Polarization Pathways Research Articles

Macrophage polarization and metabolic reprogramming in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is a macrovascular disease with high morbidity and mortality in the elderly. The limitation of the current management is that most patients can only be followed up until the AAA diameter increases to a threshold, and surgical intervention is recommended. The development of preventive and curative drugs for AAA is urgently needed. Macrophage-mediated immune inflammation is one of the key pathological links in the occurrence and development of AAA. This review article aims to evaluate the impact of immunometabolism on macrophage biology and its role in AAA. We analyze publications focusing on the polarization and metabolic reprogramming in macrophages as well as their potential impact on AAA, and summarize the potential interventions that are currently available to regulate these processes. The phenotypic and functional changes in macrophages are accompanied by significant alterations in metabolic pathways. The interaction between macrophage polarization and metabolic pathways significantly influences the progression of AAA. Macrophage polarization is a manifestation of the gross dichotomy of macrophage function into pro-inflammatory killing and tissue repair, that is, classically activated M1 macrophages and alternatively activated M2 macrophages. Macrophage functions are closely linked to metabolic changes, and the emerging field of immunometabolism is providing unique insights into the role of macrophages in AAA. It is essential to further investigate the precise metabolic changes and their functional consequences in AAA-associated macrophages.

Areca nut-induced metabolic reprogramming and M2 differentiation promote OPMD malignant transformation

BackgroundBetel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive.MethodsImmunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE.ResultsWe reported that M2 macrophages positively correlated with oral cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased mitochondrial metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters.ConclusionOur study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.

Potential predictive value of immune-related genes FUCA1 and NCKAP1L for osteosarcoma metastasis

BackgroundOsteosarcoma is a common malignant tumor with a low survival rate after metastasis. Current treatments have not proven to effectively increase patient survival rates. Immunotherapy is a promising new treatment approach, however, immune target therapy has not shown satisfactory results. This study aims to provide new insights and evidence for the use of immunotherapy in osteosarcoma, based on a comprehensive analysis of gene expression data from databases. MethodsGene expression and GSAV analysis were conducted on samples from patients with metastatic and non-metastatic osteosarcoma in the TARGET and GEO databases to identify relevant genes. These genes were further analyzed using GO, KEGG, GSVA, correlation analysis, and immune microenvironment scoring techniques. The tissue location of gene expression was confirmed through single-cell analysis. Validation of gene expression patterns was performed using polymerase chain reaction, western blot, and immunohistochemistry. ResultsThe study identified FUCA1 and NCKAP1L as significantly enriched in non-metastatic osteosarcoma, with higher expression associated with better patient survival rates. Gene function enrichment was primarily related to immune functions, with positive correlations to macrophage phagocytosis, antigen presentation, and macrophage polarization pathways. Analysis of the immune microenvironment revealed a positive correlation between gene expression and immune scores, with increased presence of macrophages, T cells, and B cells in the high expression group. Single-cell analysis and experimental results confirmed the enrichment of FUCA1 and NCKAP1L in macrophages. ConclusionThe identification of FUCA1 and NCKAP1L as potential prognostic biomarkers suggests their potential for improving patient outcomes. Modulation of macrophages may offer a promising strategy for enhancing the immune microenvironment in osteosarcoma.

Angiotensin II Type 2 Receptor Inhibits M1 Polarization and Apoptosis of Alveolar Macrophage and Protects Against Mechanical Ventilation-Induced Lung Injury.

Angiotensin II (Ang II) is associated with macrophage polarization and apoptosis, but the role of the angiotensin type 2 receptor (AT2R) in these processes remains controversial. However, the effect of AT2Rs on alveolar macrophages and mechanical ventilation-induced lung injury has not been determined.Mechanical ventilation-induced lung injury in Sprague‒Dawley (SD) rats and LPS-stimulated rat alveolar macrophages (NR8383) were used to determine the effects of AT2Rs, selective AT2R agonists and selective AT1Rs or AT2R antagonists. Macrophage polarization, apoptosis, and related signaling pathways were assessed via western blotting, QPCR and flow cytometry.AT2R expression was decreased in LPS-stimulated rat alveolar macrophages (NR8383). Administration of the AT2R agonist CGP-42112 was associated with an increase in AT2R expression and M2 polarization, but no effect was observed upon administration of the AT2R antagonist PD123319 or the AT1R antagonist valsartan. In mechanical ventilation-induced lung injury in Sprague‒Dawley (SD) rats, the administration of the AT2R agonist C21 was associated with attenuation of the pathological damage score, lung wet/dry weight, cell count and protein content in BALF. C21 can significantly reduce proinflammatory factor TNF-α, IL-1β levels, increase anti-inflammatory factor IL-4, IL-10 levels in BALF, compared with the model group (p < 0.01). Similarly, compared with those at the same time points, the M1/M2 ratios in alveolar macrophages and apoptosis in peritoneal macrophages at 4h, 6h and 8h in the mechanical ventilation models were lower after C21 administration.These findings indicated that the expression of AT2Rs in alveolar macrophages mediates M1 macrophage polarization and apoptosis and that AT2Rs play a protective role in mediating mechanical ventilation-induced lung injury.

Multifunctional graphene/Ti3C2Tx MXene aerogel inlaid with Ni@TiO2 core-shell microspheres for high-efficiency electromagnetic wave absorption and thermal insulation

The demand for high-performance electromagnetic wave absorbing (EMA) materials featured with strong attenuation ability, extended absorption bandwidth and ultralight property is imperative yet remains challenging. Herein, a three-dimensional hierarchically porous reduced graphene oxide (rGO)/Ti3C2Tx MXene aerogel embedded with Ni@TiO2 core–shell microspheres was prepared via directional freeze-drying followed by a mild annealing process. The divergence in structure and multicomponent dielectric/magnetic features bring about optimized impedance matching characteristic, multiple polarization and loss pathways, collectively contributing to the excellent absorption performance. As a result, the Ni@TiO2/MXene/rGO (NTMRG-2) aerogel exhibits optimized EMA capability with a maximal effective absorption bandwidth (EABmax) of 6.48 GHz at a lower loading level of 5 wt% in the supporting matrix, covering the whole Ku band. Additionally, it achieves a minimum reflection loss (RLmin) of −71.4 dB with a matching thickness of 2.04 mm. Moreover, the aerogel also exhibits an ultra-light density of 5.58 mg cm−3, superior thermal insulation capacity (close to air) and hydrophobicity, underscoring its potential for multiple applications in various scenarios.

Inhibition of spinal BRD4 alleviates pyroptosis and M1 microglia polarization via STING-IRF3 pathway in morphine-tolerant rats

BackgroundMorphine tolerance has been a challenging medical issue. Neuroinflammation is considered as a critical mechanism for the development of morphine tolerance. Bromodomain-containing protein 4 (BRD4), a key regulator in cell damage and inflammation, participates in the development of chronic pain. However, whether BRD4 is involved in morphine tolerance and the underlying mechanisms remain unknown. MethodsThe morphine-tolerant rat model was established by intrathecal administration of morphine twice daily for 7 days. Behavior test was assessed by a tail-flick latency test. The roles of BRD4, pyroptosis, microglia polarization and related signaling pathways in morphine tolerance were elucidated by Western blot, real-time quantitative polymerase chain reaction, and immunofluorescence. ResultsRepeated morphine administration upregulated BRD4 level, induced pyroptosis, and promoted microglia M1-polarization in spinal cord, accompanied by the release of proinflammatory cytokines, such as TNF-α and IL-1β. JQ-1, a BRD4 antagonist, alleviated the development of morphine tolerance, diminished pyroptosis and induced the switch of microglia from M1 to M2 phenotype. Mechanistically, stimulator of interferon gene (STING)- interferon regulatory factor 3 (IRF3) pathway was activated and the protective effect of JQ-1 against morphine tolerance was at least partially mediated by inhibition of STING-IRF3 pathway. ConclusionThis study demonstrated for the first time that spinal BRD4 contributes to pyroptosis and switch of microglia polarization via STING-IRF3 signaling pathway during the development of morphine tolerance, which extend the understanding of the neuroinflammation mechanism of morphine tolerance and provide an alternative strategy for the precaution against of this medical condition.

Batf3-dependent orchestration of the robust Th1 responses and fungal control during cryptococcal infection, the role of cDC1.

While type I conventional dendritic cells (cDC1s) are vital for generating adaptive immunity against intracellular pathogens and tumors, their role in defense against fungal pathogen Cryptococcus neoformans remains unclear. We investigated the role of the cDC1 subset in a fungus-restricting mouse model of cryptococcal infection. The cDC1 subset displayed a unique transcriptional signature with highly upregulated T-cell recruitment, polarization, and activation pathways compared to other DC subsets. Using Batf3-/- mice, which lack the cDC1 population, our results support that Batf3-dependent cDC1s are pivotal for the development of the effective immune response against cryptococcal infection, particularly within the lung and brain. Deficiency in Batf3 cDC1 led to diminished CD4 accumulation and decreased IFNγ production across multiple organs, supporting that cDC1s are a major driver of potent Th1 responses during cryptococcal infection. Consistently, mice lacking Batf3-cDC1 demonstrated markedly diminished fungicidal activity and weaker containment of the fungal pathogen. In conclusion, Batf3-dependent cDC1 can function as a linchpin in mounting Th1 response, ensuring effective fungal control during cryptococcal infection. Harnessing cDC1 pathways may present a promising strategy for interventions against this pathogen.IMPORTANCECryptococcus neoformans causes severe meningoencephalitis, accounting for an estimated 200,000 deaths each year. Central to mounting an effective defense against these infections is T-cell-mediated immunity, which is orchestrated by dendritic cells (DCs). The knowledge about the role of specific DC subsets in shaping anti-cryptococcal immunity is limited. Here, we demonstrate that Batf3 cDC1s are important drivers of protective Th1 CD4 T-cell responses required for clearance of cryptococcal infection. Deficiency of Batf3 cDC1 in the infected mice leads to significantly reduced Th1 response and exacerbated fungal growth to the point where depleting the remaining CD4 T cells no longer affects fungal burden. Unveiling this pivotal role of cDC1 in antifungal defense is likely to be important for the development of vaccines and therapies against life-threatening fungal pathogens.

Localized Administration of Bcar3 siRNA via Nano-Self-Assembly to Treat Idiopathic Pulmonary Fibrosis by Disrupting Macrophage-Fibroblast Crosstalk.

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease characterized by chronic lung injury leading to macrophage infiltration and fibroblast activation. However, there is no effective therapeutic strategy targeting the crucial crosstalk between macrophages and fibroblasts to halt IPF progression. Studies were conducted in IPF patients and fibrotic mice models to elucidate the role of Bcar3 in the pathogenesis of pulmonary fibrosis. The effect of Bcar3 on macrophage polarization, fibroblast activation, and related signaling pathways were next investigated to unravel the underlying mechanisms. Our study elucidates a marked increase in Bcar3 expression in lung tissues from IPF patients and fibrotic mice, recording 1.7 and 7.8-fold increases compared to control subjects, respectively. Additionally, Bcar3 was found to significantly enhance macrophage activation and fibroblast differentiation, observable in both in vivo and in vitro settings. Mechanistically, the upregulation of Bcar3 in macrophages was reliant on Stat6, while in fibroblasts, it depended on TGFβR1/Smad3. Furthermore, Bcar3 augmented IL-4/Stat6 pathway in macrophages and TGF-β/Smad3 pathway in fibroblasts, supporting a synergistic activation loop that expedited lung fibrogenesis. Notably, intratracheal injection of liposomes containing Bcar3 siRNA precisely delivered gene therapeutics to lung macrophages and fibroblasts, effectively reducing Bcar3 expression to 59% of baseline levels. Importantly, this intervention protected mice from lung fibrosis induced by either FITC or bleomycin, as well as human precision-cut lung slices against TGF-β1 stimulation. Our study underscores the pivotal role of Bcar3 in orchestrating the macrophage-fibroblast crosstalk during pulmonary fibrosis progression. Targeting Bcar3 emerges as a novel therapeutic avenue to halt IPF progression and enhance patient prognosis.

DexDesign: an OSPREY-based algorithm for designing de novo D-peptide inhibitors.

With over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role in modulating polarization, signaling, and trafficking pathways. Mutations in PDZ domains lead to diseases such as cancer and cystic fibrosis, making PDZ domains attractive targets for therapeutic intervention. D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. Here, we introduce DexDesign, a novel OSPREY-based algorithm for computationally designing de novo D-peptide inhibitors. DexDesign leverages three novel techniques that are broadly applicable to computational protein design: the Minimum Flexible Set, K*-based Mutational Scan, and Inverse Alanine Scan. We apply these techniques and DexDesign to generate novel D-peptide inhibitors of two biomedically important PDZ domain targets: CAL and MAST2. We introduce a framework for analyzing de novo peptides-evaluation along a replication/restitution axis-and apply it to the DexDesign-generated D-peptides. Notably, the peptides we generated are predicted to bind their targets tighter than their targets' endogenous ligands, validating the peptides' potential as lead inhibitors. We also provide an implementation of DexDesign in the free and open source computational protein design software OSPREY.

Xiaoshuan Tongluo recipe alleviated acute hyperglycemia-enhanced hemorrhagic transformation by regulating microglia polarization in thromboembolic stroke rats

BackgroundsHemorrhagic transformation (HT) is a complication after stroke and is associated with increased mortality and disability. Hyperglycemia is a risk factor for HT incidence and seriously affects the treatment of stroke. There are no effective drugs to cure HT in the clinic. The Xiaoshuan Tongluo effective component group (XECG) is a Chinese medicine formula reconstituted by active ingredients, which is clinically used for the treatment of stroke. However, the roles of XECG in hyperglycemia-enhanced HT are not clear. This study aims to evaluate the effects of XECG on hyperglycemia-enhanced HT and explore the potential mechanisms. MethodsIn this study, a hyperglycemia-induced HT model was used. XECG (100, 200, 400 mg·kg−1) was orally administered for 5 days before the operation, and the incidence of HT was evaluated. Microglia polarization and related signaling pathways were measured to clarify the mechanisms of XECG on hyperglycemia-induced HT. ResultsOur results revealed that pretreatment with XECG alleviated neurological deficits and BBB disruption and improved the incidence and severity of HT enhanced by hyperglycemia. Further studies confirmed that XECG regulated microglial polarization by inhibiting the M1 phenotype and promoting the M2 phenotype and inhibited the activation of the HMGB1-RAGE-NF-κB signaling pathway. ConclusionsThese results suggested that pretreatment with XECG alleviated hyperglycemia-enhanced HT. XECG may be a potential drug for the treatment of HT.

Cleavage furrow-directed cortical flows bias PAR polarization pathways to link cell polarity to cell division

During development, the conserved PAR polarity network is continuously redeployed, requiring that it adapt to changing cellular contexts and environmental cues. In the early C.elegans embryo, polarity shifts from being a cell-autonomous process in the zygote to one that must be coordinated between neighbors as the embryo becomes multicellular. Here, we sought to explore how the PAR network adapts to this shift in the highly tractable C.elegans germline P lineage. We find that although P lineage blastomeres exhibit a distinct pattern of polarity emergence compared with the zygote, the underlying mechanochemical processes that drive polarity are largely conserved. However, changes in the symmetry-breaking cues of P lineage blastomeres ensure coordination of their polarity axis with neighboring cells. Specifically, we show that furrow-directed cortical flows associated with cytokinesis of the zygote induce symmetry breaking in the germline blastomere P1 by transporting PAR-3 into the nascent cell contact. This pool of PAR-3 then biases downstream PAR polarization pathways to establish the polarity axis of P1 with respect to the position of its anterior sister, AB. Thus, our data suggest that cytokinesis itself induces symmetry breaking through the advection of polarity proteins by furrow-directed flows. By directly linking cell polarity to cell division, furrow-directed cortical flows could be a general mechanism to ensure proper organization of cell polarity within actively dividing systems.

Enabling high dielectric constant and low loss tangent in BaTiO3–epoxy composites through a 3D interconnected network structure of ceramic phase

Constructing ceramic–polymer composites with a 3–3 connectivity is an effective strategy to achieve a notable increase in the dielectric constant at low ceramic contents. However, the dielectric data of the 3–3 composites with a low ceramic content (<10 vol. %) are still limited, and further investigation is thus required. Herein, composites with a 3–3 connectivity, in which BaTiO3 (BTO) and epoxy are self-connected in three dimensions, were developed and constructed at low BTO contents (2.0–8.3 vol. %). A three-dimensional network structure of the BTO ceramic (3D-BTO) was constructed via the sacrificial template method using polyurethane foam as the template. The dielectric constant and loss tangent of the composites increased with increasing BTO content. At a BTO content of 8.3 vol. %, the dielectric constant of the composite considerably increased to 33.4 at 1 kHz, which was ∼10-fold higher than that of neat epoxy (3.5). The loss tangent had a low value of< 0.030. By comparing with several theoretical models, the dielectric constants of the composites were well fitted with the effective medium theory model at low fitting factors (n = 0.008–0.013). The considerable increase in the dielectric constant of the composites with a low loss tangent at a low BTO content was attributed to the strong interfacial polarization and continuous polarization pathways through the interconnected 3D-BTO network structure in the composites. This study fills the gap in the literature by providing missing data on the dielectric properties of 3–3 composites at low ceramic contents (<10 vol. %), as well as a theoretical prediction.

Immunological mechanisms involved in macrophage activation and polarization in schistosomiasis.

Human schistosomiasis is caused by helminths of the genus Schistosoma. Macrophages play a crucial role in the immune regulation of this disease. These cells acquire different phenotypes depending on the type of stimulus they receive. M1 macrophages can be ‘classically activated’ and can display a proinflammatory phenotype. M2 or ‘alternatively activated’ macrophages are considered anti-inflammatory cells. Despite the relevance of macrophages in controlling infections, the role of the functional types of these cells in schistosomiasis is unclear. This review highlights different molecules and/or macrophage activation and polarization pathways during Schistosoma mansoni and Schistosoma japonicum infection. This review is based on original and review articles obtained through searches in major databases, including Scopus, Google Scholar, ACS, PubMed, Wiley, Scielo, Web of Science, LILACS and ScienceDirect. Our findings emphasize the importance of S. mansoni and S. japonicum antigens in macrophage polarization, as they exert immunomodulatory effects in different stages of the disease and are therefore important as therapeutic targets for schistosomiasis and in vaccine development. A combination of different antigens can provide greater protection, as it possibly stimulates an adequate immune response for an M1 or M2 profile and leads to host resistance; however, this warrants in vitro and in vivo studies.

Interplay of four types of RNA modification writers revealed distinct tumor microenvironment and biological characteristics in pancreatic cancer.

Pancreatic cancer (PC) is one of the most lethal malignancies and carries a dismal mortality and morbidity. Four types of RNA modification (namely m6A, m1A, APA and A-to-I) could be catalyzed by distinct enzymatic compounds ("writers"), mediating numerous epigenetic events in carcinogenesis and immunomodulation. We aim to investigate the interplay mechanism of these writers in immunogenomic features and molecular biological characteristics in PC. We first accessed the specific expression pattern and transcriptional variation of 26 RNA modification writers in The Cancer Genome Atlas (TCGA) dataset. Unsupervised consensus clustering was performed to divide patients into two RNA modification clusters. Then, based on the differentially expressed genes (DEGs) among two clusters, RNA modification score (WM_Score) model was established to determine RNA modification-based subtypes and was validated in International Cancer Genome Consortium (ICGC) dataset. What's more, we manifested the unique status of WM_Score in transcriptional and post-transcriptional regulation, molecular biological characteristics, targeted therapies and immunogenomic patterns. We documented the tight-knit correlations between transcriptional expression and variation of RNA modification writers. We classified patients into two distinct RNA modification patterns (WM_Score_high and _low), The WM_Score_high subgroup was correlated with worse prognosis, Th2/Th17 cell polarization and oncogenic pathways (e.g. EMT, TGF-β, and mTORC1 signaling pathways), whereas the WM_Score_low subgroup associated with favorable survival rate and Th1 cell trend. WM_Score model also proved robust predictive power in interpreting transcriptional and post-transcriptional events. Additionally, the potential targeted compounds with related pathways for the WM_Score model were further identified. Our research unfolds a novel horizon on the interplay network of four RNA modifications in PC. This WM_Score model demonstrated powerful predictive capacity in epigenetic, immunological and biological landscape, providing a theoretical basis for future clinical judgments of PC.

The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders.

Normal neural circuits and functions depend on proper neuronal differentiation, migration, synaptic plasticity, and maintenance. Abnormalities in these processes underlie various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Neural development and maintenance are regulated by many proteins. Among them are Par3, Par6 (partitioning defective 3 and 6), and aPKC (atypical protein kinase C) families of evolutionarily conserved polarity proteins. These proteins perform versatile functions by forming tripartite or other combinations of protein complexes, which hereafter are collectively referred to as "Par complexes." In this review, we summarize the major findings on their biophysical and biochemical properties in cell polarization and signaling pathways. We next summarize their expression and localization in the nervous system as well as their versatile functions in various aspects of neurodevelopment, including neuroepithelial polarity, neurogenesis, neuronal migration, neurite differentiation, synaptic plasticity, and memory. These versatile functions rely on the fundamental roles of Par complexes in cell polarity in distinct cellular contexts. We also discuss how cell polarization may correlate with subcellular polarization in neurons. Finally, we review the involvement of Par complexes in neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease. While emerging evidence indicates that Par complexes are essential for proper neural development and maintenance, many questions on their in vivo functions have yet to be answered. Thus, Par3, Par6, and aPKC continue to be important research topics to advance neuroscience.

Circular RNA UBAP2 (hsa_circ_0007367) Correlates with Microcirculatory Perfusion and Predicts Outcomes of Cardiogenic Shock Patients Undergoing Extracorporeal Membrane Oxygenation Support.

Severe microcirculatory disturbance is common in patients with cardiogenic shock necessitating extracorporeal membrane oxygenation (ECMO), however, biomarkers linked to microcirculation and clinical outcome are scarce. Herein we identified a circular RNA, hsa_circ_0007367, rooted from the ubiquitin-associated protein 2 (UBAP2) gene, namely circUBAP2, and evaluated its biological function and the associations with microcirculation and the prognosis. Patients on ECMO with cardiogenic shock were included if qualified sublingual microcirculation parameters could be obtained and were categorized into the survivor group or non-survivor group. Macro-circulatory, microcirculatory data, cytokine levels, and relative circUBAP2 expressions were collected before, at 24 h, and at ECMO weaning off, respectively. The effects of circUBAP2 on the migration, polarization, cytokine productions, and inflammatory pathways in macrophage NR8383 cells were investigated using in vitro methods. Thirty-three patients with an average age of 58.0 years were enrolled, including 19 survivors and 14 non-survivors. The survivors had higher small vessel density, perfused small vessel density (PSVD), and microvascular flow index (MFI) throughout the ECMO course than did the non-survivors. Relative expression of circUBAP2 (hsa_circ_0007367) correlated with the microcirculatory parameters and satisfactorily predicted the 30-day in-hospital mortality. A multivariable logistic model was developed, showing following four predictors: age (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.00-1.12), time from shock to ECMO (OR 1.10, 95% CI 1.01-1.20), PVSD (OR 0.14, 95% CI 0.02-0.89), and the circUBAP2 expression (OR 0.25, 95% CI 0.08-0.78). In addition, circUBAP2 inhibited the migratory activity and promoted M2 polarization in macrophages, declining the productions of cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1β, and monocyte chemotactic protein [MCP]-1) and the PI3K/Akt/mTOR pathway. The expression of circUBAP2 correlates with microcirculatory perfusion and has the potential in predicting outcomes for on-ECMO patients with cardiogenic shock.

PHRONESIS: A One-Shot Approach for Sequential Assignment of Protein Resonances by Ultrafast MAS Solid-State NMR Spectroscopy.

Solid‐state NMR (ssNMR) spectroscopy has emerged as the method of choice to analyze the structural dynamics of fibrillar, membrane‐bound, and crystalline proteins that are recalcitrant to other structural techniques. Recently, 1H detection under fast magic angle spinning and multiple acquisition ssNMR techniques have propelled the structural analysis of complex biomacromolecules. However, data acquisition and resonance‐specific assignments remain a bottleneck for this technique. Here, we present a comprehensive multi‐acquisition experiment (PHRONESIS) that simultaneously generates up to ten 3D 1H‐detected ssNMR spectra. PHRONESIS utilizes broadband transfer and selective pulses to drive multiple independent polarization pathways. High selectivity excitation and de‐excitation of specific resonances were achieved by high‐fidelity selective pulses that were designed using a combination of an evolutionary algorithm and artificial intelligence. We demonstrated the power of this approach with microcrystalline U‐13C,15N GB1 protein, reaching 100 % of the resonance assignments using one data set of ten 3D experiments. The strategy outlined in this work opens up new avenues for implementing novel 1H‐detected multi‐acquisition ssNMR experiments to speed up and expand the application to larger biomolecular systems.

Effects of electrical stimulation on cytokine-induced macrophage polarization.

Macrophages have two functionalized phenotypes, M1 and M2, and the regulation of M1/M2 polarization of macrophages is critical for tissue repair. Tissue-derived immune factors are considered the major drivers of macrophage polarization. Based on the main cytokine-induced polarization pathways, we tested the effect of electrical stimulation (ES) of macrophages on the regulation of M1/M2 polarization and a possible synergistic effect with the cytokines. Indium tin oxide (ITO) planar microelectrodes were used to produce ES under different voltages, frequencies and waveforms. We evaluated the influence of ES on the cytokine-induced M1/M2 polarization using mouse bone marrow-derived macrophages cultured with both lipopolysaccharide (LPS)/IFN-γ factors and IL-4 factors for M1 and M2, respectively. The results showed that ES promoted the cytokine-induced macrophage polarization. Importantly, we found that stimulation with a square waveform selectively promoted LPS/IFN-γ-induced M1 polarization, while stimulation with a sinusoidal waveform promoted both LPS/IFN-γ-induced M1, and IL-4-induced M2 polarization. Mechanistically, stimulation with a square waveform affected the intracellular ion concentration, whereas stimulation with a sinusoidal waveform promoted both the intracellular ion concentration and membrane receptors. We hereby establish an ES-mediated strategy for immunomodulation via macrophage polarization.

Study on the polarization pathways of macrophages and related diseases

Macrophage is a relatively stable heterogeneous immune cell isolated from monocytes in plasma, which plays a certain role in maintaining stable environment, host defense, phagocytosis and immune information transmission. Under the influence of different environmental factors, macrophages can be polarized into Ml and M2, and this process is reversible. The special phenotype of macrophage polarization can play a role in alleviating or curing the disease, and the polarization process is affected by the stimulation of different signaling pathways [1]. This chapter will review the classical types of macropage polarization, the most important information pathways and regulatory mechanisms, in an attempt to provide a basis for subsequent regulation and the occurrence and progression of lesions.

TNF-α/TNFR1 regulates the polarization of Kupffer cells to mediate trichloroethylene-induced liver injury

We have previously shown trichloroethylene (TCE) induced immune liver injury, and TNF-α/TNFR1 pathway as a probably mechanism underlying the immune damage, but the pathogenic mechanism is still unclear. The study aims to investigate whether TNF-α and its receptors regulate Kupffer cell polarization and downstream inflammation signaling pathways during TCE sensitization, to clarify the mechanism of TCE-mediated immune liver injury. 6–8 weeks old SPF BALB/c female mice were used to establish a TCE sensitization model. We found that in the TCE sensitization positive group, liver injury was aggravated, Kupffer cells activated and polarized to M1 type. The expression of M1 Kupffer cell marker proteins CD11c and CD16/32 increased in the TCE positive group, so did TNF-α and TNFR1 in liver. The expression of P-IKK protein, PP65 protein and P-STAT3 protein increased in the TCE sensitization positive group, and the downstream inflammatory factors IL-1β and IL-6 also increased in the TCE sensitization positive group. After using the TNFR1 inhibitor R7050, we found that M1 Kupffer cell polarization, TNF-α expression, signal pathway expression and inflammatory factors IL-1β and IL-6 expression declined, and the liver damage relieved. Briefly, the use of R7050 to inhibit TNF-α/TNFR1 changing the polarization of liver M1 Kupffer cell, thereby inhibiting the activation of related downstream signaling pathways and reducing the secretion of inflammatory factors. TNF-α/TNFR1 regulates the polarization of M1 Kupffer cells inflammatory play an important role in liver immune damage.