Molecular Neurobiology最新文献

In this study, we explored the potential application of [d-Ala2, d-Leu5]-enkephalin (DADLE) in anti-ageing field in response to the trend of increasing global population ageing. We aimed to reveal experimentally whether DADLE can positively affect the lifespan and health of aged mammals through its unique anti-inflammatory or metabolic mechanisms. Forty-two female C57/BL6J mice aged 18 months were intraperitoneally injected with DADLE or normal saline for 2 months. Cognitive and motor functions were assessed using a water maze and treadmill stress test, respectively. The expressions of P16INK4A, Lamin B1 and sirtuin 1 were observed in the hippocampus and heart. The level of pro-inflammatory cytokines in the serum was measured by enzyme-linked immunosorbent assay. The telomere length of the mice was determined using the polymerase chain reaction method. Transcriptome analysis of 6-month-old female C57BL/6 J mice brains and hearts was assessed for body weight effects. Supplementation of exogenous DADLE to aged mice has demonstrated significant benefits, including improved motor function, enhanced cognitive performance and significantly extended lifespan. DADLE treatment resulted in a substantial increase in anti-ageing markers and a corresponding decrease in pro-ageing markers in the heart and brain of these mice. DADLE attenuated age-related inflammation, as evidenced by reductions in serum pro-inflammatory cytokines and inflammatory cell infiltration in tissues. Furthermore, DADLE supplementation significantly prolonged relative telomere length in aged female mice, suggesting a potential mechanism for its anti-ageing effects. Transcriptome analysis revealed that immune response and cellular signalling pathways are intricately involved in the protective effects of DADLE in aged mice, providing further insights into its mechanism of action. Inflammatory reaction may be improved by DADLE by regulating the infiltration of inflammatory cells in the liver and kidney and regulating the cognitive function of the brain and the ageing of the heart in mice.

Demyelination is a frequent yet crippling neurological disease associated with multiple sclerosis (MS). The cuprizone (CZ) model, which causes demyelination through oxidative stress and neuroinflammation, is a popular tool used by researchers to examine this process. The polyphenol resveratrol (RESV) has become a promising neuroprotective agent in seeking for efficient therapies. In a rat model given CZ, we created and examined iron oxide nanoparticles (IONPs) loaded with RESV (IONP-RESV) to see how effective they were as a therapeutic agent against free RESV. According to molecular mechanisms, exposure to CZ resulted in a marked downregulation of myelin proteolipid protein (PLP) expression and an overexpression of the inflammatory markers tumor necrosis factor-α (TNF-α) and S100β, which are indicators of demyelination and neuroinflammation. It is remarkable that these CZ-induced alterations could be reversed by therapy with either RESV or IONP-RESV. Interestingly, IONP-RESV showed even stronger anti-inflammatory activity, as shown by a more noticeable downregulation of TNF-α and S100β expression. These results were confirmed by histopathological examination of the cerebral cortices. Our findings support the better neuroprotective benefits of RESV-loaded IONPs over free RESV in reducing demyelination and neuroinflammation brought on by CZ. Owing to their pro-remyelinating, anti-inflammatory, and antioxidant properties, RESV-loaded IONPs show promise as a neurotherapeutic intervention in the future for neurological diseases such as multiple sclerosis.

Contactin-associated protein1 (Caspr1) plays an important role in the formation and stability of myelinated axons. In Caspr1 mutant mice, autophagy-related structures accumulate in neurons, causing axonal degeneration; however, the mechanism by which Caspr1 regulates autophagy remains unknown. To illustrate the mechanism of Caspr1 in autophagy process, we demonstrated that Caspr1 knockout in primary neurons from mice along with human cell lines, HEK-293 and HeLa, induced autophagy by downregulating the PI3K/AKT/mTOR signaling pathway to promote the conversion of microtubule-associated protein light chain 3 I (LC3-I) to LC3-II. In contrast, Caspr1 overexpression in cells contributed to the upregulation of this signaling pathway. We also demonstrated that Caspr1 knockout led to increased LC3-I protein expression in mice. In addition, Caspr1 could inhibit the expression of autophagy-related 4B cysteine peptidase (ATG4B) protein by directly binding to ATG4B in overexpressed Caspr1 cells. Intriguingly, we found an accumulation of ATG4B in the Golgi apparatuses of cells overexpressing Caspr1; therefore, we speculate that Caspr1 may restrict ATG4 secretion from the Golgi apparatus to the cytoplasm. Collectively, our results indicate that Caspr1 may regulate autophagy by modulating the PI3K/AKT/mTOR signaling pathway and the levels of ATG4 protein, both in vitro and in vivo. Thus, Caspr1 can be a potential therapeutic target in axonal damage and demyelinating diseases.

Alcohol Use Disorder (AUD), characterized by repeated alcohol consumption and withdrawal symptoms, poses a significant public health issue. Alcohol-induced impairment of the intestinal barrier results in alterations in intestinal permeability and the composition of the intestinal microbiota. Such alterations lead to a reduced relative abundance of intestinal lactic acid bacteria. However, the role of gut microbiota in alcohol consumption is not yet fully understood. In this study, we explore the mechanism by which gut microbiota regulates alcohol consumption, specifically using extracellular vesicles derived from Lactobacillus plantarum (L-EVs). L-EVs were administered to Sprague-Dawley rats either through intraperitoneal injection or microinjection into the ventral tegmental area (VTA), resulting in a significant reduction in alcohol consumption 72 hours after withdrawal. The observed reduction was akin to the effect of an intra-VTA microinjection of Brain-Derived Neurotrophic Factor (BDNF). Intriguingly, the microinjection of K252a (a Trk B antagonist) into the VTA blocked the reducing effect of L-EVs on alcohol consumption. The intraperitoneal injection of L-EVs restored the diminished BDNF expression in the VTA of alcohol-dependent rats. Furthermore, L-EVs rescued the low BDNF expression in alcohol-incubated PC12 cells. In conclusion, our study demonstrates that L-EVs attenuated alcohol consumption by enhancing BDNF expression in alcohol-dependent rats, thus suggesting the significant therapeutic potential of L-EVs in preventing excessive alcohol consumption.

Many species, including fruit flies (Drosophila melanogaster), are sexually dimorphic. Phenotypic variation in morphology, physiology, and behavior can affect development, reproduction, health, and aging. Therefore, designating sex as a variable and sex-blocking should be considered when designing experiments. The brain regulates phenotypes throughout the lifespan by balancing survival and reproduction, and sex-specific development at each life stage is likely. Changes in morphology and physiology are governed by differential gene expression, a quantifiable molecular marker for age- and sex-specific variations. We assessed the fruit fly brain transcriptome at three adult ages for gene expression signatures of sex, age, and sex-by-age: 6698 genes were differentially expressed between sexes, with the most divergence at 3 days. Between ages, 31.1% of 6084 differentially expressed genes (1890 genes) share similar expression patterns from 3 to 7 days in females, and from 7 to 14 days in males. Most of these genes (90.5%, 1712) were upregulated and enriched for chemical stimulus detection and/or cilium regulation. Our data highlight an important delay in male brain gene regulation compared to females. Because significant delays in expression could confound comparisons between sexes, studies of sexual dimorphism at phenotypically comparable life stages rather than chronological age should be more biologically relevant.

Depression is a serious disabling disease worldwide. Accumulating evidence supports that there is a close relationship between depression and inflammation, and then inhibition of neuroinflammation may be another mechanism for the treatment of depression. Transcutaneous auricular vagus stimulation (taVNS), as a noninvasive transcutaneous electrical stimulation, could effectively treat depression, but its mechanism is unclear. In this study, rats with depression-like behavior were induced by intraperitoneal injection of lipopolysaccharide (LPS). The rats were randomly divided to control group, LPS group, taVNS + LPS group, and the same as the α7 nicotinic acetylcholine chloride receptor (α7nAChR) (- / -) gene knockout rats. The expressions of tumor necrosis factor alpha (TNF-ɑ) and phosphorylated-Janus kinase2 (p-JAK2), phosphorylated-signal transducer and activator of transcription3(p-STAT3) in the hypothalamus, amygdala, and hippocampus were detected by Western blot. We observed that LPS significantly decreased the sucrose preference, the time of into the open arms in the elevated plus maze, and the number of crossing and reaping in the open field test. TaVNS treatment improves these depression-like behaviors, but taVNS is not effective in α7nAChR (- / -) gene knockout rats. The expression of TNF-ɑ significantly increased, and the expression of p-Jak2 and p-STAT3 markedly decreased in the hypothalamus and amygdala induced by LPS. TaVNS could significantly reverse the abovementioned phenomena but had rare improvement effect for α7nAChR (- / -) rats. We conclude that the antidepressant effect of taVNS for LPS-induced depressive rats is related to α7nAchR/JAK2 signal pathway in the hypothalamus and amygdala.

Schizophrenia is a disastrous mental disorder. Identification of diagnostic biomarkers and therapeutic targets is of significant importance. In this study, five datasets of schizophrenia post-mortem prefrontal cortex samples were downloaded from the GEO database and then merged and de-batched for the analyses of differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA). The WGCNA analysis showed the six schizophrenia-related modules containing 12,888 genes. The functional enrichment analyses indicated that the DEGs were highly involved in immune-related processes and functions. The immune cell infiltration analysis with the CIBERSORT algorithm revealed 12 types of immune cells that were significantly different between schizophrenia subjects and controls. Additionally, by intersecting DEGs, WGCNA module genes, and an immune gene set obtained from online databases, 151 schizophrenia-associated immune-related genes were obtained. Moreover, machine learning algorithms including LASSO and Random Forest were employed to further screen out 17 signature genes, including GRIN1, P2RX7, CYBB, PTPN4, UBR4, LTF, THBS1, PLXNB3, PLXNB1, PI15, RNF213, CXCL11, IL7, ARHGAP10, TTR, TYROBP, and EIF4A2. Then, SVM-RFE was added, and together with LASSO and Random Forest, a hub gene (EIF4A2) out of the 17 signature genes was revealed. Lastly, in a schizophrenia rat model, the EIF4A2 expression levels were reduced in the model rat brains in a brain-regional dependent manner, but can be reversed by risperidone. In conclusion, by using various bioinformatic and biological methods, this study found 17 immune-related signature genes and a hub gene of schizophrenia that might be potential diagnostic biomarkers and therapeutic targets of schizophrenia.

Neurodegenerative disorders like Huntington's disease (HD) are a major threat to human health, with severe gait abnormalities and pathological changes (oxidative stress, neuroinflammation, and apoptosis) playing important roles in their development. The effects of artemisinin (ART) alone and in combination with the ERK antagonist PD98059 against 3-nitropropionic acid (3-NPA)-induced cell death and oxidative stress in SH-SY5Y cells were determined using the MTT and DCFH-DA assays, as well as RT-qPCR assays. In vivo, possible neuroprotective effects of ART (10, 20, and 40 mg/kg i.p.) against the neurotoxicity generated by 21-day 3-NPA (10 mg/kg i.p.) treatment was evaluated in rats by assessing behavioral parameters on days 1, 14, and 21. Further, various biochemical, inflammatory, apoptotic markers, histopathological changes, and protein expression were assessed using brain striatal samples. ART significantly mitigated the neurotoxic effect of 3-NPA in SH-SY5Y cells by regulating the mRNA expression of ERK, Bax, Bcl2, and cytochrome C. However, ART's neuroprotective activity was reduced in the presence of PD98059. Also, ART treatment for 21 days substantially alleviated the behavioral impairments associated with 3-NPA toxicity. It reduced the oxidative stress induced by 3-NPA, as evidenced by the lower levels of MDA, nitrite, and improved catalase, SOD activity, and GSH levels. ART treatment restored 3-NPA-induced histopathological alterations in the striatal area. ART effectively suppressed neuroinflammatory (IL-6) and apoptotic markers (caspase 3 and 9), increasing BDNF levels and restoring the p-ERK1/2, Nrf2, and HO-1 expression. ART could exert its neuroprotective effect via antioxidant, anti-inflammatory, and antiapoptotic properties with a possible involvement of the ERK/BDNF/Nrf2/HO-1 pathway.

The genetic transcription profile and underlying molecular mechanisms of ischemic stroke (IS) remain elusive. To address this issue, four mRNA and one miRNA expression profile of rats with middle cerebral artery occlusion (MCAO) were acquired from the Gene Expression Omnibus (GEO) database. A total of 780 differentially expressed genes (DEGs) and 56 miRNAs (DEMs) were screened. Gene set and functional enrichment analysis revealed that a substantial number of immune-inflammation-related pathways were abnormally activated in IS. Through weighted gene co-expression network analysis, the turquoise module was identified as meaningful. By taking the intersection of the turquoise module genes, DEM-target genes, and all DEGs, 354 genes were subsequently obtained as key IS-related genes. Among them, six characteristic genes were identified using the least absolute shrinkage and selection operator. After validation with three external datasets, transforming growth factor beta 1 (Tgfb1) was selected as the hub gene. This finding was further confirmed by gene expression pattern analysis in both the MCAO model rats and clinical IS patients. Moreover, the expression of the hub genes exhibited a negative correlation with the modified Rankin scale score (P < 0.05). Collectively, these results expand our knowledge of the genetic profile and molecular mechanisms involved in IS and suggest that the Tgfb1 gene is a potential biomarker of this disease.

Autism spectrum disorder (ASD) etiology probably involves a complex interplay of both genetic and environmental risk factors, which includes pre- and perinatal exposure to environmental stressors. Thus, this study evaluated the effects of prenatal exposure to valproic acid (VPA) combined with maternal deprivation (MD) on behavior, oxidative stress parameters, and inflammatory state at a central and systemic level in male and female rats. Pregnant Wistar rats were exposed to VPA during gestation, and the offspring were submitted to MD. Offspring were tested for locomotor and social behavior; rats were euthanized, where the cerebellum, posterior cortex, prefrontal cortex, and peripheric blood were collected for oxidative stress and inflammatory analysis. It was observed that young rats (25-30 days old) exposed only to VPA presented a lower social approach when compared to the control group. VPA + MD rats did not present the same deficit. Female rats exposed to VPA + MD presented oxidative stress in all brain areas analyzed. Male rats in the VPA and VPA + MD groups presented oxidative stress only in the cerebellum. Regarding inflammatory parameters, male rats exposed only to MD exhibited an increase in pro-inflammatory cytokines in the blood and in the cortex total. The same was observed in females exposed only to VPA. Animals exposed to VPA + MD showed no alterations in the cytokines analyzed. In summary, gestational (VPA) and perinatal (MD) insults can affect molecular mechanisms such as oxidative stress and inflammation differently depending on the sex and brain area analyzed. Combined exposition to VPA and MD triggers oxidative stress especially in female brains without evoking an inflammatory response.