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Diabetic kidney disease (DKD) is a severe microvascular complication of diabetes associated with high mortality and disability rates. Inflammation has emerged as a key pathological mechanism in DKD, prompting interest in novel therapeutic approaches targeting inflammatory pathways. Interleukin-6 (IL-6), a well-established inflammatory cytokine known for mediating various inflammatory responses, has attracted great attention in the DKD field. Although multiple in vivo and in vitro studies highlight the potential of targeting IL-6 in DKD treatment, its exact roles in the disease remains unclear. This review presents the roles of IL-6 in the pathogenesis of DKD, including immunoinflammation, metabolism, hemodynamics, and ferroptosis. In addition, we summarize the current status of IL-6 inhibitors in DKD-related clinical trials and discuss the potential of targeting IL-6 for treating DKD in the clinic.

Background Cognitive decline occurs frequently in Parkinson’s disease (PD), which greatly decreases the quality of life of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by overactivated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using a rotenone-induced mouse PD model. Methods To evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by Morris water maze, objective recognition, and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation, and apoptosis were determined by immunohistochemistry and Western blot or immunofluorescence staining. The gene expression of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively. Results Rotenone dose-dependently induced cognitive deficits in mice by showing decreased performance of rotenone-treated mice in the novel objective recognition, passive avoidance, and Morris water maze compared with that of vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, and Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. A time course experiment revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 and minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in mice treated with combined PLX3397 or minocycline and rotenonee compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis. Conclusions Taken together, our findings suggested that microglial activation contributes to cognitive impairments in a rotenone-induced mouse PD model via neuroinflammation, oxidative stress, and apoptosis, providing novel insight into the immunopathogensis of cognitive deficits in PD.

Image style transfer is a challenging problem in computer vision which aims at rendering an image into different styles. A lot of progress has been made to transfer the style of one painting of a representative artist in real time, whereas less attention has been focused on transferring an artist’s style from a collection of his paintings. This task requests capturing the artist’s precise style from his painting collection. Existing methods did not pay more attention on the possible disruption of original content details and image structures by texture elements and noises, which leads to the structure deformation or edge blurring of the generated images. To address this problem, we propose IFFMStyle, a high-quality image style transfer framework. Specifically, we introduce invalid feature filtering modules (IFFM) to the encoder–decoder architecture to filter the content-independent features in the original image and the generated image. Then, the content-consistency constraint is used to enhance the model’s content-preserving capability. We also introduce style perception consistency loss to jointly train a network with content loss and adversarial loss to maintain the distinction of different semantic content in the generated image. Additionally, we have no requirement for paired content image and style image. The experimental results show that the stylized image generated by the proposed method significantly improves the quality of the generated images, and can realize the style transfer based on the semantic information of the content image. Compared with the advanced method, our method is more favored by users.

Background The loss of locus coeruleus noradrenergic (LC/NE) neurons in the brainstem is reported in multiple neurodegenerative disorders, including Parkinson’s disease (PD). However, the mechanisms remain unclear. Strong evidence suggested that microglia-mediated neuroinflammation contributes to neurodegeneration in PD. We recently recognized integrin CD11b, the α-chain of macrophage antigen complex-1 (Mac-1, also called CR3), as a key regulator for microglial activation. However, whether CD11b is involved in LC/NE neurodegeneration in PD remains to be investigated. Methods LC/NE neurodegeneration and microglial activation were compared between wild type (WT) and CD11b KO mice after treated with paraquat and maneb, two pesticides that widely used to create PD model. The role of NLRP3 inflammasome in CD11b-mediated microglial dysfunction and LC/NE neurodegeneration was further explored. LC/NE neurodegeneration, microglial phenotype, and NLRP3 inflammasome activation were determined by using Western blot, immunohistochemistry, and RT-PCR technologies. Results Paraquat and maneb co-exposure elevated the expressions of CD11b in the brainstem of mice, and CD11b knockout significantly reduced LC/NE neurodegeneration induced by paraquat and maneb. Mitigated microglial activation and gene expressions of proinflammatory cytokines were also observed in paraquat and maneb-treated CD11b −/− mice. Mechanistically, CD11b-mediated NLRP3 inflammasome activation contributes to paraquat and maneb-induced LC/NE neurodegeneration. Compared with WT controls, CD11b deficiency reduced paraquat and maneb-induced NLRP3 expression, caspase-1 activation, and interleukin-1β production in mice. Furthermore, inhibition of NLRP3 inflammasome by glybenclamide, a sulfonylurea inhibitor of NLRP3 inflammasome, was found to be able to suppress microglial proinflammatory activation and nuclear factor-κB activation induced by paraquat and maneb. Moreover, reduced reactive oxygen species production, NADPH oxidase, and inducible nitric oxide synthase expressions as well as 4-hydroxynonenal and malondialdehyde levels were detected in combined glybenclamide and paraquat and maneb-treated mice compared with paraquat and maneb alone group. Finally, we found that glybenclamide treatment ameliorated LC/NE neurodegeneration and α-synuclein aggregation in paraquat and maneb-treated mice. Conclusion Our findings suggested that CD11b mediates LC/NE neurodegeneration through NLRP3 inflammation-dependent microglial proinflammatory activation in a two pesticide-induced mouse PD model, providing a novel insight into the immune pathogenesis of LC/NE neuronal damage in related disorders.

Introduction The mechanisms of cognitive impairments in Parkinson’s disease (PD) remain unknown. Accumulating evidence revealed that brain neuroinflammatory response mediated by microglial cells contributes to cognitive deficits in neuropathological conditions and macrophage antigen complex-1 (Mac1) is a key factor in controlling microglial activation. Objectives To explore whether Mac1-mediated microglial activation participates in cognitive dysfunction in PD using paraquat and maneb-generated mouse PD model. Methods Cognitive performance was measured in wild type and Mac1 −/− mice using Morris water maze test. The role and mechanisms of NADPH oxidase (NOX)–NLRP3 inflammasome axis in Mac1-mediated microglial dysfunction, neuronal damage, synaptic degeneration and phosphorylation (Ser129) of α-synuclein were explored by immunohistochemistry, Western blot and RT-PCR. Results Genetic deletion of Mac1 significantly ameliorated learning and memory impairments, neuronal damage, synaptic loss and α-synuclein phosphorylation (Ser129) caused by paraquat and maneb in mice. Subsequently, blocking Mac1 activation was found to mitigate paraquat and maneb-elicited microglial NLRP3 inflammasome activation in both in vivo and in vitro. Interestingly, stimulating activation of NOX by phorbol myristate acetate abolished the inhibitory effects of Mac1 blocking peptide RGD on paraquat and maneb-provoked NLRP3 inflammasome activation, indicating a key role of NOX in Mac1-mediated NLRP3 inflammasome activation. Furthermore, NOX1 and NOX2, two members of NOX family, and downstream PAK1 and MAPK pathways were recognized to be essential for NOX to regulate NLRP3 inflammasome activation. Finally, a NLRP3 inflammasome inhibitor glybenclamide abrogated microglial M1 activation, neurodegeneration and phosphorylation (Ser129) of α-synuclein elicited by paraquat and maneb, which were accompanied by improved cognitive capacity in mice. Conclusions Mac1 was involved in cognitive dysfunction in a mouse PD model through NOX–NLRP3 inflammasome axis-dependent microglial activation, providing a novel mechanistic basis of cognitive decline in PD.

Microglia-mediated chronic neuroinflammation is a common pathological feature of Parkinson’s disease (PD). Strong evidence suggests that activated microglia can lesion neurons by releasing exosomes. However, the mechanisms of exosome release from activated microglia remain unclear. We recently revealed a key role of complement receptor 3 (CR3) in regulating microglial activation in the process of progressive neurodegeneration. This study aimed to investigate whether CR3 can regulate exosome release from activated microglia, as well as the underlying mechanisms. We found that LPS, an inducer of microglial M1 activation, induced exosome release from activated microglia. Inhibition of exosome synthesis suppressed LPS-induced microglial activation, gene expression of proinflammatory factors, and related neurotoxicity. Silencing or knocking out CR3 attenuated LPS-induced exosome release in microglia. NADPH oxidase (NOX2) was further identified as a downstream signal of CR3, mediating microglial exosome release and related neurotoxicity. CR3 silencing blocked LPS-induced NOX2 activation and superoxide production through inhibition of p47phox phosphorylation and membrane translocation. Moreover, NOX2 activation elicited by PMA or supplementation of H2O2 recovered exosome release from CR3-silenced microglia. Subsequently, we demonstrated that the CR3-NOX2 axis regulates syntenin-1 to control microglial exosome release. Finally, we observed that the expression of CR3 was increased in the brain of LPS-treated mice, and genetic ablation of CR3 significantly reduced LPS-induced NOX2 activation, microglial M1 polarization, and exosome production in mice. Overall, our findings revealed a critical role of the CR3-NOX2 axis in controlling microglial exosome release and related neurotoxicity through syntenin-1, providing a novel target for the development of a therapeutic strategy for neuroinflammation-mediated neurodegeneration.

The study aimed to evaluate the clinical efficacy and safety of brivaracetam (BRV) as monotherapy or adjuvant therapy for adults with seizures. Observational studies of BRV were systematically searched. We estimated the pooled incidence of interests (responder rate, seizure-free rate, adverse effects (AEs), and withdrawal rate) with their corresponding 95% confidence intervals (CIs). Thirty-five studies, including 10,956 patients, were included. The 50% responder rates were 36% (95% CI: 0.26-0.47), 35% (95% CI: 0.21-0.49), and 40% (95% CI: 0.24-0.56), respectively, and the pooled seizure-free rates were 19.0% (95% CI: 0.17-0.25), 21.0% (95% CI: 0.15-0.27), and 23.3% (95% CI: 0.14-0.31), respectively, at 3, 6, and 12 months of BRV treatment. Subgroup analysis showed that although previous levetiracetam (LEV) failure can affect the response to BRV, treatment with BRV could still be beneficial for these patients. Furthermore, a remarkable reduction in seizure frequency and lower AEs were found among patients who switched directly from LEV to BRV. In addition, BRV, used as the first add-on or monotherapy, displayed a high 50% responder rate and seizure-free rate. The pooled incidence of AEs at 3, 6, and 12 months of BRV treatment were 39.0% (95% CI: 0.27-0.50), 29.0% (95% CI: 0.18-0.39), and 34.0% (95% CI: 0.25-0.44), respectively; the withdrawal rates due to AEs were 7.0% (95% CI: 0.03-0.10), 11.1% (95% CI: 0.05-0.17), and 10.0% (95% CI: 0.07-0.13) at the same follow-up point. Our meta-analysis has shown BRV to be effective and well-tolerated in both short-term and long-term usage when used as monotherapy or adjuvant therapy for adults with seizures in real-world settings. BRV may be a valuable treatment when used as monotherapy, as a first add-on, and in patients who switched directly from LEV or previously failed to respond to or tolerate LEV. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251085564.

Wheat is extensively utilized in various processed foods due to unique proteins forming from the gluten network. The gluten network in food undergoes morphological and molecular structural changes during food processing, affecting the final quality and digestibility of the food. The present review introduces the formation of the gluten network and the role of gluten in the key steps of the production of several typical food products such as bread, pasta, and beer. Also, it summarizes the factors that affect the digestibility of gluten, considering that different processing conditions probably affect its structure and properties, contributing to an in-depth understanding of the digestion of gluten by the human body under various circumstances. Nevertheless, consumption of gluten protein may lead to the development of celiac disease (CD). The best way is theoretically proposed to prevent and treat CD by the inducement of oral tolerance, an immune non-response system formed by the interaction of oral food antigens with the intestinal immune system. This review proposes the restoration of oral tolerance in CD patients through adjunctive dietary therapy via gluten-encapsulated/modified dietary polyphenols. It will reduce the dietary restriction of gluten and help patients achieve a comprehensive dietary intake by better understanding the interactions between gluten and food-derived active products like polyphenols.