Preserving flow, saving lives: Successful treatment of aortic valve failure in acute myocardial infarction without flow down-regulation using ECMO - a case report and mini review.

Direct percutaneous coronary intervention (PPCI) has significantly reduced cardiac mortality in patients with acute myocardial infarction (AMI), but the mortality rate remains high for those who develop cardiogenic shock (CS), reaching 40% to 50%. Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) provides robust hemodynamic support and oxygen delivery for AMI patients with refractory CS, ensuring adequate organ perfusion and oxygen supply. However, there is currently no standardized optimal Mean Arterial Pressure (MAP) range during V-A ECMO support. Achieving the proper MAP is crucial for adequate myocardial perfusion, cardiac function recovery, successful weaning off of V-A ECMO, and improving long-term outcomes. In this case study, we successfully treated a 55-year-old man with AMI and refractory cardiogenic shock using V-A ECMO. By adjusting ECMO blood flow and employing hemodynamic strategies, including vasoactive drugs, we optimized the MAP, leading to improved cardiac function and successful weaning off of V-A ECMO. This presents a potential opportunity for MAP optimization under ECMO support in patients with acute myocardial infarction and cardiogenic shock.

Lactate inhibits interferon-α response in ovarian cancer by inducing STAT1 ubiquitin degradation.

The emergence of lactate, produced by lactate dehydrogenase A (LDHA), as an important regulator of the immune response in tumor development has garnered attention in recent research. But, many questions still need to be clarified regarding the relationship between lactate and anti-tumor immunity. Here, we reported that both exogenous and endogenous lactate reduced the protein level and activation of the signal transducer and activator of transcription 1(STAT1) in ovarian cancer cells. As a consequence, the expression of IFNα-STAT1 regulated genes was weakened. This, in turn, weakened the antitumor effect of IFNα by impeding NKT and CD8+T cells recruitment. Strikingly, we found that LDHA knockdown did not result in the downregulation of STAT1 mRNA level in ovarian cancer cells. Instead, we observed that lactate triggered the degradation of STAT1 through the proteasomal pathway. Notably, we identified that lactate reduced the stability of STAT1 by promoting the expression of F-box only protein 40 (Fbxo40). This protein interacts with STAT1 and potentially acts as an E3 ubiquitin ligase, leading to the induction of STAT1 polyubiquitination and degradation. Importantly, ectopic over-expression of the Fbxo40 gene significantly inhibited the expression of ISGs in LDHA knockdown cells. In the TCGA tumor data, we observed that high expression of Fbxo40 negatively correlates with overall survival in ovarian cancer patients. Collectively, our findings reveal lactate as a negative regulator of the IFNα-STAT1 signaling axis in ovarian cancer. This discovery suggests that strategies aimed at targeting lactate for ovarian cancer prevention and treatment should consider the impact on the IFNα-STAT1 response.

Multi-omics integrated analyzed the origin of intrahepatic mucinous cholangiocarcinoma: a case report.

Intrahepatic mucinous cholangiocarcinoma (IMCC) is a rare subtype of intrahepatic cholangiocarcinoma (IHCC). Limited data describe the genetic characteristics of IMCC and insights on its pathogenesis are lacking. Here, we employed a multi-omics approach to analyze somatic mutations, transcriptome, proteome and metabolome of tumor tissue obtained from a case of IMCC in order to clarify the pathogenesis of IMCC. A total of 54 somatic mutations were detected, including a G12D mutation in KRAS that is likely to be involved in the onset of IMCC. The genes consistently up-regulated at the transcription level and in the proteome were enriched for mucin and mucopolysaccharide biosynthesis, for cell cycle functions and for inflammatory signaling pathways. The consistently down-regulated genes were enriched in bile synthesis and fatty acid metabolism pathways. Further multi-omics analysis found that mucin synthesis by MUC4 and MUC16 was elevated by up-regulated expression of mesothelin (MSLN). Moreover, transcription factor ONECUT3 was identified that possibly activates the transcription of mucin and mucopolysaccharide biosynthesis in IMCC.

MIF promotes Th17 cell differentiation in Hashimoto's thyroiditis by binding HVEM and activating NF-κB signaling pathway.

Hashimoto's thyroiditis is a typical thyroid autoimmune disease and Th17 cells are crucial in its development. In recent years, MIF (Macrophage Migration Inhibitory Factor) has been found to promote the secretion of IL-17A and the production and differentiation of Th17 cells. However, the specific mechanism of it remains unclear. Here, we found that the expression of MIF, IL-17A and HVEM (Herpes Virus Entry Mediator) were up-regulated in HT patients. The proportion of Th17 cells in peripheral blood mononuclear cells was positively correlated with the serum MIF protein level. We further found that the expression of HVEM and the phosphorylation level of NF-κB in peripheral blood mononuclear cells of HT patients were significantly increased. Therefore, we speculated that MIF promotes Th17 cell differentiation through HVEM and NF-κB signaling pathways. Further mechanism studies showed that MIF could directly bind to HVEM, and the stimulation of rhMIF in vitro could increase the expression of HVEM and activate NF-κB signaling pathways to promote Th17 cell differentiation. After blocking HVEM with HVEM antibody, the effect of MIF on Th17 cell differentiation disappeared. The results above show that the differentiation of Th17 cells is promoted by MIF combined with HVEM through NF-κB signaling pathways. Our research provides a new theory to the regulation mechanism of Th17 cell differentiation and gives hint to new potential therapeutic targets for HT.

NEUROLOGIC IMPAIRMENT IN PATIENTS WITH EXTRACORPOREAL CARDIOPULMONARY RESUSCITATION SUPPORT: CLINICAL FEATURES AND LONG-TERM OUTCOMES.

ABSTRACT: Introduction: The present study aimed to explore the clinical features and long-term outcomes associated with neurologic impairment in patients with cardiac arrest (CA) who received extracorporeal cardiopulmonary resuscitation (ECPR). Methods: A total of 37 adult CA patients who underwent venoarterial extracorporeal membrane oxygenation and were admitted to our department between January 2015 and February 2022 were divided according to neurologic impairment. Baseline and CPR- and ECMO-related characteristics were compared between the two groups. Long-term neurologic outcomes were collected via telephone follow-ups. Results: Twenty-four (64.9%) ECPR-supported patients developed neurologic impairments. The two groups differed significantly in median age (P = 0.026), proportion of intra-aortic balloon pump (IABP) support (P = 0.011), proportion of continuous renal replacement therapy (P = 0.025), and median serum creatinine (Cr) level (P = 0.012) pre-ECMO. The 28-day mortality (P = 0.001), hospital mortality (P = 0.003), median duration from CA to restoration of spontaneous circulation (P = 0.029), proportion of patients with nonpulsatile perfusion (NP) >12 hours (P = 0.040), and median ECMO duration (P = 0.047) were higher in the neurologic impairment group. In contrast, the group without neurologic impairment exhibited a longer median intensive care unit length of stay (P = 0.047), longer median hospital LOS (P = 0.031), and more successful ECMO weaning (P = 0.049). Moreover, NP >12 hours combined with IABP support (odds ratio [OR], 14.769; 95% confidence interval [CI], 1.417~153.889; P = 0.024) and serum Cr level (OR, 1.028; 95% CI, 1.001~1.056; P = 0.043) were independent risk factors for neurologic impairment. Furthermore, neurologic impairment was associated with significantly worse 90-day survival (hazards ratio, 4.218; 95% CI, 1.745~10.2; P = 0.0014). Conclusions: The incidence of neurologic impairment was higher in patients who received ECPR and was closely related to 28-day mortality and discharge survival. NP >12 hours combined with IABP support and serum Cr levels were independent risk factors for neurologic impairments in ECPR-supported patients. Neurologic impairment significantly adversely affected the long-term outcomes of ECPR-supported patients after discharge.

Chemokine (C-X-C motif) ligand 1 maintains the immune surveillance function of natural killer cells via the PDK2/mTOR signaling pathway.

Chemokine (C-X-C motif) ligand 1 (CXCL1) is mainly expressed on neutrophils and macrophages and has neutrophil chemoattractant activity. However, natural killer (NK) cells also express CXCL1. We were curious about the role played by CXCL1 in NK cells. Knocking out CXCL1 in hematopoietic cells does not affect the occurrence of NK cells; however, it does hinder NK cell maturity. CXCL1 deletion enhances the expression of immature markers and decreases the expression of functional markers in NK cells, which may explain why it hinders the maturation of NK cells. Specific knockout of CXCL1 in NK cells (CXCL1flox/flox Ncr1-cre) leads to impaired IFN-γ production and degranulation of NK cells. The lack of CXCL1 may prevent IFN-γ production and degranulation of NK cells by inhibiting the phosphorylation of AKTS473 and S6. Therefore, we have discovered a new role for CXCL1 in regulating NK cell development and immune surveillance, providing a novel theoretical basis for immunotherapy based on NK cells and potential therapeutic targets for the clinical use of NK cells. 1. Knockout of CXCL1 in hematopoietic cells inhibits the maturation of NK cells. 2. Knockout of CXCL1 in NK cells inhibits the clearance of lymphoma by NK cells and reduces IFN-γ production and CD107 expression in NK cells. 3. CXCL1 activates the PKD2/mTOR signaling pathway, and promotes the production of IFN-γ and the expression of CD107a in NK cells.

[Design and application of flushing device of a totally enclosed sputum suction tube for reducing the incidence of ventilator-associated pneumonia].

Ventilator-associated pneumonia (VAP) is one of the most common infectious diseases in patients undergoing mechanical ventilation in intensive care unit (ICU). Although the use of closed sputum suction tube for sputum suction is the most common nursing measure for patients with tracheal intubation in ICU, and it is also an important measure to reduce the occurrence of VAP, the existing clinical technology still needs to use external flushing solution for humidification and flushing. In the process of use, the flushing operation has the risk that the amount of flushing fluid cannot be controlled, resulting in a large amount of flushing fluid entering the patient's airway, causing the patient to suffocate. The sputum attached to the wall of the sputum suction tube cannot be completely flushed, and the prolonged retention of the sputum leads to the proliferation of colonized bacteria, aggravating the infection of patients. Repeated pipe flushing not only increases consumables, but also increases the workload of medical staff. For this reason, the author has designed a fully enclosed sputum suction tube flushing device, which has obtained the National Utility Model Patent of China (patent number: CN 2019 2 1198740.5). This device is an integrated design, and the materials used for sputum suction, humidification and flushing are fully enclosed, without air exposure, and can be operated strictly without bacteria. Pulse flushing with syringe can clean the sputum attached to the inner wall and reduce the incidence of VAP. The volume of flushing fluid can be effectively controlled during use to ensure patient safety and reduce waste. It is worth popularizing and applying in clinical practice to optimize the operation steps and reduce the workload of medical staff.

Ibrutinib-Associated Cardiotoxicity: From the Pharmaceutical to the Clinical.

Ibrutinib is the first-in-class Bruton tyrosine kinase (BTK) inhibitor that has revolutionized the treatment of B cell malignancies. Unfortunately, increased incidences of cardiotoxicity have limited its use. Despite over a decade of research, the biological mechanisms underlying ibrutinib cardiotoxicity remain unclear. In this review, we discuss the pharmacological properties of ibrutinib, the incidence and mechanisms of ibrutinib-induced cardiotoxicity, and practical management to prevent and treat this condition. We also synopsize and discuss the cardiovascular adverse effects related to other more selective BTK inhibitors, which may guide the selection of appropriate BTK inhibitors.

SHARPIN promotes cell proliferation of cholangiocarcinoma and inhibits ferroptosis via p53/SLC7A11/GPX4 signaling.

SHARPIN is a tumor-associated gene involved in the growth and proliferation of many tumor types. A function of SHARPIN in cholangiocarcinoma (CCA) is so far unclear. Here, we studied the role and function of SHARPIN in CCA and revealed its relevant molecular mechanism. The expression of SHARPIN was analyzed in cholangiocarcinoma tissues from patients using immunohistochemistry, quantitative PCR, and western blot analysis. Expression of SHARPIN was suppressed/overexpressed by siRNA silencing or lentiviral overexpression vector, and the effect on cell proliferation was determined by the CCK-8 assay and flow cytometry. Accumulation of reactive oxygen species was measured with MitoTracker, and JC-1 staining showed mitochondrial fission/fusion and mitochondrial membrane potential changes as a result of the silencing or overexpression. The ferroptosis marker solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and the antioxidant enzymes superoxide dismutase 1 (SOD-1) and SOD-2 were analyzed by western blot. The results showed that SHARPIN expression was increased in CCA tissue, and this was involved in cell proliferation. SHARPIN silencing resulted in accumulated reactive oxygen species, reduced mitochondrial fission, and a reduced mitochondrial membrane potential. Silencing of SHARPIN inhibited the ubiquitination and degradation of p53, and downregulated levels of SLC7A11, GPX4, SOD-1, and SOD-2, all of which contributed to excessive oxidative stress that leads to ferroptosis. Overexpression of SHARPIN would reverse the above process. The collected data suggest that in CCA, SHARPIN-mediated cell ferroptosis via the p53/SLC7A11/GPX4 signaling pathway is inhibited. Targeting SHARPIN might be a promising approach for the treatment of CCA.

Silybin suppresses ovarian cancer cell proliferation by inhibiting isocitrate dehydrogenase 1 activity.

Metabolic reprogramming is a sign of malignant tumors, and targeting the metabolism of tumor cells has become a promising therapeutic approach. Here, we report that Silybin (a nontoxic flavonoid commonly used for liver protection) exhibits prominent anti-tumor effects on human ovarian cancer cells. Treatment of an ovarian cancer cell line with Silybin interfered with glutamine metabolism and the tricarboxylic acid cycle. We applied the drug affinity responsive target stability approach to show that Silybin binds to isocitrate dehydrogenase 1 (IDH1). This combination leads to reduced phosphorylation of IDH1 and inhibits enzyme activity. IDH1 dysfunction significantly increases the ratio of NADP/NADPH in the cell, causing an increase in reactive oxygen species generation. Immunohistochemistry demonstrated that IDH1 was increased in ovarian cancer samples compared with normal para-tumoral tissues. Xenograft murine experiments indicated that Silybin administered orally suppressed the growth of the tumor formed by ovarian cancer cells. In combination, our data strongly suggest that Silybin targets IDH1 in ovarian cancer cells and may be a novel treatment candidate.

Comparison of Clinical Efficacy and Safety between Misoprostol and Oxytocin in the Prevention of Postpartum Hemorrhage: A Meta-Analysis.

In order to systematically evaluate the clinical efficacy and safety of misoprostol versus oxytocin in the prevention of postpartum hemorrhage, this paper provides evidence-based reference for clinical medication, computerized retrieval of Chinese biomedical literature database (CBM), PubMed, Embase, Cochrane Library, and clinical trials. The retrieval period is from the establishment of each database to October 1, 2021. Published randomized controlled trials (RCTS) are included in this study. The literature is screened and evaluated according to inclusion and exclusion criteria, and meta-analysis is performed using RevMan 5.3 software. A total of 13 RCTS are included, with a total of 24754 parturients. The meta-analysis shows the average blood loss (SMD = 0.10, 95% CI (-0.11, 0.32), P=0.35), the time of the third stage of labor (SMD = 0, 95% CI (-0.07, 0.08), P=0.95), and blood transfusion rate (RR = 0.80, 95% CI (0.63, 1.02), P=0.07). However, the incidences of shivering (RR = 2.61, 95% CI (1.79, 0.81), P < 0.00001) and vomiting (RR = 2.78, 95% CI (1.85, 4.18), P < 0.00001) are significantly higher than those in oxytocin group. The effect of misoprostol on preventing postpartum hemorrhage is similar to that of oxytocin, but the incidence of adverse reactions is high, and the occurrence of adverse reactions should be closely watched in the use process. Due to the limitations of the included studies, multicenter, large-sample, and high-quality RCTS are still needed in the future to further verify this conclusion.

Vitamin C Inhibits Ubiquitination of Glutamate Transporter 1 (GLT-1) in Astrocytes by Downregulating HECTD1.

Excitatory neurotoxicity caused by the accumulation of glutamate in the synaptic cleft is an important cause of Parkinson's disease (PD). Astrocyte glutamate transporter 1 (GLT-1) is the main transporter responsible for transporting glutamate, and investigations toward the regulation of GLT-1 in astrocytes can reveal important insights. Vitamin C (VC) has important protective effects on the brain, but its effect on the regulation of GLT-1 expression is unclear. The purpose of this study was to explore any regulatory effect of VC on GLT-1 expression in astrocytes and to clarify the possible mechanism of such regulation. We found that GLT-1 expression was impaired in 1-methyl-4-phenylpyridinium iodide (MPP+)-treated astrocytes, and the transport capacity for glutamate was significantly reduced. Pretreatment with VC restored the GLT-1 expression in the MPP+-treated astrocytes. Intraperitoneal VC administration in a PD murine model confirmed that GLT-1 expression was restored in midbrain tissue. The VC-dependent rescue of GLT-1 expression in the MPP+-treated astrocytes was shown to be due to inhibition of GLT-1 ubiquitination. Transcriptome sequence analysis revealed a number of differentially expressed genes as a result of VC treatment on MPP+-treated astrocytes, including the downregulation of HECT Domain E3 ubiquitin protein ligase 1 (Hectd1). After knocking down Hectd1, the impaired GLT-1 expression caused by MPP+ was alleviated, while overexpression of Hectd1 significantly reduced the expression of GLT-1. After overexpression of Hectd1, VC could no longer increase GLT-1 expression of MPP+-treated astrocytes, indicating that HECTD1 is essential for VC regulation of GLT-1. Thus, VC reduces the ubiquitination of GLT-1 in astrocytes by inhibiting the expression of HECTD1. Our findings have identified a novel mechanism by which VC regulates the expression of GLT-1 in astrocytes.

Heparin-free adventitia pulmonary oxygenation in the treatment of trauma complicated with severe pulmonary infection: a case report.

The application of Venovenous (VV) extracorporeal membrane oxygenation (ECMO) in trauma and patients with severe bleeding tendency has been controversial. However, VV ECMO without anticoagulation contributes to reducing the risk of bleeding during ECMO maintenance. VV ECMO serves critical roles in therapy of patients with severe pulmonary infection and failure in conventional therapy. The common peripheral catheterization approach for VV ECMO is femoral vein-internal jugular vein catheterization, and bilateral femoral vein catheterization can also achieve the purpose of respiratory support for patients with limited cervical catheterization. In this case report, we described a patient with post-traumatic cervical spinal cord injury and severe pulmonary infection who was successfully treated with heparin-free intravenous ECMO.

Clinical Characteristics of 10 Pregnant and Postpartum Women With Extracorporeal Membrane Oxygenation: A Retrospective Study.

Background: The aim of study was to summarize the clinical characteristics and experience of extracorporeal membrane oxygenation (ECMO) in pregnant and postpartum patients. Methods and Results: We retrospectively reviewed 131 consecutive ECMO patients at our center from May 2015 to May 2021. A total of 10 Chinese patients were pregnant or postpartum at the time of ECMO initiation. Patients ranged in age from 25 to 36 years (median age 30.5 years). The ECMO duration ranged from 3 to 31 days (median duration 8 days). There was a stabilizing trend of acid-base balance and decreasing lactic acid over the 3 days following ECMO initiation. Seven (70%) patients survived at least 48 h after weaning from ECMO. Four (40%) patients survived until discharge, and four (40%) fetuses survived until discharge. Conclusion: ECMO provides a suitable temporary cardiopulmonary support for pregnant and postpartum patients. ECMO shows a favorable effect on short-term stability in critical obstetric patients.

Pretreatment of Ascorbic Acid Inhibits MPTP-Induced Astrocytic Oxidative Stress through Suppressing NF-κB Signaling.

Astrocytes are a major constituent of the central nervous system (CNS). Astrocytic oxidative stress contributes to the development of Parkinson's disease (PD). Maintaining production of antioxidant and detoxification of reactive oxygen and nitrogen species (ROS/RNS) in astrocytes is critical to prevent PD. Study has illuminated that ascorbic acid (AA) stimulates dopamine synthesis and expression of tyrosine hydroxylase in human neuroblastoma cells. However, the role and regulatory mechanisms of AA on detoxification of astrocytes are still unclear. The purpose of our study is in-depth study of the regulatory mechanism of AA on detoxification of astrocytes. We found that AA pretreatment decreased the expression of ROS and inducible nitric oxide synthase (iNOS) in MPP+-treated astrocytes. In contrast, the expression levels of antioxidative substances-including superoxide dismutase (SOD), glutathione (GSH), and glutamate-cysteine ligase modifier (GCLM) subunit-were upregulated after AA pretreatment in MPP+-treated astrocytes. However, inhibition of NF-κB prevented such AA induced increases in antioxidative substances following MPP+ treatment in astrocytes, suggesting that AA improved antioxidative function of astrocytes through inhibiting NF-κB-mediated oxidative stress. Furthermore, in vivo studies revealed that AA preadministration also suppressed NF-κB and upregulated the expression levels of antioxidative substances in the midbrain of MPTP-treated mice. Additionally, pretreatment of AA alleviated MPTP-induced PD-like pathology in mice. Taken together, our results demonstrate that preadministration of AA improves the antioxidative function of astrocytes through suppressing NF-κB signaling, following alleviated the pathogenesis of PD which induced by MPTP. Hence, our findings elucidate a novel protective mechanism of AA in astrocytes.

Chronic shift-lag promotes NK cell ageing and impairs immunosurveillance in mice by decreasing the expression of CD122.

Long-term subjection to shift work increases the risk of cancer. The purpose of the present study was to explore the mechanism by which chronic circadian disruption impairs natural killer (NK) cell immunosurveillance. Mice were subjected to light-dark reverse every 4 days for 12 weeks to disrupt normal circadian rhythm. NK cell development and function were evaluated by flow cytometry. The mRNA and protein levels of period 1 (per1) and per2 were suppressed, while circadian locomotor output cycle kaput (CLOCK) was increased in the shifted mice, indicating successful generation of the circadian rhythm disruption mouse model. Chronic shift-lag promoted NK cell ageing, which is likely due to the reduction in Ly49 family receptor expression in shifted NK. We further studied the effects of circadian rhythm disruption on NK cell function. Chronic shift-lag inhibited NK cell secretion of granular CD107a and interferon gamma. Moreover, chronic shift-lag attenuated the clearance of MHC-I-deficient tumour cells by NK cells in vivo and promoted lung metastasis of B16F10 melanomas. Furthermore, chronic shift-lag reduced NK cell killing function, which may be due to the suppression of Eomes transcription factor expression, which inhibiting the transcription of CD122. In conclusion, our findings suggest that chronic circadian disruption attenuates NK cell cytolytic activity by decreasing the expression of CD122.

A High-Salt Diet Disturbs the Development and Function of Natural Killer Cells in Mice.

A high-salt diet (HSD) is common worldwide and can lead to cardiovascular disease, chronic inflammation, and autoimmune diseases. Moreover, increasing evidence shows that HSD is closely related to a variety of immune diseases. Natural killer (NK) cells are important innate immune cells that directly kill their targets via degranulation and secretion of interferon gamma (IFN-γ). NK cells play a vital role in resisting viruses and preventing the malignant transformation of cells; however, whether HSD affects the development and function of NK cells has not yet been elucidated. Therefore, the purpose of the present study was to understand the effects of HSD on the development and function of NK cells, in addition to investigating the underlying molecular mechanism. Our results show that the number of NK cells in the spleen and lungs of HSD-fed mice was significantly reduced, which may be due to the inhibition of NK cell proliferation. Further, the development of NK cells in mice was evaluated, and it was found that HSD reduced the effective NK cell subset (CD27+CD11b-). Moreover, it was also found that the ability of NK cells to secrete CD107a and IFN-γ in HSD-fed mice was decreased following stimulation with RMA-S and YAC-1 tumor cells. Finally, the underlying molecular mechanism was evaluated, and it was found that HSD increased the production of reactive oxygen species (ROS) by NK cells, while the expression of CD122 was decreased, suggesting that HSD downregulates CD122 expression in NK cells via ROS signaling, thereby reducing the responsiveness to IL-15 and ultimately inhibiting NK cell function. The present research discovered a novel mechanism by which HSD inhibits the function of NK cells, providing an alternative avenue for the treatment of immune diseases caused by HSD.

Combined deficiency of SLAMF8 and SLAMF9 prevents endotoxin-induced liver inflammation by downregulating TLR4 expression on macrophages.

Classical signaling lymphocyte activating molecule (SLAM) family receptors are abundant within many types of immune cells, whereas the nonclassical SLAM family receptors SLAMF8 and SLAMF9, which uniquely lack cytoplasmic signaling motifs, are highly expressed by myeloid cells. Due to the potential redundancy, whether these two receptors regulate macrophage function remains largely unknown. Here, we show that SLAMF8 and SLAMF9 co-regulate macrophage-mediated liver inflammation. To overcome the redundancy, we generated mice that simultaneously lacked SLAMF8 and SLAMF9 using CRISPR-Cas9 technology. Although macrophage differentiation was not altered by the combined deficiency of SLAMF8 and SLAMF9, the loss of these two receptors significantly protected against lipopolysaccharide (LPS)-induced liver injury. SLAMF8 and SLAMF9 double-deficient mice had a prolonged survival rate and less infiltration of inflammatory cells. The depletion of macrophages using clodronate liposomes abolished the effects of SLAMF8 and SLAMF9 deficiencies on LPS-induced liver injury, which demonstrates that these receptors are required for macrophage activation following LPS challenge. Moreover, the deficiency of SLAMF8 and SLAMF9 suppressed the secretion of inflammatory cytokines by downregulating the expression of Toll-like receptor-4 (TLR4), a receptor that specifically binds LPS, which led to decreased mitogen-activated protein kinases (MAPK) signaling activation. Notably, combined injections of truncated extracellular SLAMF8 and SLAMF9 proteins significantly alleviated LPS-induced liver injury. Thus, our findings provide insights into the role of SLAMF8 and SLAMF9 in endotoxin-induced liver injury and suggest that SLAMF8 and SLAMF9 are potential therapeutic targets for acute hepatic injury.

Human umbilical cord mesenchymal stem cells pretreated with Angiotensin-II attenuate pancreas injury of rats with severe acute pancreatitis.

Mesenchymal stem cells (MSCs) pretreatment is an effective route for improving cell-based therapy of endothelial cell survival, vascular stabilization, and angiogenesis. We hypothesized that the application of human umbilical cord-MSCs (hUC-MSCs) pretreated with angiotensin-II (Ang-II) might be a potential therapeutic approach for severe acute pancreatitis (SAP). Therefore, the effect of Ang-II pretreated hUC-MSCs on SAP was investigated in vitro and in vivo. METHODS: In the present study, human umbilical cord-derived MSCs pretreated with or without Ang-II were delivered through the tail vein of rats 12 h after induction of SAP. Pancreatitis severity scores and serum lipase levels, as well as the levels of VEGF and VEGFR2 were evaluated. RESULTS: We found that the administration of Ang-II-MSCs significantly inhibited pancreatic injury, as reflected by reductions of pancreatitis severity scores, serum amylase and serum lipase levels. Furthermore, the reduced apoptotic rate and increased tube formation in human umbilical vein endothelial Cells (HUVEC) were found resulting from the administration of Ang-II-MSC-CM. Moreover, knockdown of VEGFR2 can block the effect of Ang-II-MSC-CM on preventing HUVEC from apoptosis, as well as the capacity of tube formation was also suppressed. In addition, the expression of increased Bcl-2 and alleviated caspase-3 were observed in HUVEC and HUVEC transfectants exposure to Ang-II-MSC-CM. CONCLUSION: Collectively, these results elucidated that the pretreatment of hUC-MSCs with Ang-II improved the outcome of MSC-based therapy for SAP via enhancing angiogenesis and ameliorating endothelial cell dysfunction in a VEGFR2 dependent manner.

Effect of Post-Thermal Annealing on the Performance and Charge Photogeneration Dynamics of PffBT4T-2OD/PC71BM Solar Cells.

In this work, we studied influence of post thermal annealing on the performance and charge photogeneration processes of PffBT4T-2OD/PC71BM solar cells. As-prepared device exhibits a high-power conversion efficiency of 9.5%, much higher than that after thermal annealing. To understand this phenomenon, we studied charge photogeneration processes in these solar cells by means of time resolved spectroscopy. We associate the degradation of solar cell performance with the reduction of exciton dissociation efficiency and with increased bimolecular recombination of photogenerated charges as a result of annealing. We correlate the generation of localized PffBT4T-2OD polarons observed via spectro-electrochemical measurements with enhancement of the bimolecular charge recombination of annealed solar cells.