[Exploring the mechanism of IgA vasculitis pathogenesis through the interaction of thrombin and inflammatory factors using urinary proteomics]. / è¿ç”¨å°¿è›‹ç™½ç»„å­¦æŠ€æœ¯æŽ¢ç´¢å‡è¡€é ¶ä¸Žç‚Žç—‡å› å­ç›¸äº’ä½œç”¨å‚ä¸ŽIgAè¡€ç®¡ç‚Žå‘ç— çš„æœºåˆ¶.

OBJECTIVES: To explore the evidence, urinary biomarkers, and partial mechanisms of hypercoagulability in the pathogenesis of IgA vasculitis (IgAV). METHODS: Differential expression of proteins in the urine of 10 healthy children and 10 children with IgAV was screened using high-performance liquid chromatography-tandem mass spectrometry, followed by Reactome pathway analysis. Protein-protein interaction (PPI) network analysis was conducted using STRING and Cytoscape software. In the validation cohort, 15 healthy children and 25 children with IgAV were included, and the expression levels of differential urinary proteins were verified using enzyme-linked immunosorbent assay. RESULTS: A total of 772 differential proteins were identified between the IgAV group and the control group, with 768 upregulated and 4 downregulated. Reactome pathway enrichment results showed that neutrophil degranulation, platelet activation, and hemostasis pathways were involved in the pathogenesis of IgAV. Among the differential proteins, macrophage migration inhibitory factor (MIF) played a significant role in neutrophil degranulation and hemostasis, while thrombin was a key protein in platelet activation and hemostasis pathways. PPI analysis indicated that thrombin directly interacted with several proteins involved in inflammatory responses, and these interactions involved MIF. Validation results showed that compared to healthy children, children with IgAV had significantly higher urine thrombin/creatinine and urine MIF/creatinine levels (P<0.05). CONCLUSIONS: Thrombin contributes to the pathogenesis of IgAV through interactions with inflammatory factors. Urinary thrombin and MIF can serve as biomarkers reflecting the hypercoagulable and inflammatory states in children with IgAV.

NLRP3 inflammasome pathway is involved in olfactory bulb pathological alteration induced by MPTP.

Olfactory bulb, as one of sensory organs opening to the outside, is susceptible to toxic environment and easy to deteriorate. Recent studies in Parkinson's disease (PD) patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys have shown that abnormal α-synuclein is accumulated in the olfactory glomeruli, suggesting that the lesions of PD are not only confined to the substantia nigra (SN) but also located in the olfactory bulb. Thus, olfactory bulb might be the region of onset in PD pathogenesis and a targeted region for diagnosis and treatment of PD. However, the relationship between olfactory bulb and pathogenesis of PD remains unclear. In the present study, we investigated the inflammatory pathological alterations in olfactory bulb and the underlying mechanisms in chronic MPTP mice. Mice were treated with MPTP/P, i.e., MPTP (25 mg/kg, s.c.) plus probenecid (250 mg/kg, i.p.) every 4 days, for ten times. The mice displayed typical parkinsonian syndrome. Then we examined their olfactory function and the pathologic changes in olfactory bulb. The mice showed obvious olfactory dysfunction in a buried pellet test. Immunohistochemical studies revealed that tyrosine hydroxylase (TH) protein levels were significantly decreased, whereas abnormal α-synuclein was significantly increased in the olfactory bulbs. Furthermore, the olfactory bulbs in MPTP/P-treated mice showed significantly increased levels of interleukin-1ß (IL-1ß), caspase-1, glial fibrillary acidic protein (GFAP), Toll receptor 4 (TLR4), phosphorylation of p65, as well as activated molecules of NOD-like receptor protein 3 (NLRP3) that were associated with neuroinflammation. Our results demonstrate that MPTP/P-caused olfactory bulb damage might be related to NLRP3-mediated inflammation.

NLRP3 inflammasome activation in the thymus of MPTP-induced Parkinsonian mouse model.

Ample evidence shows that Parkinson's disease (PD) is more than simply a central nervous system (CNS) disorder: the immune system appears to participate in PD pathogenesis. Extracellular misfolded α-synuclein (α-syn) may trigger an inflammatory response in the brain. Abnormal immune responses are involved in the development of PD, but little is known about the relationship between the thymus malfunction and the pathogenesis of PD. The present study investigated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced impairment in thymus and explored possible mechanisms involved in PD pathogenesis. After subcutaneous injection of MPTP (25 mg/kg) every 4 days for 40-days, immune responses became unbalanced, with increased IL-1ß concentrations. On histopathology, mice treated with MPTP displayed pathological involution and damaged ultrastructure of the thymus. Both the PD-related oligomeric α-synuclein and oxidative stress related nitrated-α-synuclein (Tyr125, Tyr133) in mice treated with MPTP were elevated. Correspondingly, oxidative stress damage was detected in the form of increased 8-hydroxyguanosine staining. Moreover, MPTP significantly increased expression of caspase-8, NF-κB, NLPR3, and caspase-1 in the thymus. These results suggested that MPTP was toxic to mouse thymus via a mechanism involving the NF-κB and NLRP3 inflammasome pathway. These results suggested that environmental factors may lead to pathological changes in the thymus that are similar to those in the central nervous system. A disordered thymus might take part in the development of PD, and its enhanced immune response might promote the degenerative changes in the brain.

A Novel Bibenzyl Compound (20C) Protects Mice from 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine/Probenecid Toxicity by Regulating the α-Synuclein-Related Inflammatory Response.

The novel bibenzyl compound 2-[4-hydroxy-3-(4- hydroxyphenyl) benzyl]-4-(4- hydroxyphenyl) phenol (20C) plays a neuroprotective role in vitro, but its effects in vivo have not yet been elucidated. In this study, we estimated the efficacy of 20C in vivo using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p) mouse model from behavior, dopamine, and neuron and then the possible mechanisms for these effects were further investigated. The experimental results showed that 20C improved behavioral deficits, attenuated dopamine depletion, reduced dopaminergic neuron loss, protected the blood-brain barrier (BBB) structure, ameliorated α-synuclein dysfunction, suppressed glial activation, and regulated both nuclear factor-κB (NF-κB) signaling and the NOD-like receptor protein (NLRP) 3 inflammasome pathway. Our results indicated that 20C may prevent neurodegeneration in the MPTP/p mouse model by targeting α-synuclein and regulating α-synuclein-related inflammatory responses, including BBB damage, glial activation, NF-κB signaling, and the NLRP3 inflammasome pathway.

Reassessment of subacute MPTP-treated mice as animal model of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model remains the most commonly used animal model of Parkinson's disease (PD). There are three MPTP-treatment schemes: acute, subacute and chronic. Considering the advantages of the period and similarity to PD, the subacute model was often chosen to assess the validity of new candidates, but the changes caused by the subacute MPTP treatment and the appropriate positive control for this model remain to be further confirmed. The aim of this study was: to estimate the value of the subacute MPTP mouse model in aspects of behavioral performance, biochemical changes and pathological abnormalities, and to find effective positive drugs. Male C57BL/6 mice were injected with MPTP (30 mg·kg-1·d-1, ip) for 5 consecutive days. Three days before MPTP injection, the mice were orally administered selegiline (3 mg·kg-1·d-1), pramipexole (3 mg·kg-1·d-1), or medopar (100 mg·kg-1·d-1) for 18 days. Behavioral performance was assessed in the open field test, pole test and rotarod test. Neurotransmitters in the striatum were detected using HPLC. Protein levels were measured by Western blot. Pathological characteristics were examined by immunohistochemistry. Ultrastructure changes were observed by electron microscopy. The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system. Additionally, MPTP significantly increased the α-synuclein levels and the number of astrocytes in the striatum, and destroyed the blood-brain barrier (BBB) in the substantia nigra pars compacta. Both selegiline and pramipexole were able to protect the mice against MPTP injuries. We conclude that the subacute MPTP mouse model does not show visible motor defects; it is not enough to evaluate the validity of a candidate just based on behavioral examination, much attention should also be paid to the alterations in neurotransmitters, astrocytes, α-synuclein and the BBB. In addition, selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.

Pathological α-synuclein exacerbates the progression of Parkinson's disease through microglial activation.

Parkinson's disease (PD) is characterized by α-synuclein accumulation, dopaminergic neuron loss and inflammation. α-Synuclein can be secreted by neurons and activate microglia to different degrees. Excessive microglial activation can increase the production of tumor necrosis factor alpha (TNF-α), interleukin-1-ß (IL-1ß), interleukin-6 (IL-6), interferon-γ (INF-γ), inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS) and nitric oxide (NO), and can also enhance microglial phagocytosis and migration as well as lymphocyte infiltration. Pathological α-synuclein and microglial activation can potentiate each other, leading to the loss of dopaminergic neurons and accelerated PD degeneration. This review will mainly describe the profiles of α-synuclein-activated microglia, with particular emphasis on the signaling cascades involved in this process.

Ginsenoside Rg1 attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced parkinsonism mouse model by targeting α-synuclein abnormalities in the substantia nigra.

Parkinson's disease (PD) is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of aggregated α-synuclein in specific central nervous system (CNS) regions. Disease development is attributed to α-synuclein abnormalities, particularly aggregation and phosphorylation. The ginsenoside Rg1, an active component of ginseng, possesses neuroprotective and anti-inflammatory effects. The purpose of the present study was to evaluate these activities of Rg1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid (MPTP/p)-induced PD mouse model for the first time and to elucidate the underlying mechanisms. Oral treatment with Rg1 significantly attenuated the high MPTP-induced mortality, behavior defects, loss of dopamine neurons and abnormal ultrastructure changes in the SNpc. Other assays indicated that the protective effect of Rg1 may be mediated by its anti-neuroinflammatory properties. Rg1 regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) in the SNpc. Rg1 also alleviated the unusual MPTP-induced increase in oligomeric, phosphorylated and disease-related α-synuclein in the SNpc. In conclusion, Rg1 protects dopaminergic neurons, most likely by reducing aberrant α-synuclein-mediated neuroinflammation, and holds promise for PD therapeutics.

Clinical, demographic and psychological characteristics of infertile male smokers in Northeast China.

OBJECTIVES: To investigate clinical, demographic and psychological characteristics of infertile male smokers in northeast China. METHODS: Serum and semen samples were collected from infertile men. Semen analysis was performed according to conventional procedures. Serum follicle-stimulating hormone, luteinizing hormone and testosterone levels were quantified. Psychological anxiety and depression were evaluated by the self-rating anxiety scale (SAS) and self-rating depression scale (SDS), respectively. RESULTS: Both SDS and SAS scores were significantly higher in smokers (n = 704) than in nonsmokers (n = 372); in addition, sperm viability and motility were significantly lower in smokers than in nonsmokers. Spearman's correlation coefficient analysis revealed significant positive correlations between duration of smoking and SDS and SAS scores, and between cigarettes smoked per day and SDS and SAS scores. CONCLUSIONS: Cigarette smoking has a negative effect on sperm viability and motility, and is associated with increased SDS and SAS scores.