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Frizzled receptors (FZDs) are a family of seven-span transmembrane receptors with hallmarks of G protein-coupled receptors (GPCRs) that serve as receptors for secreted Wingless-type (WNT) ligands in the WNT signaling pathway. Functionally, FZDs play crucial roles in regulating cell polarity, embryonic development, cell proliferation, formation of neural synapses, and many other processes in developing and adult organisms. In this review, we will introduce the basic structural features and review the biological function and mechanism of FZDs in the progression of human cancers, followed by an analysis of clinical relevance and therapeutic potential of FZDs. We will focus on the development of antibody-based and small molecule inhibitor-based therapeutic strategies by targeting FZDs for human cancers.

Background Sepsis is an important public health issue, and it is urgent to develop valuable indicators to predict the prognosis of sepsis. Our study aims to assess the predictive value of ICU admission (Neutrophil + Monocyte)/lymphocyte ratio (NMLR) on the 30-day mortality of sepsis patients. Methods A retrospective analysis was conducted in septic patients, and the data were collected from Medical Information Mart for Intensive Care IV (MIMIC-IV). Univariate and multivariate Cox regression analyses were conducted to investigate the relation between ICU admission NMLR and 30-day mortality. Restricted cubic spline (RCS) was performed to determine the optimum cut-off value of ICU admission NMLR. Survival outcomes of the two groups with different ICU admission NMLR levels were estimated using the Kaplan-Meier method and compared by the log-rank test. Results Finally, 7292 patients were recruited in the study, of which 1601 died within 30 days of discharge. The non-survival group had higher ICU admission NMLR values than patients in the survival group (12.24 [6.44–23.67] vs. 8.71 [4.81–16.26], P < 0.001). Univariate and multivariate Cox regression analysis demonstrated that ICU admission NMLR was an independent prognostic predictor on 30-day mortality (Univariate: P < 0.001; multivariate: P = 0.011). The RCS model demonstrated the upturn and non-linear relationship between ICU admission NMLR and 30-day mortality (Nonlinearity: P = 0.0124). According to the KM curve analysis,30-day survival was worse in the higher ICU admission NMLR group than that in the lower ICU admission NMLR group (Log rank test, P < 0.0001). Conclusion The elevated ICU admission NMLR level is an independent risk factor for high 30-day mortality in patients with sepsis.

The Oxford Acute Severity of Illness Score (OASIS) has shown fair prognosis predictive value in critically ill patients, but its predictive value has not been assessed in septic patients. The aim of this study was to evaluate the performance of the OASIS for the assessment of mortality in septic patients, especially when compared with the Sepsis-related Organ Failure Assessment (SOFA) score. A retrospective cohort study was conducted using data from a public database and septic patients were identified using the Sepsis-3 criteria. The primary outcome was hospital mortality. Data were mainly analyzed using multivariable logistic regression and receiver operating characteristic (ROC) curves. Sensitive analyses were performed in patients with an ICD-9-CM code for sepsis and ROC curves analyses were also conducted in septic patients stratified by the Simplified Acute Physiology Score (SAPS) II as subgroup analyses. A total of 10,305 septic patients were included. The OASIS was found to be significantly associated with hospital mortality (odds ratio 1.07 per one-point increase, 95% confidence interval [1.06-1.08]), while ROC curves analyses showed the discriminatory power of the OASIS for hospital mortality was statistically significantly lower than that of the SOFA score (area under the ROC curve: 0.652 vs 0.682, < 0.001). Results of sensitive analyses were consistent, but the significant difference existed only when the SAPS II was higher than 50 according to results of the subgroup analyses. The OASIS might serve as an initial predictor of clinical outcomes for septic patients, but one should be circumspect when it is applied to severer patients.

Gastric cancer (GC) is notoriously resistant to current therapies due to tumor heterogeneity. Cancer stem cells (CSCs) possess infinite self-renewal potential and contribute to the inherent heterogeneity of GC. Despite its crucial role in chemoresistance, the mechanism of stemness maintenance of gastric cancer stem cells (GCSCs) remains largely unknown. Here, we present evidence that lengsin, lens protein with glutamine synthetase domain (LGSN), a vital cell fate determinant, is overexpressed in GCSCs and is highly correlated with malignant progression and poor survival in GC patients. Ectopic overexpression of LGSN in GCSC-derived differentiated cells facilitated their dedifferentiation and treatment resistance by interacting with vimentin and inducing an epithelial-to-mesenchymal transition. Notably, genetic interference of LGSN effectively suppressed tumor formation by inhibiting GCSC stemness maintenance and provoking gasdermin-D-mediated pyroptosis through vimentin degradation/NLRP3 signaling. Depletion of LGSN combined with the chemo-drugs 5-fluorouracil and oxaliplatin could offer a unique and promising approach to synergistically rendering this deadly cancer eradicable in vivo. Our data place focus on the role of LGSN in GCSC regeneration and emphasize the critical importance of pyroptosis in battling GCSC.

Background Injury of alveolar epithelial cells and capillary endothelial cells is crucial in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) are a promising cell source for ALI/ARDS treatment. Overexpression of Fork head box protein M1 (FoxM1) facilitates MSC differentiation into alveolar type II (AT II) cells in vitro. Moreover, FoxM1 has been shown to repair the endothelial barrier. Therefore, this study explored whether overexpression of FoxM1 promotes the therapeutic effect of bone marrow-derived MSCs (BMSCs) on ARDS by differentiation of BMSCs into AT II cells or a paracrine mechanism. Methods A septic ALI model was established in mice by intraperitoneal administration of lipopolysaccharide. The protective effect of BMSCs-FoxM1 on ALI was explored by detecting pathological variations in the lung, total protein concentration in bronchoalveolar lavage fluid (BALF), wet/dry (W/D) lung weight ratio, oxidative stress levels, cytokine levels, and retention of BMSCs in the lung. In addition, we assessed whether FoxM1 overexpression promoted the therapeutic effect of BMSCs on ALI/ARDS by differentiating into AT II cells using SPC −/− mice. Furthermore, the protective effect of BMSCs-FoxM1 on lipopolysaccharide-induced endothelial cell (EC) injury was explored by detecting EC proliferation, apoptosis, scratch wounds, tube formation, permeability, and oxidative stress, and analyzing whether the Wnt/β-catenin pathway contributes to the regulatory mechanism in vitro using a pathway inhibitor. Results Compared with BMSCs-Vector, treatment with BMSCs-FoxM1 significantly decreased the W/D lung weight ratio, total BALF protein level, lung injury score, oxidative stress, and cytokine levels. With the detected track of BMSCs-FoxM1, we observed a low residency rate and short duration of residency in the lung. Notably, SPC was not expressed in SPC −/− mice injected with BMSCs-FoxM1. Furthermore, BMSCs-FoxM1 enhanced EC proliferation, migration, and tube formation; inhibited EC apoptosis and inflammation; and maintained vascular integrity through activation of the Wnt/β-catenin pathway, which was partially reversed by XAV-939. Conclusion Overexpression of FoxM1 enhanced the therapeutic effect of BMSCs on ARDS, possibly through a paracrine mechanism rather than by promoting BMSC differentiation into AT II cells in vivo, and prevented LPS-induced EC barrier disruption partially through activating the Wnt/β-catenin signaling pathway in vitro.

Background Lung endothelial barrier injury plays an important role in the pathophysiology of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Mesenchymal stem cells (MSCs) therapy has shown promise in ARDS treatment and restoration of the impaired barrier function. It has been reported that Wnt5a shows protective effects on endothelial cells. Therefore, the study aimed to investigate whether overexpression of Wnt5a could promote the protective effects of MSCs on Lipopolysaccharide (LPS)-induced endothelial cell injury. Methods To evaluate the protective effects of MSCs overexpressing Wnt5a, we assessed the migration, proliferation, apoptosis, and angiogenic ability of endothelial cells. We assessed the transcription of protective cellular factors using qPCR and determined the molecular mechanism using Western blot analysis. Results Overexpression of Wnt5a upregulated the transcription of protective cellular factors in MSCs. Co-culture of MSC Wnt5a promoted endothelial migration, proliferation and angiogenesis, and inhibited endothelial cell apoptosis through the PI3K/AKT pathway. Conclusions Overexpression of Wnt5a promoted the therapeutic effect of MSCs on endothelial cell injury through the PI3K/AKT signaling. Our study provides a novel approach for utilizing genetically modified MSCs in the transplantation therapy for ARDS.

Background A large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese. Methods We conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated. Results After meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported loci FGG rs2066865 ( p -value = 3.81 × 10 −14 ), ABO rs582094 ( p -value = 1.16 × 10 −10 ) and newly reported locus FABP2 rs1799883 ( p -value = 7.59 × 10 −17 ). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G (rs1799883) promoted the transcription and protein expression of FABP2 . Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population. Conclusions We identified FABP2 , related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.

Sepsis is a life-threatening and inflammatory disease with high morbidity and mortality. Red blood cell distribution width to platelet count ratio (RPR) was known as an inflammatory biomarker and was related to poor outcomes of various diseases. This study was intended to explore the association between RPR and mortality of sepsis patients. A retrospective cohort study was undertaken in patients with sepsis, and the data were collected from a public database called Medical Information Mart for Intensive Care III (MIMIC-III). The primary outcome was 28-day mortality while the secondary outcomes were 90-day mortality and ICU mortality. Multivariable regression analyses, as well as interaction and stratified analyses, were conducted to investigate the relation between RPR and sepsis mortality. In total, we enrolled 7531 patients with 1316 deaths. RPR was independently correlated with 28-day mortality (per 0.1 increase: HR=1.04; 95% CI 1.02-1.06), 90-day mortality (per 0.1 increase: HR=1.04; 95% CI 1.03-1.06) and ICU mortality (per 0.1 increase: OR=1.06; 95% CI 1.02-1.10). Twenty-eight-day survival was worse in the high RPR (≥0.134) group according to the Kaplan-Meier curve analyses (Log rank test, p<0.001). In stratified analyses, Sequential Organ Failure Assessment (SOFA) score and length of ICU stay had interactive effects with the high RPR (≥0.134) group on 28-day mortality. RPR is a novel biomarker that indicates poor prognosis of sepsis patients. Clinicians are required to pay more attention to those patients with high RPR.

The level of soluble urokinase-type plasminogen activator receptor (suPAR) is significantly increased in sepsis. We investigated whether suPAR could be a valuable biomarker in sepsis. We measured suPAR and procalcitonin (PCT) levels, recorded the Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment scores of engaged subjects, and drew Receiver Operating Characteristics curves. The plasma suPAR and serum PCT levels of the sepsis group were higher than those of the systemic inflammatory response syndrome and control groups. Using suPAR to distinguish systemic inflammatory response syndrome from sepsis on day 1, the area under the curve (AUC) curve was 0.817, and when suPAR and PCT were used in combination to diagnose sepsis, the AUC was 0.927. At a cutoff point of 9.52 ng/mL, the sensitivity and specificity for diagnosis of sepsis using suPAR were 71.93% and 95.46%, respectively. At a cutoff point of 12.01 ng/mL, the sensitivity and specificity for distinguishing survival and mortality by suPAR were 87.1% and 72.5%, respectively. When suPAR and the APACHE II score were combined to distinguish survival from mortality, the AUC was 0.857. The plasma suPAR level was positively correlated with the serum PCT level (r = 0.326, P < .001), APACHE II score (r = 0.492, P < .001), and Sequential Organ Failure Assessment score (r = 0.386, P < .001). Use of both plasma suPAR and PCT levels enhanced the efficiency of sepsis diagnosis, and the combination of plasma suPAR and APACHE II score improved mortality prediction.

Background/Aims: In the process of abnormal apoptosis of pulmonary alveolar type II epithelial A549 cells in acute respiratory distress syndrome (ARDS), inducible nitric oxide synthase (iNOS) activity in the lung, nitric oxide (NO) production, and the level of protein S-nitrosylation were increased. However, the role of excessive NO production in sepsis-induced ARDS is controversial. Additionally, ghrelin is a growth hormone that exerts an inhibitory role in cell apoptosis. We examined the effect of NO and S-nitrosylation on apoptosis of A549 cells induced by Lipopolysaccharide (LPS) and molecular mechanism underlying the anti-apoptotic effect of ghrelin in this process. Methods: Flow cytometry and qPCR were used to detect lentiviral infection efficiency and iNOS gene level, respectively. Extracellular and intracellular NO levels were observed by Griess assay kit and DAF-FM DA. Mitochondrial transmembrane potential, apoptosis rate and SNO levels were determined by flow cytometry, Biotin-Switch method and immunofluoresence staining. The expression of iNOS, apoptotic proteins and JNK were assessed by immunoblot analysis. Results: The results showed about two times increase in iNOS expression and intracellular NO levels response to LPS exposure at 24 hours (P< 0.05), while not in extracellular NO levels. NO donors, S-nitroso-N-acetylpenicillamine (SNAP) significantly raised (36.7%, P< 0.05; 38.4%, P< 0.05; 41.8%, P< 0.05) extracellular NO levels without influencing the intracellular NO levels. LPS increased the apoptosis rate (42.4%±2.6% vs 2.8%±1%, P< 0.05) of A549 accompanied by increased Bax levels and decreased Bcl-2 levels through activating JNK signaling, which was reversed when we diminished the iNOS expression in A549 cells using lentiviral vectors encoding iNOS shRNA in the presence of LPS (24.8%±3.8% vs 42.4%±2.6%, P< 0.05). However, the apoptosis rate was increased when SNAP was added (38.8%±1.3% vs 24.8%±3.8%, P< 0.05). Furthermore, we investigated whether ghrelin exert a protective role against LPS-induced apoptosis and the potential mechanism involved in. Ghrelin alone appeared to decrease iNOS expression (32.3%, P< 0.05; 42.3%, P< 0.05), which showed no signifiant difference between LPS+ghrelin group and LPS group. However, this study showed that ghrelin decreased the intracellular NO production (38.9%, P< 0.05), protein S-nitrosylation levels (33.5%, P< 0.05), Bax protein expression (70.2%, P< 0.05), whereas increasing Bcl-2 protein expression (14.1%, P< 0.05) and mitochondrial transmembrane potential (∆ΨM) (20.7%, P< 0.05) in the presence of LPS. Conclusion: The data suggested that NO derived from iNOS induced by LPS stimulation exerts an important role in promoting apoptosis of A549 cells, and ghrelin abolished intracellular NO production and protein S-nitrosylation levels, abrogating the apoptosis of A549 cells partly through inhibiting mitochondrial-dependent pathways.