Exploring MAP2K3 as a prognostic biomarker and potential immunotherapy target in glioma treatment.

Glioma, the most prevalent primary brain tumor in adults, is characterized by significant invasiveness and resistance. Current glioma treatments include surgery, radiation, chemotherapy, and targeted therapy, but these methods often fail to eliminate the tumor completely, leading to recurrence and poor prognosis. Immune checkpoint inhibitors, a class of commonly used immunotherapeutic drugs, have demonstrated excellent efficacy in treating various solid malignancies. Recent research has indicated that unconventional levels of expression of the MAP2K3 gene closely correlates with glioma malignancy, hinting it could be a potential immunotherapy target. Our study unveiled substantial involvement of MAP2K3 in gliomas, indicating the potential of the enzyme to serve as a prognostic biomarker related to immunity. Through the regulation of the infiltration of immune cells, MAP2K3 can affect the prognosis of patients with glioma. These discoveries establish a theoretical foundation for exploring the biological mechanisms underlying MAP2K3 and its potential applications in glioma treatment.

The Involvement of Immune Cells Between Ischemic Stroke and Gut Microbiota.

Ischemic stroke, a disease with high mortality and disability rate worldwide, currently has no effective treatment. The systemic inflammation response to the ischemic stroke, followed by immunosuppression in focal neurologic deficits and other inflammatory damage, reduces the circulating immune cell counts and multiorgan infectious complications such as intestinal and gut dysfunction dysbiosis. Evidence showed that microbiota dysbiosis plays a role in neuroinflammation and peripheral immune response after stroke, changing the lymphocyte populations. Multiple immune cells, including lymphocytes, engage in complex and dynamic immune responses in all stages of stroke and may be a pivotal moderator in the bidirectional immunomodulation between ischemic stroke and gut microbiota. This review discusses the role of lymphocytes and other immune cells, the immunological processes in the bidirectional immunomodulation between gut microbiota and ischemic stroke, and its potential as a therapeutic strategy for ischemic stroke.

JAK2/STAT3 Axis Intermediates Microglia/Macrophage Polarization During Cerebral Ischemia/Reperfusion Injury.

BACKGROUND: Subtypes of microglia/macrophage regulate the inflammation in the opposite direction during ischemic stroke. JAK2/STAT3 signaling pathway participates in the development of stroke-related inflammation via ischemic stimulation. However, the relationship between JAK2/STAT3 pathway and microglia/macrophage phenotype transformation is unclear. METHODS: This study established a transient middle cerebral artery occlusion (tMCAO) model in male STAT3f/f and STAT3f/f LysMcre+ mice and evaluated the neurological deficit on the 3rd day using Longa score. The brains were stained by TTC to determine the infarction volume. Western blotting and QPCR were used to determine the expression of JAK2/STAT3 pathway and microglia/macrophage-related markers. Immunofluorescence staining was used to detect the levels of polarization-related indexes. QPCR also assessed the effect of STAT3 knockout on inflammatory factors in the infarction. Moreover, established the OGD/R model using BV2 cells to further verify the role of STAT3 on microglia/macrophage polarization. RESULTS: For the conditioned STAT3-KO mice, the infarction was significantly increased after MCAO, accompanied by the aggravation of neurological deficit. Higher expression of iNOS and CD16/32 than Arg-1, Ym-1, and CD206 in vivo and in vitro, and decreased p-STAT3/STAT3 ratio in STAT3f/f LysMcre+ mice, while the p-JAK2/JAK2 ratio increased. In addition, increased M1/M2 ratio and elevated expression of IL-1ß, IL-6, TNF-α with STAT3 deletion, as well as increased CD68+/iNOS+ cell numbers. CONCLUSION: Collectively, these results reveal that JAK2/STAT3 signaling pathway regulates the microglia/macrophage polarization (skewing toward the M2 polarization) during the CIRI, thus alleviating brain damage. Therefore, approaches targeting JAK2/STAT3 activation are promising therapies for ischemic stroke.

MICAL2 Promotes Proliferation and Migration of Glioblastoma Cells Through TGF-ß/p-Smad2/EMT-Like Signaling Pathway.

Recent studies showed that molecule interacting with CasL2 (MICAL2) could be a novel tumor growth factor, and it is closely associated with tumor growth and invasion. However, the role it plays in glioblastoma (GBM) and its potential mechanisms are currently unknown. Our study is designed to identify the effect of MICAL2 on GBM cells and the potential mechanisms behind it. Here, we found that MICAL2 interacts with TGF receptor-type I (TGFRI) and promotes the proliferation and migration of glioblastoma through the TGF-ß/p-Smad2/EMT-like signaling pathway. MICAL2-knockdown inhibited the proliferation of glioblastoma cells, which was related to cell cycle arrest and downregulation of DNA replication. The invasion abilities of U87 and U251 cells were reduced after the knockdown of MICAL2. MICAL2 promoted the growth of GBM in nude mice. High MICAL2 predicts poor outcome of GBM patients. MICAL2 could be identified as a novel promising therapeutic target for human GBM.

Influence of Polypropylene Fibre Factor on Flowability and Mechanical Properties of Self-Compacting Geopolymer.

The possibility of using geopolymer instead of Portland cement could effectively reduce carbon dioxide emissions from cement manufacturing. Fibre-reinforced self-compacting geopolymers have great potential in civil engineering applications, such as chord member grouting for concrete-filled steel tubular truss beams. However, to the best of the authors' knowledge, the quantitative relationship between FF and the properties of the fibre-reinforced geopolymer has been rarely reported. In this research, 26 groups of mixtures were used to study the influence of the polypropylene fibre factor (FF) on the flowability and mechanical properties and also the compactness of the fibre-reinforced self-compacting geopolymer. At the same volume fraction, geopolymers with long fibres present worse flowability than those having short fibres due to the easier contacting of long fibres. By growing the FF the influence of fibre addition on the V-funnel flow rate is more significant than the slump spread. This can be ascribed to the consequence of fibre addition and friction by the V-funnel which estimates the restrained deformability. For FF lesser than critical factor Fc = 100, influence of fibres is negligible and fibres are far apart from each other and, thus, they cannot restrict cracking under load and transfer the load to improve the mechanical properties. For FF between the Fc = 100 and density factor Fd = 350, a noteworthy enhancement of mechanical properties was obtained and the geopolymer was still adequately workable to flow by weight of self, without any symbols of instability and fibre clumping. Under this condition, better fibre dispersal and reinforcing productivity can lead to better hardened properties. For FF higher than Fd = 350, fibres tend to come to be entwined together and form clumping resulting from the fibre balling, resulting in worse hardened properties. This research offers a sensible basis for the application of the workability regulator of the fresh properties of fibre-reinforced geopolymer as an operative way to basically obtain ideal mechanical properties.

Janus Kinase Inhibition Ameliorates Ischemic Stroke Injury and Neuroinflammation Through Reducing NLRP3 Inflammasome Activation via JAK2/STAT3 Pathway Inhibition.

Background: Inflammatory responses play a multiphase role in the pathogenesis of cerebral ischemic stroke (IS). Ruxolitinib (Rux), a selective oral JAK 1/2 inhibitor, reduces inflammatory responses via the JAK2/STAT3 pathway. Based on its anti-inflammatory and immunosuppressive effects, we hypothesized that it may have a protective effect against stroke. The aim of this study was to investigate whether inhibition of JAK2 has a neuroprotective effect on ischemic stroke and to explore the potential molecular mechanisms. Methods: Rux, MCC950 or vehicle was applied to middle cerebral artery occlusion (MCAO) mice in vivo and an oxygen-glucose deprivation/reoxygenation (OGD/R) model in vitro. After 3 days of reperfusion, neurological deficit scores, infarct volume and brain water content were assessed. Immunofluorescence staining and western blots were used to measure the expression of NLRP3 inflammasome components. The infiltrating cells were investigated by flow cytometry. Proinflammatory cytokines were assessed by RT-qPCR. The expression of the JAK2/STAT3 pathway was measured by western blots. Local STAT3 deficiency in brain tissue was established with a lentiviral vector carrying STAT3 shRNA, and chromatin immunoprecipitation (ChIP) assays were used to investigate the interplay between NLRP3 and STAT3 signaling. Results: Rux treatment improved neurological scores, decreased the infarct size and ameliorated cerebral edema 3 days after stroke. In addition, immunofluorescence staining and western blots showed that Rux application inhibited the expression of proteins related to the NLRP3 inflammasome and phosphorylated STAT3 (P-STAT3) in neurons and microglia/macrophages. Furthermore, Rux administration inhibited the expression of proinflammatory cytokines, including TNF-α, IFN-γ, HMGB1, IL-1ß, IL-2, and IL-6, suggesting that Rux may alleviate IS injury by inhibiting proinflammatory reactions via JAK2/STAT3 signaling pathway regulation. Infiltrating macrophages, B, T, cells were also reduced by Rux. Local STAT3 deficiency in brain tissue decreased histone H3 and H4 acetylation on the NLRP3 promoter and NLRP3 inflammasome component expression, indicating that the NLRP3 inflammasome may be directly regulated by STAT3 signaling. Rux application suppressed lipopolysaccharide (LPS)-induced NLRP3 inflammasome secretion and JAK2/STAT3 pathway activation in the OGD/R model in vitro. Conclusion: JAK2 inhibition by Rux in MCAO mice decreased STAT3 phosphorylation, thus inhibiting the expression of downstream proinflammatory cytokines and the acetylation of histones H3 and H4 on the NLRP3 promoter, resulting in the downregulation of NLRP3 inflammasome expression.

The differences between copper sulfate and tribasic copper chloride on growth performance, redox status, deposition in tissues of pigs, and excretion in feces.

OBJECTIVE: The objective of this experiment was to compare the effects of adding 130 mg/kg Cu from either copper sulfate (CS) or tribasic copper chloride (TBCC) on growth performance, mineral deposition in tissues, and the excretion in feces of pigs as well as changes in the mineral contents in tissues and feces when the supplemental Cu level was decreased from 130 mg/kg to 10 mg/kg. METHODS: A total of 72 pigs (32.6±1.2 kg) were randomly assigned to a CS diet or a TBCC diet with 6 pens per treatment. The trial lasted 102 d and included 3 phases (phase 1, 1 to 30 d; phase 2, 31 to 81 d; and phase 3, 82 to 102 d). The supplemental levels of Cu in the 2 treatments were 130 mg/kg in phase 1 and 2 and 10 mg/kg in phase 3. RESULTS: The results showed that pigs fed the CS diet tended to have higher average daily gain than pigs fed the TBCC diet during d 1 to 81 (p<0.10). Compared with CS, TBCC increased the activities of aspartate transaminase (AST), ceruloplasmin, and superoxide dismutase in serum on d 30 (p<0.05). The TBCC decreased the Cu level in the liver on d 81 (p<0.05) and increased the Mn level in the liver on d 102 (p<0.05). The concentration of Cu in feces sharply decreased when the supplemental Cu level in diet changed from 130 mg/kg to 10 mg/kg in both diets (p<0.05). CONCLUSION: The result suggested that TBCC and CS had no significant difference on growth performance but TBCC had higher activities of AST and antioxidant enzymes and lower liver Cu than CS when pigs fed diets with 130 mg Cu/kg diet.