the glutamatergic synaptic transmission in hippocampal neurons. Immunofluorescence was utilized to show the glial cell activation and neuronal loss. Furthermore, the proportion of microglia was analyzed using flow cytometry. Seizure dynamics influenced the expression of IRAK-M. Its knockout dramatically exacerbated the seizures and the pathology in epilepsy and increased the N-methyl-d-aspartate receptor (NMDAR) expression, thereby enhancing glutamatergic synaptic transmission in hippocampal CA1 pyramidal neurons in mice. Furthermore, IRAK-M deficiency augmented hippocampal neuronal loss via a possible mechanism of NMDAR-mediated excitotoxicity. IRAK-M deletion promotes microglia toward the M1 phenotype, which resulted in high levels of proinflammatory cytokines and was accompanied by a visible increase in the expressions of key microglial polarization-related proteins, including p-STAT1, TRAF6, and SOCS1. The findings demonstrate that IRAK-M dysfunction contributes to the progression of epilepsy by increasing M1 microglial polarization and glutamatergic synaptic transmission. This is possibly related to NMDARs, particularly Grin2A and Grin2B, which suggests that IRAK-M could serve as a novel therapeutic target for the direct alleviation of epilepsy.

Coadministration of epigallocatechin-3-gallate (EGCG) and caffeine in low dose ameliorates obesity and nonalcoholic fatty liver disease in obese rats.

Epigallocatechin-3-gallate (EGCG) and caffeine in tea exert anti-obesity effects and induces nonalcoholic fatty liver disease (NAFLD) amelioration. However, previous studies usually performed a high-dose EGCG administration, whereas the insecurity was arisen in recent researches. In this study, we treated obese rats with an elaborate dose-40 mg/kg EGCG, 20 mg/kg caffeine, and the coadministration of them as low dose, which were similar to the daily intake; 160 mg/kg EGCG as high dose, which was the maximum safe dose had touched the contentious edge. The results suggested that the coadministration of EGCG and caffeine exerted more remarkable function on suppressing body weight gain, reducing white adipose tissue weight and decreasing the energy intake than single use. This may be due to the variation in serum lipid profile, oxidative stress, and adipose-derived and inflammatory cytokines. The pathological micrographs showed long-term high-fat diets caused severe NAFLD, but it was ameliorated at different levels by all of the administrations. In summary, low dose of EGCG or caffeine only showed a mild effect of anti-obesity and NAFLD amelioration. The coadministration of them could exert a superior curative effect as well as high dose EGCG but no anxiety regarding safety.

[Screening active ingredients of Shenkangwan that regulate endothelial-mesenchymal transition of endothelial cells in vitro].

OBJECTIVE: To screen the effective components of Shenkangwan that regulate endothelial-mesenchymal transition in endothelial cells for optimizing prescription of Shenkangwan. METHODS: ALK5 was identified as one of the target receptors that regulate endothelial-mesenchymal transition of endothelial cells using molecular docking technique. Nine molecules were screened as the candidate effective components in Shenkangwan, among which calycosin, ononin and stigmasterol were selected for testing. Glomerular epithelial cells were exposed to high glucose and treated with calycosin, ononin, or stigmasterol, and the cellular expressions of α-smooth muscle actin (α-SMA) and vimentin mRNA were detected with real-time fluorescence quantitative PCR. The phosphorylation of SMAD2/3 in the cells was detected using Western blotting. RESULTS: Calycosin, ononin and stigmasterol did not produce significant cytotoxicity in glomerular epithelial cells (P>0.05). The cells exposed to high glucose and calycosin treatment showed significantly decreased mRNA levels of α-SMA and vimentin (P<0.05) and inhibited phosphorylation of SMAD2/3. Ononin and stigmasterol did not produce such effects in the cells. CONCLUSION: In endothelial cells with high glucose-induced injury, calycosin can inhibit the up-regulation of α-SMA and vimentin and inhibit phosphorylation of SMAD2/3 to regulate endothelial-mesenchymal transition and improve diabetic nephropathy.