Molecular Neurobiology最新文献

The purpose of this study was to investigate the relationship between oxidative stress and cognitive function, encompassing cognitive performance, intelligence, memory, reaction time, speech and vision by a bidirectional Mendelian randomisation study. Independent genetic variants associated with glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX), peroxiredoxin (PRDX), sulfhydryl oxidase (SOX) and thyroid peroxidase (TPO) were explored using a genome-wide association study (GWAS). The inverse variance weighted (IVW) or Wald ratio method was employed to ascertain the relationship between antioxidant enzymes and cognitive function. The MR analyses indicated that the MR effect estimates of GST (β = 0.0352, P = 0.0047, FDR = 0.0164) and TPO (β = 0.0531, P = 0.0003, FDR = 0.0021) were significantly associated with cognitive performance elevation. Furthermore, genetically predicted GST (β = 0.0334, P = 0.0043, FDR = 0.0151) and TPO (β = 0.0496, P = 0.0031, FDR = 0.0151) were found to be associated with high intelligence. Additionally, there were also some associations of SOX (β = 0.0243, P = 0.0283, FDR = 0.066) on high cognitive performance, TPO (β = 0.1189, P = 0.0315, FDR = 0.2205) on larger maximum digits remembered correctly, and SOX (β = - 0.2435, P = 0.0395, FDR = 0.1185) on reaction time. Nevertheless, the associations between antioxidant enzymes and speech and linguistic disorders, as well as visual disturbances, were not significant. We did not find reverse causation between antioxidant enzymes and cognitive function traits. This study provides evidence of potential causal relationships between oxidative stress and cognitive function.

Plants and their derived phytochemicals have a long history of treating a wide range of illnesses for several decades. They are believed to be the origin of a diverse array of medicinal compounds. One of the compounds found in kudzu root is puerarin, a isoflavone glycoside commonly used as an alternative medicine to treat various diseases. From a biological perspective, puerarin can be described as a white needle crystal with the chemical name of 7-hydroxy-3-(4-hydroxyphenyl)-1-benzopyran-4-one-8-D-glucopyranoside. Besides, puerarin is sparingly soluble in water and produces no color or light yellow solution. Multiple experimental and clinical studies have confirmed the significant therapeutic effects of puerarin. These effects span a wide range of pharmacological effects, including neuroprotection, hepatoprotection, cardioprotection, immunomodulation, anticancer properties, anti-diabetic properties, anti-osteoporosis properties, and more. Puerarin achieves these effects by interacting with various cellular and molecular pathways, such as MAPK, AMPK, NF-κB, mTOR, β-catenin, and PKB/Akt, as well as different receptors, enzymes, and growth factors. The current review highlights the molecular mechanism of puerarin as a neuroprotective agent in the treatment of various neurodegenerative and neurological diseases. Extensive cellular, animal, and clinical research has provided valuable insights into its effectiveness in conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, cerebral stroke, depression, and more.

As the brain's resident immune patrol, microglia mediate endogenous immune responses to central nervous system injury in ischemic stroke, thereby eliciting either neuroprotective or neurotoxic effects. The association of microglia-mediated neuroinflammation with the progression of ischemic stroke is evident through diverse signaling pathways, notably involving inflammasomes. Within microglia, inflammasomes play a pivotal role in promoting the maturation of interleukin-1β (IL-1β) and interleukin-18 (IL-18), facilitating pyroptosis, and triggering immune infiltration, ultimately leading to neuronal cell dysfunction. Addressing the persistent and widespread inflammation holds promise as a breakthrough in enhancing the treatment of ischemic stroke.

Numerous natural antioxidants have been developed into agents for neurodegenerative diseases (NDs) treatment. Rosmarinic acid (RA), an excellent antioxidant, exhibits neuroprotective activity, but its anti-NDs efficacy remains puzzling. Here, Caenorhabditis elegans models were employed to systematically reveal RA-mediated mechanisms in delaying NDs from diverse facets, including oxidative stress, the homeostasis of neural and protein, and mitochondrial disorders. Firstly, RA significantly inhibited reactive oxygen species accumulation, reduced peroxide malonaldehyde production, and strengthened the antioxidant defense system via increasing superoxide dismutase activity. Besides, RA reduced neuronal loss and ameliorated polyglutamine and ɑ-synuclein-mediated dyskinesia in NDs models. Further, in combination with the data and molecular docking results, RA may bind specifically to Huntington protein and ɑ-synuclein to prevent toxic protein aggregation and thus enhance proteostasis. Finally, RA ameliorated mitochondrial dysfunction including increasing adenosine triphosphate and mitochondrial membrane potential levels and rescuing mitochondrial membrane proteins' expressions and mitochondrial structural abnormalities via regulating mitochondrial dynamics genes and improving the mitochondrial kinetic homeostasis. Thus, this study systematically revealed the RA-mediated neuroprotective mechanism and promoted RA as a promising nutritional intervention strategy to prevent NDs.

Peripheral surgery-induced neural inflammation is a key pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the mechanism underlying neuroinflammation and associated neural injury remains elusive. Surgery itself can lead to gut damage, and the occurrence of POCD is accompanied by high levels of TNF-α in the serum and blood‒brain barrier (BBB) damage. Reductions in stress, inflammation and protein loss have been emphasized as strategies for enhanced recovery after surgery (ERAS). We designed an amino acids and dipeptide (AAD) formula for injection that could provide intestinal protection during surgery. Through the intraoperative infusion of AAD based on the ERAS concept, we aimed to explore the effect of AAD injection on POCD and its underlying mechanism from the gut to the brain. Here, we observed that AAD injection ameliorated neural injury in POCD, in addition to restoring the function of the intestinal barrier and BBB. We also found that TNF-α levels decreased in the ileum, blood and hippocampus. Intestinal barrier protectors and TNF-α inhibitors also alleviated neural damage. AAD injection treatment decreased HMGB1 production, pyroptosis, and M1 microglial polarization and increased M2 polarization. In vitro, AAD injection protected the impaired gut barrier and decreased TNF-α production, alleviating damage to the BBB by stimulating cytokine transport in the body. HMGB1 and Caspase-1 inhibitors decreased pyroptosis and M1 microglial polarization and increased M2 polarization to protect TNF-α-stimulated microglia in vitro. Collectively, these findings suggest that the gut barrier-TNF-α-BBB-HMGB1-Caspase-1 inflammasome-pyroptosis-M1 microglia pathway is a novel mechanism of POCD related to the gut-brain axis and that intraoperative AAD infusion is a potential treatment for POCD.

Helicid (HEL) has been found to possess antidepressant pharmacological activity. The paper was to testify to the precise molecular mechanism through which HEL regulates lncRNA-NONRATT030918.2 to exert an antidepressant impression in depression models. A depression model stimulated using chronic unpredictable mild stress (CUMS) was created in rats, and the depressive state of the rats was assessed through behavioral experiments. Additionally, an in vitro model of PC12 cells induced by corticosterone (CORT) was established, and cytoactive was tested using the CCK8. The subcellular localization of the NONRATT030918.2 molecule was confirmed through a fluorescence in situ hybridization experiment. The relationship between NONRATT030918.2, miRNA-128-3p, and Prim1 was analyzed using dual-luciferase reporter gene assay, RNA Binding Protein Immunoprecipitation assay, and RNA pull-down assay. The levels of NONRATT030918.2, miRNA-128-3p, and Prim1 were tested using Q-PCR. Furthermore, the levels of Prim1, Bax, Bcl-2, and caspase3 were checked through Western blot. The HEL can alleviate the depression-like behavior of CUMS rats (P < 0.05), and reduce the mortality of hippocampal via downregulating the level of NONRATT030918.2 (P < 0.05). In CORT-induced PC12 cells, intervention with HEL led to decreased expression of NONRATT030918.2 and Prim1 (P < 0.05), as well as increased expression of miRNA-128-3p (P < 0.05). This suggests that HEL regulates the expression of NONRATT030918.2 to upregulate miRNA-128-3p (P < 0.05), which in turn inhibits CORT-induced apoptosis in PC12 cells by targeting Prim1 (P < 0.05). The NONRATT030918.2/miRNA-128-3p/Prim1 axis could potentially serve as a crucial regulatory network for HEL to exert its neuroprotective effects.

Microglia and astrocytes are key players in neuroinflammation and ischemic stroke. A1 astrocytes are a subtype of astrocytes that are extremely neurotoxic and quickly kill neurons. Although the detrimental A1 astrocytes are present in many neurodegenerative diseases and are considered to accelerate neurodegeneration, their role in the pathophysiology of ischemic stroke is poorly understood. Here, we combined RNA-seq, molecular and immunological techniques, and behavioral tests to investigate the role of A1 astrocytes in the pathophysiology of ischemic stroke. We found that astrocyte phenotypes change from a beneficial A2 type in the acute phase to a detrimental A1 type in the chronic phase following ischemic stroke. The activated microglial IL1α, TNF, and C1q prompt commitment of A1 astrocytes. Inhibition of A1 astrocytes induction attenuates reactive gliosis and ameliorates morphological and functional defects following ischemic stroke. The crosstalk between astrocytic C3 and microglial C3aR contributes to the formation of A1 astrocytes and morphological and functional defects. In addition, NF-κB is activated following ischemic stroke and governs the formation of A1 astrocytes via direct targeting of inflammatory cytokines and chemokines. Taken together, we discovered that A2 astrocytes and A1 astrocytes are enriched in the acute and chronic phases of ischemic stroke respectively, and that the C3/C3aR/NF-κB signaling leads to A1 astrocytes induction. Therefore, the C3/C3aR/NF-κB signaling is a novel therapeutic target for ischemic stroke treatment.

PRNP Q160X is one of the five dominantly inheritable nonsense mutations causing familial prion diseases. Till now, it remains unclear how this type of nonsense mutations causes familial prion diseases with unique clinical and pathological characteristics. Human prion protein (PrP) Q160X mutation is equivalent to Q159X in mouse PrP, which produces the mutant fragment PrP1-158. Through intracerebroventricular injection of recombinant adeno-associated virus in newborn mice, we successfully overexpressed mouse PrP1-158-FLAG in the central nervous system. Interestingly, high level PrP1-158-FLAG expression in the brain caused death in these mice with an average survival time of 60 ± 9.1 days. Toxicity correlated with levels of PrP1-158-FLAG but was independent of endogenous PrP. Histopathological analyses showed microgliosis and astrogliosis in mouse brains expressing PrP1-158-FLAG and most of PrP1-158-FLAG staining appeared intracellular. Biochemical characterization revealed that the majority of PrP1-158-FLAG were insoluble and a significant part of PrP1-158-FLAG appeared to contain an un-cleaved signal peptide that may contribute to its cytoplasmic localization. Importantly, an ~10-kDa proteinase K-resistant PrP fragment was detected, which was the same as those observed in patients suffering from this type of prion diseases. To our knowledge, this is the first animal study of familial prion disease caused by Q159X that recapitulates key features of human disease. It will be a valuable tool for investigating the pathogenic mechanisms underlying familial prion diseases caused by nonsense mutations.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the selective loss of motor neurons. A bidirectional communication system known as the "microbiota-gut-brain" axis has a regulatory function in neurodegenerative disorders. The impact of probiotics on ALS through the "microbiota-gut-brain" axis remains uncertain. A longitudinal investigation was conducted to examine the alterations in the structure of the ileum and colon in mutant superoxide dismutase 1 (SOD1^G93A) transgenic mice models of ALS by using immunofluorescence and Western blotting. Subsequently, the mice were administered a multistrain probiotic mixture (LBE) or vehicle orally, starting from 60 days of age until the terminal stage of the disease. The effects of these agents on the behavior, gut microbiota, microbial metabolites, and pathological processes of the spinal and intestine of SOD1^G93A mice were analyzed, with a focus on exploring potential protective mechanisms. SOD1^G93A mice exhibit various structural abnormalities in the intestine. Oral administration of LBE improved the proinflammatory response, reduced aberrant superoxide dismutase 1 (SOD1) aggregation, and protected neuronal cells in the intestine and spinal cord of SOD1^G93A mice. Furthermore, LBE treatment resulted in a change in intestinal microbiota, an increase in short-chain fatty acid levels, and an enhancement in autophagy flux. SOD1^G93A mice exhibited various structural abnormalities in the intestine. LBE can improve the proinflammatory response, reduce aberrant SOD1 aggregation, and protect neuronal cells in the spinal cord and intestine of SOD1^G93A mice. The positive effect of LBE can be attributed to increased short-chain fatty acids and enhanced autophagy flux.

Duchenne muscular dystrophy (DMD), a lethal X-linked recessive genetic disease, is characterized by progressive muscle wasting which will lead to premature death by cardiorespiratory complications in their late twenties. And 2.5-19% DMD carriers that also suffer from skeletal muscle damage or dilated cardiomyopathy when diagnosed as soon as possible is meaningful for prenatal diagnosis and advance warning for self-health. The current DMD carrier screening mainly relies on detecting serum creatine kinase activity, covering only 50-70% DMD carriers which will cause many false negatives and require the discovery of highly effective biomarker and simple detection procedure for DMD carriers. In this article, we have compiled a comprehensive summary of all documented biomarkers associated with DMD and categorized them based on their expression patterns. We specifically pinpointed novel DMD biomarkers, previously unreported in DMD carriers, and conducted further investigations to explore their potential. Compared to creatine kinase activity alone in DMD carriers, creatine kinase-MM can improve the specificity from 73 to 81%. And our investigation revealed another promising protein: proto-oncogene tyrosine-protein kinase receptor (RET). When combined with creatine kinase-MM (creatine kinase-MM/RET ratio), it significantly enhances the specificity (from 81 to 83%) and sensitivity (from 71.4 to 93%) of detecting DMD carriers in serum. Moreover, we successfully devised an efficient method for extracting RET from dried blood spots. This breakthrough allowed us to detect both creatine kinase-MM and RET using dried blood spots without compromising the detection rate.