Homeostatic Macrophages Prevent Preterm Birth and Improve Neonatal Outcomes by Mitigating In Utero Sterile Inflammation in Mice.

Preterm birth (PTB), often preceded by preterm labor, is a major cause of neonatal morbidity and mortality worldwide. Most PTB cases involve intra-amniotic inflammation without detectable microorganisms, termed in utero sterile inflammation, for which there is no established treatment. In this study, we propose homeostatic macrophages to prevent PTB and adverse neonatal outcomes caused by in utero sterile inflammation. Single-cell atlases of the maternal-fetal interface revealed that homeostatic maternal macrophages are reduced with human labor. M2 macrophage treatment prevented PTB and reduced adverse neonatal outcomes in mice with in utero sterile inflammation. Specifically, M2 macrophages halted premature labor by suppressing inflammatory responses in the amniotic cavity, including inflammasome activation, and mitigated placental and offspring lung inflammation. Moreover, M2 macrophages boosted gut inflammation in neonates and improved their ability to fight systemic bacterial infections. Our findings show that M2 macrophages are a promising strategy to mitigate PTB and improve neonatal outcomes resulting from in utero sterile inflammation.

Single-Cell RNA Sequencing Deconstructs the Distribution of Immune Cells Within Abdominal Aortic Aneurysms in Mice.

BACKGROUND: Inflammation is a key component in the development of abdominal aortic aneurysm (AAA), yet insights into the roles of immune cells and their interactions in this process are limited. METHODS: Using single-cell RNA transcriptomic analysis, we deconstructed the CD45+ cell population in elastase-induced murine AAA at the single-cell level. We isolated each group of immune cells from murine AAA tissue at different time points and divided them into several subtypes, listed the remarkable differentially expressed genes, explored the developmental trajectories of immune cells, and demonstrated the interactions among them. RESULTS: Our findings reveal significant differences in several immune cell subsets, including macrophages, dendritic cells, and T cells, within the AAA microenvironment compared with the normal aorta. Especially, conventional dendritic cell type 1 exclusively existed in the AAA tissue rather than the normal aortas. Via CellChat analysis, we identified several intercellular communication pathways like visfatin, which targets monocyte differentiation and neutrophil extracellular trap-mediated interaction between neutrophils and dendritic cells, which might contribute to AAA development. Some of these pathways were validated in human AAA. CONCLUSIONS: Despite the absence of external pathogenic stimuli, AAA tissues develop a complex inflammatory microenvironment involving numerous immune cells. In-depth studies of the inflammatory network shall provide new strategies for patients with AAA.

Inhibitory interferon regulatory factor 5 binding peptide suppresses abdominal aortic aneurysm expansion in vivo.

Abdominal aortic aneurysm (AAA) is a critical condition characterized by the expansion of the infrarenal aorta, often leading to high mortality upon rupture. The absence of treatment for asymptomatic AAAs urgently necessitates uncovering the underlying mechanisms of their development. This study utilized mice to induce AAA through porcine pancreatic elastase with BAPN feeding and found that mice receiving the IRF5-binding peptide (IBP) demonstrated significantly slowed AAA expansion and reduced adventitia degradation compared to the control group. Additionally, the IBP group showed decreased macrophage infiltration and reduced matrix metalloproteinase-9 (MMP9) activity. Targeting IRF5 with IBP offers new avenues for potential treatments for asymptomatic AAAs.

One-year outcomes of a novel venous stent for symptomatic iliofemoral venous obstruction: prospective cohort study.

BACKGROUND: A stent with characteristics of a hybrid design may have advantages in improving the patency of symptomatic iliofemoral vein obstruction. This study assessed the safety and effectiveness of the V-Mixtent Venous Stent in treating symptomatic iliofemoral outflow obstruction. METHODS: Eligible patients had a Clinical-Etiologic-Anatomic-Physiologic (CEAP) C classification of ≥ 3 or a Venous Clinical Severity Score (VCSS) pain score of ≥ 2. The primary safety endpoint was the rate of major adverse events within 30 days. The primary effectiveness endpoint was the 12-month primary patency rate. Secondary endpoints included changes in VCSS from baseline to 6 and 12 months, alterations in CEAP C classification, Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-14) scores at 12 months, and stent durability measures. RESULTS: Between December 2020 and November 2021, 171 patients were enrolled across 15 institutions. A total of 185 endovenous stents were placed, with 91.81% of subjects receiving one stent and 8.19% receiving 2 stents. Within 30 days, only two major adverse events occurred (1.17%; 95% confidence interval [CI], 0.14-4.16%), below the literature-defined performance goal of 11% (P < .001). The 12-month primary patency rate (91.36%; 95% CI, 85.93-95.19%; P < .001) exceeded the literature-defined performance goal. VCSS changes from baseline demonstrated clinical improvement at 6 months (- 4.30 ± 3.66) and 12 months (- 4.98 ± 3.67) (P < .001). Significant reduction in symptoms, as measured by CEAP C classification and CIVIQ-14, was observed from pre-procedure to 12 months (P < .001). CONCLUSIONS: The 12-month outcomes confirm the safety and effectiveness of the V-Mixtent Venous Stent in managing symptomatic iliofemoral venous outflow obstruction, including clinical symptom improvement compared to before treatment.

Stabilizing Anode-Electrolyte Interface for Dendrite-Free Zn-Ion Batteries Through Orientational Plating with Zinc Aspartate Additive.

The stability of aqueous Zn-ion batteries (AZIBs) is detrimentally influenced by the formation of Zn dendrites and the occurrence of parasitic side reactions at the Zn metal anode (ZMA)-electrolyte interface. The strategic manipulation of the preferential crystal orientation during Zn2+ plating serves as an essential approach to mitigate this issue. Here, Zn aspartate (Zn-Asp), an electrolyte additive for AZIBs, is introduced not only to optimize the solvation structure of Zn2+ , but also to crucially promote preferential Zn2+ plating on the (002) crystal plane of ZMA. As a result, both side reactions and Zn dendrites are effectively inhibited, ensuring an anode surface free of both dendrites and by-products. The implementation of Zn-Asp leads to significant enhancements in both Zn||Zn symmetric and Zn||Ti batteries, which demonstrate robust cyclability of over 3200 h and high Coulombic efficiency of 99.29%, respectively. Additionally, the Zn||NaV3 O8 ·1.5H2 O full battery exhibits remarkable rate capability, realizing a high capacity of 240.77 mA h g-1 at 5 A g-1 , and retains 92.7% of its initial capacity after 1000 cycles. This research underscores the vital role of electrolyte additives in regulating the preferential crystal orientation of ZMA, thereby contributing to the development of high-performing AZIBs.

Bi-Functional Agarose-Filled Porous Polysulfone Protective Layer for Dendrite-Free Zn Anode.

The uneven electric field and slow Zn2+ desolvation lead to rapid dendrite growth during Zn plating and stripping, which severely deteriorates the performance of Zn metal anodes (ZMAs) in Zn-ion batteries (ZIBs). Although polymer-based artificial protective (PBAP) layers are widely applied to homogenize the electric field of ZMAs, they often fail to promote the desolvation process that eventually induces Zn dendrite growth. Herein, a bi-functional protective layer, comprising a finger-like porous matrix of polysulfone (PSF) and a hydroxyl-rich filler of agarose (AG), is constructed to suppress Zn dendrite growth. COMSOL simulation demonstrates the ZMAs with bi-functional protective layers (Zn@PSF/AG) exhibit uniform electric field and Zn2+ distribution. Besides, the Zn@PSF/AG has both low desolvation energy and nucleation overpotential, effectively promoting the desolvation of Zn2+. Therefore, the Zn@PSF/AG symmetric cell exhibits excellent cycling performance, achieving 4200 h at 1 mA cm-2/1 mAh cm-2 and 1000 h at 5 mA cm-2/5 mAh cm-2. When coupling with ZnxV2O5 (ZnVO) cathode, the ZnVO‖Zn@PSF/AG full cell shows similarly high cycling stability, maintaining 72% of its capacity after 7000 cycles at 10 A g-1. This research highlights the positive roles of PBAP layer with multi-functional matrix-filler structure in developing long-life ZIBs.

Deficiency of thrombospondin-2 alleviates intimal hyperplasia in mice by modulating vascular smooth muscle cell proliferation and migration.

Thrombospondin-2 (Tsp2), a glycoprotein in the extracellular matrix, plays a critical role in the maintenance of vascular homeostasis. However, its role in the pathogenesis of cardiovascular disorders such as intimal hyperplasia is not fully elucidated. This study, therefore, aims to explore the effect of Tsp2 on intimal hyperplasia and its associated underlying mechanisms. Intimal hyperplasia (IH) was established using a modified wire-mediated femoral artery injury model. Immunofluorescence and qPCR identified upregulated Tsp2 expression in the injured femoral artery compared with the uninjured femoral artery. Similarly, TSP2 expression was also increased in human samples from the atherosclerotic femoral artery and colocalized with vascular smooth muscle cells (VSMCs). Compared with the wild-type littermates, Tsp2 knockout mice displayed a mitigated IH in the injured femoral artery, as demonstrated by a decreased neointimal area and intimal/median ratio. Primary mouse VSMCs were cultured to explore the mechanism by which Tsp2 influenced IH in vitro. PDGF-stimulated VSMCs presented an elevated Tsp2 expression and enhanced migration and proliferation. However, Tsp2 knockdown by siRNA blocked the increased migration and proliferation of VSMCs. Further analysis identified an association between Notch3 and IH when the intracellular domain of Notch3 (Nicd3) was upregulated in PDGF-stimulated VSMCs and femoral arteries with IH in human tissues. Along with the overexpression and downregulation of Tsp2, the Nicd3 expression was also up and downregulated accordingly. Tsp2 was associated with IH and may serve as a therapeutic target for IH. Downregulation of Tsp2 could mitigate the progression of IH by modulating the proliferation and migration of VSMCs.

Distinct Cellular Immune Responses to SARS-CoV-2 in Pregnant Women.

Pregnant women are at increased risk of adverse outcomes, including preeclampsia and preterm birth, that may result from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Pregnancy imprints specific maternal immune responses that can modulate host susceptibility to microbial infection; therefore, recent studies have focused on the humoral response against SARS-CoV-2 in pregnant women. However, the pregnancy-specific cellular immune responses triggered by SARS-CoV-2 infection are poorly understood. In this study, we undertook an extensive in vitro investigation to determine the cellular immune responses to SARS-CoV-2 particles and proteins/peptides in pregnant women. First, we show that SARS-CoV-2 particles do not alter the pregnancy-specific oxidative burst of neutrophils and monocytes. Yet, SARS-CoV-2 particles/proteins shift monocyte activation from the classical to intermediate states in pregnant, but not in nonpregnant, women. Furthermore, SARS-CoV-2 proteins, but not particles or peptide pools, mildly enhance T cell activation during pregnancy. As expected, B cell phenotypes are heavily modulated by SARS-CoV-2 particles in all women; yet, pregnancy itself further modified such responses in these adaptive immune cells. Lastly, we report that pregnancy itself governs cytokine responses in the maternal circulation, of which IFN-ß and IL-8 were diminished upon SARS-CoV-2 challenge. Collectively, these findings highlight the differential in vitro responses to SARS-CoV-2 in pregnant and nonpregnant women and shed light on the immune mechanisms implicated in coronavirus disease 2019 during pregnancy.

Comparative analysis of clinical efficacy of stereotactic robot-guided puncture hematoma drainage and conventional puncture hematoma drainage in the treatment of intracerebral hemorrhage.

Objective: To compare and analyze the clinical effectiveness of conventional puncture hematoma drainage and stereotactic robot-guided puncture hematoma drainage in managing intracerebral hemorrhage. Methods: This is clinical comparative research. One hundred and twenty patients with the intracerebral hemorrhage who underwent puncture hematoma drainage in Baoding No.1 Central Hospital from March 2020 to May 2023 were included and were assigned into the control groups(n=60) and experimental groups(n=60) according to different treatment methods. The experimental group underwent stereotactic robot-guided puncture hematoma drainage, while the control group underwent conventional puncture hematoma drainage treatment. The duration and situation of surgery, levels of inflammatory factors, as well as preoperative and 1-week postoperative GCS scores and NIHSS scores were compared and analyzed between the two groups. Results: In comparison with the control group, the experimental group exhibited considerably less surgical duration(p=0.00), higher amount of intraoperative blood drainage and hematoma clearance rate(p=0.00). The experimental group possessed a substantially more reduced incidence of complications(10%) in comparison with the control group(25%), with a statistically substantial distinction(p=0.03). After therapy, CRP, TNF-a, and IL-6 degrees were considerably more decreased (p=0.00) in the experimental group in comparison with the control group, while GCS grades were considerably more prominent and NIHSS grades were considerably more reduced (p=0.00). Conclusion: Stereotactic robot-guided puncture hematoma drainage is a dependable and safe operative method to treat patients who had intracerebral hemorrhage, resulting in various benefits such as short length of operation, less injury, less inflammatory reaction, high hematoma clear efficiency and satisfactory recovery of neurological function.

Interfacial Engineering of Zn Metal via a Localized Conjugated Layer for Highly Reversible Aqueous Zinc Ion Battery.

Aqueous zinc-ion batteries are regarded as promising and efficient energy storage systems owing to remarkable safety and satisfactory capacity. Nevertheless, the instability of zinc metal anodes, characterized by issues such as dendrite growth and parasitic side reactions, poses a significant barrier to widespread applications. Herein, we address this challenge by designing a localized conjugated structure comprising a cyclic polyacrylonitrile polymer (CPANZ), induced by a Zn2+-based Lewis acid (zinc trifluoromethylsulfonate) at a temperature of 120 °C. The CPANZ layer on the Zn anode, enriched with appropriate pyridine nitrogen-rich groups (conjugated cyclic -C=N-), exhibits a notable affinity for Zn2+ with ample deposition sites. This zincophilic skeleton not only serves as a protective layer to guide the deposition of Zn2+ but also functions as proton channel blocker, regulating the proton flux to mitigate the hydrogen evolution. Additionally, the strong adhesion strength of the CPANZ layer guarantees its sustained protection to the Zn metal during long-term cycling. As a result, the modified zinc electrode demonstrates long cycle life and high durability in both half-cell and pouch cells. These findings present a feasible approach to designing high performance aqueous anodes by introducing a localized conjugated layer.

Synthesis of Ni3 B/Ni via Vacuum-Induced for Ultrahigh Stable and Efficient Methanol Oxidation.

Designing efficient catalysts to promote the electrochemical oxidation of anodes is the core of the development of electrochemical synthesis technologies, such as HER and CO2 RR. Here, a novel vacuum induction strategy is used to synthesize nickel boride/nickel (Ni3 B/Ni) heterostructure catalyst for electrochemical oxidation of methanol into formic acid. The catalyst has extremely high reactivity (only 146.9 mV overpotential at 10 mA cm-2 , the maximum current density reaches 555.70 mA mg-1 and 443.87 mA cm-2 ), ultra-high selectivity (Faraday efficiency of methanol conversion to formic acid is close to 100%), and ultra-long life (over 50 h at 100 mA cm-2 ). In-suit electrochemical impedance spectroscopy proved that MeOH is oxidized first and inhibits the phase transition of the electrocatalyst to the high-valent electrooxidation products, which not only enables the high selectivity of MeOH oxidation but also ensures high stability of the catalyst. The mechanism studies by density functional theory calculations show that the potential determining step, the formation of *CH2 O, occurs most favorably in the Ni3 B/Ni heterostructure. These results provide references for the development of MeOH oxidation catalysts with high activity, high stability, high selectivity, and low cost.

Trapping and diffusion of hydrogen in iron-doped Y2O3.

Y2O3 is a promising material for use as a tritium permeation barrier (TPB) coating and as dispersed particles in oxide dispersion strengthened steels for experimental fusion reactors. By using first-principles approaches, we found that substituting Fe for Y in Y2O3 is the most energetically favourable under O-deficient and H-rich conditions, leading to easier formation of the nearby O vacancies. These O vacancies serve as effective trapping sites for H atoms with a formation energy of -2.36 eV. The presence of Fe defects also makes it more difficult for H atoms to migrate in Y2O3 from three possible H-related defects. These findings suggest that incorporating Fe into Y2O3 could yield a better TPB and provide insight into the improved H trapping ability of Y2O3 with Fe dopants.

Differential immunophenotype of circulating monocytes from pregnant women in response to viral ligands.

BACKGROUND: Viral infections during pregnancy can have deleterious effects on mothers and their offspring. Monocytes participate in the maternal host defense against invading viruses; however, whether pregnancy alters monocyte responses is still under investigation. Herein, we undertook a comprehensive in vitro study of peripheral monocytes to characterize the differences in phenotype and interferon release driven by viral ligands between pregnant and non-pregnant women. METHODS: Peripheral blood was collected from third-trimester pregnant (n = 20) or non-pregnant (n = 20, controls) women. Peripheral blood mononuclear cells were isolated and exposed to R848 (TLR7/TLR8 agonist), Gardiquimod (TLR7 agonist), Poly(I:C) (HMW) VacciGrade™ (TLR3 agonist), Poly(I:C) (HMW) LyoVec™ (RIG-I/MDA-5 agonist), or ODN2216 (TLR9 agonist) for 24 h. Cells and supernatants were collected for monocyte phenotyping and immunoassays to detect specific interferons, respectively. RESULTS: The proportions of classical (CD14hiCD16-), intermediate (CD14hiCD16+), non-classical (CD14loCD16+), and CD14loCD16- monocytes were differentially affected between pregnant and non-pregnant women in response to TLR3 stimulation. The proportions of pregnancy-derived monocytes expressing adhesion molecules (Basigin and PSGL-1) or the chemokine receptors CCR5 and CCR2 were diminished in response to TLR7/TLR8 stimulation, while the proportions of CCR5- monocytes were increased. Such differences were found to be primarily driven by TLR8 signaling, rather than TLR7. Moreover, the proportions of monocytes expressing the chemokine receptor CXCR1 were increased during pregnancy in response to poly(I:C) stimulation through TLR3, but not RIG-I/MDA-5. By contrast, pregnancy-specific changes in the monocyte response to TLR9 stimulation were not observed. Notably, the soluble interferon response to viral stimulation by mononuclear cells was not diminished in pregnancy. CONCLUSIONS: Our data provide insight into the differential responsiveness of pregnancy-derived monocytes to ssRNA and dsRNA, mainly driven by TLR8 and membrane-bound TLR3, which may help to explain the increased susceptibility of pregnant women to adverse outcomes resulting from viral infection as observed during recent and historic pandemics.

Preparation of silk fibroin/hyaluronic acid composite hydrogel based on thiol-ene click chemistry. / 基于巯基-çƒ¯ç‚¹å‡»åŒ–å­¦åˆ¶å¤‡ä¸ç´ è›‹ç™½/é€æ˜Žè´¨é ¸å¤åˆæ°´å‡èƒ¶.

OBJECTIVES: To design and prepare silk fibroin/hyaluronic acid composite hydrogel. METHODS: The thiol modified silk fibroin and the double-bond modified hyaluronic acid were rapidly cured into gels through thiol-ene click polymerization under ultraviolet light condition. The grafting rate of modified silk fibroin and hyaluronic acid was characterized by 1H NMR spectroscopy; the gel point and the internal microstructure of hydrogels were characterized by rheological test and scanning electron microscopy; the mechanical properties were characterized by compression test; the swelling rate and degradation rate were determined by mass method. The hydrogel was co-cultured with the cells, the cytotoxicity was measured by the lactate dehydrogenase method, the cell adhesion was measured by the float count method, and the cell growth and differentiation on the surface of the gel were observed by scanning electron microscope and fluorescence microscope. RESULTS: The functional group substitution degrees of modified silk fibroin and hyaluronic acid were 17.99% and 48.03%, respectively. The prepared silk fibroin/hyaluronic acid composite hydrogel had a gel point of 40-60 s and had a porous structure inside the gel. The compressive strength was as high as 450 kPa and it would not break after ten cycles. The water absorption capacity of the composite hydrogel was 4-10 times of its own weight. Degradation experiments showed that the hydrogel was biodegradable, and the degradation rate reached 28%-42% after 35 d. The cell biology experiments showed that the cytotoxicity of the composite gel was low, the cell adhesion was good, and the growth and differentiation of the cells on the surface of the gel were good. CONCLUSIONS: The photocurable silk fibroin/hyaluronic acid composite hydrogel can form a gel quickly, and has excellent mechanical properties, adjustable swelling rate and degradation degree, good biocompatibility, so it has promising application prospects in biomedicine.

The immunobiology of preterm labor and birth: intra-amniotic inflammation or breakdown of maternal-fetal homeostasis.

In brief: The syndrome of preterm labor comprises multiple established and novel etiologies. This review summarizes the distinct immune mechanisms implicated in preterm labor and birth and highlights potential strategies for its prevention. Abstract: Preterm birth, the leading cause of neonatal morbidity and mortality worldwide, results from preterm labor, a syndrome that includes multiple etiologies. In this review, we have summarized the immune mechanisms implicated in intra-amniotic inflammation, the best-characterized cause of preterm labor and birth, as well as novel etiologies non-associated with intra-amniotic inflammation (i.e. formally known as idiopathic). While the intra-amniotic inflammatory responses driven by microbes (infection) or alarmins (sterile) have some overlap in the participating cellular and molecular processes, the distinct natures of these two conditions necessitate the implementation of specific approaches to prevent adverse pregnancy and neonatal outcomes. Intra-amniotic infection can be treated with the correct antibiotics, whereas sterile intra-amniotic inflammation could potentially be treated by administering a combination of anti-inflammatory drugs (e.g. betamethasone, inflammasome inhibitors, etc.). Recent evidence also supports the role of fetal T-cell activation as a newly described trigger for preterm labor and birth in a subset of cases diagnosed as idiopathic. Moreover, herein we also provide evidence of two maternally-driven immune mechanisms responsible for preterm births formerly considered to be idiopathic. First, the impairment of maternal Tregs can lead to preterm birth, likely due to the loss of immunosuppressive activity resulting in unleashed effector T-cell responses. Secondly, homeostatic macrophages were shown to be essential for maintaining pregnancy and promoting fetal development, and the adoptive transfer of homeostatic M2-polarized macrophages shows great promise for preventing inflammation-induced preterm birth. Collectively, in this review, we discuss the established and novel immune mechanisms responsible for preterm birth and highlight the potential targets for novel strategies aimed at preventing the multi-etiological syndrome of preterm labor leading to preterm birth.

P-Doped Cotton Stalk Carbon for High-Performance Lithium-Ion Batteries and Lithium-Sulfur Batteries.

Biomass as a carbon material source is the characteristic of green chemistry. Herein, a series of hierarchical P-doped cotton stalk carbon materials (HPCSCMs) were prepared from cheap and abundant biowaste cotton stalk. These materials possess a surface area of 3463.14 m2 g-1 and hierarchical pores. As lithium-ion battery (LIB) anodes, the samples exhibit 1100 mAh g-1 at 0.1 A g-1 after 100 cycles and hold 419 mAh g-1 at 1 A g-1 after 1000 cycles, with nearly 100% capacity retention. After HPCSCMs are loaded with sulfur (S/HPCSCMs), the samples (S/HPCSCMs-2) deliver a discharge capacity of 413 mAh g-1 at 0.1 A g-1 after 100 cycles as lithium-sulfur (Li-S) battery cathodes. This excellent electrochemical performance can be attributed to P in carbon networks, which not only provides more active sites, but also improves electrical conductivity.

Pregnancy tailors endotoxin-induced monocyte and neutrophil responses in the maternal circulation.

OBJECTIVE: To comprehensively characterize monocyte and neutrophil responses to E. coli and its product [lipopolysaccharide (LPS) or endotoxin] in vitro during pregnancy. MATERIAL OR SUBJECTS: Peripheral blood was collected from pregnant women during the third trimester (n = 20) and from non-pregnant women (n = 20). METHODS: The number, phagocytic activity, and reactive oxygen species (ROS) production of peripheral monocytes and neutrophils were investigated using flow cytometry. The phenotypes of peripheral monocytes and neutrophils after acute or chronic LPS stimulation were also determined using flow cytometry. Cytokine profiles were quantified for LPS-stimulated peripheral blood mononuclear cells (PBMCs) and a whole blood TruCulture® system using a multiplex immunoassay. RESULTS: Increased number, phagocytic activity, and ROS production capacity of monocytes and neutrophils were found in pregnant compared to non-pregnant women. Additionally, specific subsets of pro-inflammatory monocytes (IL-6+CD14+ or MIP-1α+CD14+ cells) and neutrophils (IL-1ß+CD15+ or MIP-1ß+CD15+ cells) were increased in pregnant women in response to acute LPS stimulation. Moreover, distinct subsets of intermediate-activated monocytes expressing CD142, IL-6, and IL-1RA were increased in pregnant women upon chronic LPS stimulation. Last, pregnant women displayed a different cytokine profile than non-pregnant women in LPS-stimulated PBMCs and in whole blood. CONCLUSIONS: Pregnancy tailors the immune responses of circulating monocytes and neutrophils to endotoxin, a Gram-negative bacterial product.

The IRE1/JNK signaling pathway regulates inflammation cytokines and production of glomerular extracellular matrix in the acute kidney injury to chronic kidney disease transition.

BACKGROUND: The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is extremely complex. Incomplete renal tubule repair, inflammation, and endoplasmic reticulum (ER) stress all play major roles. AKI activates ER stress, and the sensor protein inositol-requiring kinase-1 (IRE1) mediates inflammation by promoting the phosphorylation of C-jun NH2-terminal kinase (JNK). The interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway is associated with the secretion of renal extracellular matrix (ECM) and fibrosis. It remains unclear whether these signaling pathways play a role in the AKI-CKD transition. METHODS: In this study, a mouse model of ischemia-reperfusion (I/R) with bilateral renal artery clipping was used. IRE1 or JNK inhibitors were also injected to confirm their roles in the AKI-CKD transition. The renal function of the mice was determined by observing the pathology of the renal tubules and glomeruli through electron microscopy, immunohistochemistry, western blotting and quantitative real-time PCR. RESULTS: I/R stimulates ER stress and the IRE1/JNK pathway in the renal tubules in a short period of time, leading to continuous inflammation. Long-term I/R injury activates the STAT3 pathway in the glomeruli, activates mesangial cells proliferation, causes secretion of large amounts of glomerular ECM, and promotes glomerular sclerosis. This damage to the renal tubules and glomeruli is significantly reduced in I/R model mice pretreated with IRE1 or JNK inhibitors. CONCLUSION: These findings suggested that the IRE1/JNK pathway regulates the inflammatory cytokines caused by AKI and continues to activate the STAT3 pathway and production of ECM in the glomeruli at late stages, suggesting the feasibility of targeted therapy for the AKI-CKD transition.

Clarithromycin prevents preterm birth and neonatal mortality by dampening alarmin-induced maternal-fetal inflammation in mice.

BACKGROUND: One of every four preterm neonates is born to a woman with sterile intra-amniotic inflammation (inflammatory process induced by alarmins); yet, this clinical condition still lacks treatment. Herein, we utilized an established murine model of sterile intra-amniotic inflammation induced by the alarmin high-mobility group box-1 (HMGB1) to evaluate whether treatment with clarithromycin prevents preterm birth and adverse neonatal outcomes by dampening maternal and fetal inflammatory responses. METHODS: Pregnant mice were intra-amniotically injected with HMGB1 under ultrasound guidance and treated with clarithromycin or vehicle control, and pregnancy and neonatal outcomes were recorded (n = 15 dams each). Additionally, amniotic fluid, placenta, uterine decidua, cervix, and fetal tissues were collected prior to preterm birth for determination of the inflammatory status (n = 7-8 dams each). RESULTS: Clarithromycin extended the gestational length, reduced the rate of preterm birth, and improved neonatal mortality induced by HMGB1. Clarithromycin prevented preterm birth by interfering with the common cascade of parturition as evidenced by dysregulated expression of contractility-associated proteins and inflammatory mediators in the intra-uterine tissues. Notably, clarithromycin improved neonatal survival by dampening inflammation in the placenta as well as in the fetal lung, intestine, liver, and spleen. CONCLUSIONS: Clarithromycin prevents preterm birth and improves neonatal survival in an animal model of sterile intra-amniotic inflammation, demonstrating the potential utility of this macrolide for treating women with this clinical condition, which currently lacks a therapeutic intervention.

Dabigatran Use after Argatroban for Heparin-induced Thrombocytopenia with Thrombosis: A Case Series and Literature Review.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is immune-mediated thrombotic thrombocytopenia following the use of heparin, which contributes to a high limb-amputation rate and mortality if not appropriately handled. There is growing evidence suggesting that novel oral anticoagulants (NOACs) may be effective for treating HIT. METHODS: We described five rare cases of patients with HIT associated with deep vein thrombosis treated with dabigatran, a member of NOACs. We also reviewed representative cases and literature investigating the use of NOACs to treat patients with HIT to further discuss the efficacy and safety. RESULTS AND CONCLUSIONS: Following the treatment of dabigatran after argatroban, the platelet count of patients with HIT gradually elevated and reached the normal range eventually. There was no incidence of new symptomatic, objectively-confirmed arteriovenous thromboembolism observed within the 90-day-period follow up. The patient in case 3 presented with gastric bleeding after dabigatran treatment and died in the end. The results suggested that dabigatran use after argatroban may be effective in the treatment of patients with HIT. However, safety should be reconsidered since severe complications were observed in case 3.