Diazepam inhibits LPS-induced pyroptosis and inflammation and alleviates pulmonary fibrosis in mice by regulating the let-7a-5p/MYD88 axis.

BACKGROUND AND OBJECTIVE: Pulmonary fibrosis caused by lung injury is accompanied by varying degrees of inflammation, and diazepam can reduce the levels of inflammatory factors. Therefore, the purpose of this study was to determine whether diazepam can inhibit inflammation and ameliorate pulmonary fibrosis by regulating the let-7a-5p/myeloid differentiation factor 88 (MYD88) axis. METHODS: Lipopolysaccharide (LPS) was used to induce cell pyroptosis in an animal model of pulmonary fibrosis. After treatment with diazepam, changes in cell proliferation and apoptosis were observed, and the occurrence of inflammation and pulmonary fibrosis in the mice was detected. RESULTS: The results showed that LPS can successfully induce cell pyroptosis and inflammatory responses and cause lung fibrosis in mice. Diazepam inhibits the expression of pyroptosis-related factors and inflammatory factors; moreover, it attenuates the occurrence of pulmonary fibrosis in mice. Mechanistically, diazepam can upregulate the expression of let-7a-5p, inhibit the expression of MYD88, and reduce inflammation and inhibit pulmonary fibrosis by regulating the let-7a-5p/MYD88 axis. CONCLUSION: Our findings indicated that diazepam can inhibit LPS-induced pyroptosis and inflammatory responses and alleviate pulmonary fibrosis in mice by regulating the let-7a-5p/MYD88 axis.

Melatonin MT1 receptors regulate the Sirt1/Nrf2/Ho-1/Gpx4 pathway to prevent α-synuclein-induced ferroptosis in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons and aggregation of α-synuclein (α-syn). Ferroptosis, a form of cell death induced by iron accumulation and lipid peroxidation, is involved in the pathogenesis of PD. It is unknown whether melatonin receptor 1 (MT1) modulates α-syn and ferroptosis in PD. Here, we used α-syn preformed fibrils (PFFs) to induce PD models in vivo and in vitro. In PD mice, α-syn aggregation led to increased iron deposition and ferroptosis. MT1 knockout exacerbated these changes and resulted in more DA neuronal loss and severe motor impairment. MT1 knockout also suppressed the Sirt1/Nrf2/Ho1/Gpx4 pathway, reducing resistance to ferroptosis, and inhibited expression of ferritin Fth1, leading to more release of ferrous ions. In vitro experiments confirmed these findings. Knockdown of MT1 enhanced α-syn PFF-induced intracellular α-syn aggregation and suppressed expression of the Sirt1/Nrf2/Ho1/Gpx4 pathway and Fth1 protein, thereby aggravating ferroptosis. Conversely, overexpression of MT1 reversed these effects. Our findings reveal a novel mechanism by which MT1 activation prevents α-syn-induced ferroptosis in PD, highlighting the neuroprotective role of MT1 in PD.

Identification of m6A-Related Biomarkers in Systemic Lupus Erythematosus: A Bioinformation-Based Analysis.

Background: Systemic Lupus Erythematosus (SLE), a prototypical autoimmune disorder, presents a challenge due to the absence of reliable biomarkers for discerning organ-specific damage within SLE. A growing body of evidence underscores the pivotal involvement of N6-methyladenosine (m6A) in the etiology of autoimmune conditions. Methods: The datasets, which primarily encompassed the expression profiles of m6A regulatory genes, were retrieved from the Gene Expression Omnibus (GEO) repository. The optimal model, selected from either Random Forest (RF) or Support Vector Machine (SVM), was employed for the development of a predictive nomogram model. To identify pivotal genes associated with SLE, a comprehensive screening process was conducted utilizing LASSO, SVM-RFE, and RF techniques. Within the realm of SLE susceptibility, Weighted Gene Co-expression Network Analysis (WGCNA) was harnessed to delineate relevant modules and hub genes. Additionally, MeRIP-qPCR assays were performed to elucidate key genes correlated with m6A targets. Furthermore, a Mendelian randomization study was conducted based on genome-wide association studies to assess the causative influence of MMP9 on ischemic stroke (IS), which is not only a severe cerebrovascular event but also a common complication of SLE. Results: Twelve m6A regulatory genes was identified, demonstrating statistical significance (p < 0.05) and utilized for constructing a nomogram model using the RF algorithm. EPSTI1, USP18, HP, and MMP9, as the hub genes, were identified. MMP9 uniquely correlates with m6A modification and was causally linked to an increased risk of IS, as indicated by our inverse variance weighting analysis showing an odds ratio of 1.0134 (95% CI=1.0004-1.0266, p = 0.0440). Conclusion: Our study identified twelve m6A regulators, shedding light on the molecular mechanisms underlying SLE risk genes. Importantly, our analysis established a causal relationship between MMP9, a key m6A-related gene, and ischemic stroke, a common complication of SLE, thereby providing critical insights for presymptomatic diagnostic approaches.

Ferroptosis in peripheral blood mononuclear cells of systemic lupus erythematosus.

OBJECTIVES: To investigate the evidence of ferroptosis in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE). METHODS: PBMCs were collected from 30 patients diagnosed as SLE and without any standardised treatment previously and 10 healthy controls. Meanwhile the clinical and laboratory data were collected. The intracellular Fe2+, reactive oxygen species (ROS) and lipid peroxidation (LPO) were detected by fluorescence probe and flow cytometry. The morphology of cells and intracellular organelles were observed by transmission electron microscopy. RT-qPCR and Western blot were applied to compare the expression of GPX4 in PBMCs. RESULTS: The concentration of Fe2+, levels of ROS and LPO in PBMCs from SLE patients were significantly higher than those in healthy controls (p<0.05), and significant differences between the two groups were observed in CD14+ monocytes, CD19+B cells, and CD56+ NK cells respectively. The more prominent differences were observed in SLE patients with renal involvement, liver injury and higher disease activity score. There was no significant difference in GPX4 mRNA expression between SLE patients and healthy controls, however GPX4 protein expression was significantly lower in SLE patients compared to healthy controls, with a negative correlation with the SLE disease activity index. Transmission electron microscopy revealed typical morphological features of ferroptosis such as decreased mitochondrial volume, increased mitochondrial membrane density, and disappearance of mitochondrial cristas. CONCLUSIONS: Ferroptosis occurred more frequently in PBMCs of SLE patients than healthy controls, including CD14+ monocytes, CD19+B cells, CD56+ NK cells, and so on, with negative association with SLE disease activity, which indicated the correlation between ferroptosis with the pathogenesis of SLE.

Role of α-synuclein in microglia: autophagy and phagocytosis balance neuroinflammation in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease, and is characterized by accumulation of α-synuclein (α-syn). Neuroinflammation driven by microglia is an important pathological manifestation of PD. α-Syn is a crucial marker of PD, and its accumulation leads to microglia M1-like phenotype polarization, activation of NLRP3 inflammasomes, and impaired autophagy and phagocytosis in microglia. Autophagy of microglia is related to degradation of α-syn and NLRP3 inflammasome blockage to relieve neuroinflammation. Microglial autophagy and phagocytosis of released α-syn or fragments from apoptotic neurons maintain homeostasis in the brain. A variety of PD-related genes such as LRRK2, GBA and DJ-1 also contribute to this stability process. OBJECTIVES: Further studies are needed to determine how α-syn works in microglia. METHODS: A keyword-based search was performed using the PubMed database for published articles. CONCLUSION: In this review, we discuss the interaction between microglia and α-syn in PD pathogenesis and the possible mechanism of microglial autophagy and phagocytosis in α-syn clearance and inhibition of neuroinflammation. This may provide a novel insight into treatment of PD.

Fatal Balamuthia mandrillaris infection with red plaques on the nasal dorsum as the first presentation

Abstract Balamuthia mandrillaris infection is a rare infectious disease around the world, with high rates of morbidity and mortality. Its early and correct diagnosis is a big challenge for us, and without it the delay in starting effective treatment can lead to the development of encephalitis. This is a report of a case of Balamuthia mandrillaris infection in a Chinese boy, with red plaques on the nasal dorsum as the first presentation, who finally developed into fatal encephalitis. The authors have reviewed the related literature and share the special skin features in order to favor the early diagnosis of the disease and increase the chances of survival.

Synthesis of adjustable {312}/{004} facet heterojunction MWCNTs/Bi5O7I photocatalyst for ofloxacin degradation: Novel insights into the charge carriers transport.

Multi-wall carbon nanotubes (MWCNTs) with high electrical conductivity are commonly accounted as the ideal additives to enhance the charge surface migration efficiency in photocatalysis. Theoretically, the MWCNTs-modified binary photocatalysts have potential for the change of nanocrystal structure. Herein, we reports an adjustable {312}/{004}facet heterojunction MWCNTs/Bi5O7I nanocomposite. Interestingly, the synergistic effect of {312}/{004}facet heterojunction and MWCNTs can effectively accelerate the spatial charge carriers transport. A novel {312}/{004}facet "S-scheme" pathway was proven to be the dominated pathway for the enhancement of spatial charge carriers. As a result, the MWCNTs-{312}/{004}Bi5O7I composites exhibited superior photocatalytic oxidation efficiency for a representative antibiotics ofloxacin photodegradation. Density functional theory (DFT) calculation and LC-MS/MS analysis confirmed that the possible dealkylation and oxidation pathways could be found in OFL degradation. This work provides novel insights for the relationship between charge carrier transport and facet structure-property.

Fatal Balamuthia mandrillaris infection with red plaques on the nasal dorsum as the first presentation.

Balamuthia mandrillaris infection is a rare infectious disease around the world, with high rates of morbidity and mortality. Its early and correct diagnosis is a big challenge for us, and without it the delay in starting effective treatment can lead to the development of encephalitis. This is a report of a case of Balamuthia mandrillaris infection in a Chinese boy, with red plaques on the nasal dorsum as the first presentation, who finally developed into fatal encephalitis. The authors have reviewed the related literature and share the special skin features in order to favor the early diagnosis of the disease and increase the chances of survival.

A Facile Strategy for Preparation of α-Heterobifunctional Polystyrenes with Well-Defined Molecular Weight.

A facile strategy for synthesis of α-heterobifunctional polystyrenes is reported. The novel functional polystyrenes have been successfully synthesized via a combination of atom transfer radical polymerization (ATRP) and chemical modification of end-functional groups. First, ε-caprolactone end-capped polystyrenes with controlled molecular weight and low polydispersity were prepared by ATRP of styrene using α-bromo-ε-caprolactone (αBrCL) as an initiator. Then, removal of the terminal bromine atom was performed with iso-propylbenzene in the presence of CuBr/PMDETA. Finally, ring-opening modifications of the caprolactone group were carried out with amines, n-butanol and H(2) O to produce novel polystyrenes containing two different functional groups at one end.

Synthesis, characterization and self-assembly of novel amphiphilic block copolymers with a polyhedral oligomeric silsesquioxanes moiety attached at the junction of the two blocks.

A novel well-defined amphiphilic block copolymer, with the polyhedral oligomeric silsesquioxane (POSS) moiety at the junction of the two blocks of polystyrene and poly(ethylene oxide) (PEO), was designed and synthesized. First, a macroinitiator containing a POSS moiety and a PEO chain was prepared and then atom transfer radical polymerization of styrene was carried out in the presence of the macroinitiator in bulk. The polymerization results show that the process bears the characteristics of controlled/living free radical polymerizations. The structure and molecular weight of the polymers were characterized by GPC, (1) H NMR, and FT-IR spectroscopy. The self-assembly behaviors of the polymers was investigated by TEM and SEM. It was observed that the polymers can self-assemble into vesicles in aqueous solution.

Synthesis of amphiphilic supramolecular miktoarm star copolymers by molecular recognition.

Synthesis of novel amphiphilic supramolecular miktoarm star copolymers has been achieved through complementary molecular recognition and interactions between carboxy groups and amino groups. Polystyrenes carrying two and one carboxy groups at the middle of the polymer chain are used as precursors to react with poly(ethylene oxide) (PEO) end-capped with a primary amine functionality (-NH(2) ) or a quaternary ammonium hydroxide functionality (-N(+) (CH(2) CH(3) )(3) OH(-) ). The result suggests that the basicity of the amine plays a key role in the molecular recognition procedure. The efficiency of ionic bond formation can be enhanced from 40% up to 97% by using PEO-N(+) (CH(2) CH(3) )(3) OH(-) instead of PEO-NH(2) . The obtained supramolecular polymers can be dissociated in dilute acid solution at room temperature.