FGF10 mitigates doxorubicin-induced myocardial toxicity in mice via activation of FGFR2b/PHLDA1/AKT axis.

Doxorubicin is a common chemotherapeutic agent in clinic, but myocardial toxicity limits its use. Fibroblast growth factor (FGF) 10, a multifunctional paracrine growth factor, plays diverse roles in embryonic and postnatal heart development as well as in cardiac regeneration and repair. In this study we investigated the role of FGF10 as a potential modulator of doxorubicin-induced cardiac cytotoxicity and the underlying molecular mechanisms. Fgf10+/- mice and an inducible dominant negative FGFR2b transgenic mouse model (Rosa26rtTA; tet(O)sFgfr2b) were used to determine the effect of Fgf10 hypomorph or blocking of endogenous FGFR2b ligands activity on doxorubicin-induced myocardial injury. Acute myocardial injury was induced by a single injection of doxorubicin (25 mg/kg, i.p.). Then cardiac function was evaluated using echocardiography, and DNA damage, oxidative stress and apoptosis in cardiac tissue were assessed. We showed that doxorubicin treatment markedly decreased the expression of FGFR2b ligands including FGF10 in cardiac tissue of wild type mice, whereas Fgf10+/- mice exhibited a greater degree of oxidative stress, DNA damage and apoptosis as compared with the Fgf10+/+ control. Pre-treatment with recombinant FGF10 protein significantly attenuated doxorubicin-induced oxidative stress, DNA damage and apoptosis both in doxorubicin-treated mice and in doxorubicin-treated HL-1 cells and NRCMs. We demonstrated that FGF10 protected against doxorubicin-induced myocardial toxicity via activation of FGFR2/Pleckstrin homology-like domain family A member 1 (PHLDA1)/Akt axis. Overall, our results unveil a potent protective effect of FGF10 against doxorubicin-induced myocardial injury and identify FGFR2b/PHLDA1/Akt axis as a potential therapeutic target for patients receiving doxorubicin treatment.

FGF1 alleviates LPS-induced acute lung injury via suppression of inflammation and oxidative stress.

BACKGROUND: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are devastating clinical disorders with high mortality, and for which more effective therapies are urgently needed. FGF1, the prototype member of the FGF family, is shown to exert protective effects against injurious stimuli in multiple disease models. Here we aimed to evaluate whether FGF1 pretreatment is protective against LPS-induced ALI and elucidate the potential underlying mechanisms. METHODS: For drug-treated groups, C57B/6 mice received a single i.p. injection of FGF1 (1 mg/kg) 1 h before the LPS challenge or not. To induce the ALI model, the mice were treated by intratracheal instillation of LPS (5 mg/kg). Then, histopathological changes in lung tissues were assessed by hematoxylin and eosin staining and transmission electron microscopy. ELISA and qPCR assays were used to detect pro-inflammatory cytokine levels in BALF and lung tissues, respectively. The total number of inflammatory cells (neutrophils and macrophages) in BALF were counted using the Wright-Giemsa method. The expressions of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured using their respective kits. Western blot and immunostaining were used to evaluate the expressions of antioxidants (Nrf-2, HO-1, SOD2, GPX4, and Catalase), as well as the inflammatory and/or apoptosis-related factors (TLR4, NF-κB, and Cleaved- caspase 3). RESULTS: FGF1 pretreatment significantly ameliorated the LPS-induced histopathological changes, reduced lung wet/dry ratios, ROS and MDA levels, total BALF protein, inflammatory cell infiltration, proinflammatory cytokine levels, and significantly increased the expression of antioxidant proteins (Nrf-2, HO-1, Catalase, and SOD2). In addition, FGF1 pretreatment significantly reduced the expression of TLR4 and cleaved- caspase 3, inhibited NF-κB activation, and reduced LPS-induced cell apoptosis. CONCLUSIONS: Altogether, our results suggest that FGF1 pretreatment is protective against LPS-induced ALI through mediating anti-inflammatory and antioxidant effects, which may be attributed to the downregulation of TLR4 expression and inhibition of NF-κB activation, as well as promotion of antioxidant defenses. Therefore, FGF1 administration may prove beneficial in preventative strategies for ALI/ARDS.

The Platelet-Lymphocyte Ratio Associated with Depression in Diabetes Patients in the US National Health and Nutrition Examination Survey.

BACKGROUND: This study investigated patients with diabetes mellitus (DM) and the role of the platelet-lymphocyte ratio (PLR) in comorbid clinically relevant depression (CRD) in these individuals, so as to determine the association between PLR and depression. MATERIAL AND METHODS: All data used in this research is originally from the United States National Health and Nutrition Examination Survey (NHANES). CRD in DM patients was screened via a Patient Health Questionnaire-9 (PHQ-9). PLR was calculated by platelet and lymphocyte counts. The associations between PLR and CRD in DM patients were determined using multivariable logistic regression models, weighted generalized additive models, and receiver operating characteristic curve (ROC). The second outcome was the relationship between suicide tendency and PLR. RESULTS: We selected 3537 DM patients from 2009 to 2016 in database. PLR was statistically significantly associated with risk of CRD in diabetic patients (p trend<0.05 in non-adjusted and adjusted model) and had a predictive value (AUC = 0.559). We also found a U-shaped association between PLR and CRD in patients with DM. The break point was 69.2. To the right of 69.2, the OR (95% CI) was 1.00 (1.00, 1.01). To the left of it, the OR (95% CI) was 0.97 (0.95, 1.00). We have found that PLR is not related to suicidal tendencies. CONCLUSION: PLR is an independent risk factor for CRD in DM patients, and the relationship between them is nonlinear. When PLR was around 69.2, patients with diabetes had the lowest risk of depression. Further research is needed to clarify the nonlinear relationship between PLR and depression in DM patients.

The Red Blood Cell Distribution Width-Albumin Ratio Was a Potential Prognostic Biomarker for Diabetic Ketoacidosis.

BACKGROUND: The red blood cell distribution width (RDW)-albumin ratio (RA) is a new biomarker, which is d-efined as RDW divided by albumin. This study aimed at determining the prognostic values of RA for diabetic ketoacidosis (DKA). METHODS: Data were obtained from Medical Information Mart for Intensive Care Database III V1.4 (MIMIC-III) and the RA calculated. Multivariate Cox regression analysis was performed to determine the correlation between RA and 90-day mortality or 365-day mortality. To further investigate the association with RA and mortality, the patients were divided into two groups. The second outcome was the association between the incidence of DKA-related infections and RA. RESULTS: For DKA patients in the ICU, RA was significantly correlated with 90-day mortality (HR: 2.1, 95% CI: 1.5, 3.0, p < 0.001) and 365-day mortality (HR: 1.9, 95% CI: 1.5, 2.5, p < 0.001). A high RA was independently correlated with increased 90-day mortality (HR: 7.8, 95% CI: 1.8, 34.0, p for trend <0.001) and 365-day mortality (HR: 5.2, 95% CI: 2.4, 11.3, p for trend <0.001). Moreover, RA was found to be an independent predictor for sepsis and septic shock in patients with DKA (HR: 2.9, 95% CI: 2.0, 4.1, p < 0.001). After adjusting for confounders, the statistical outcome was the same. CONCLUSION: A high RA is significantly correlated with increased all-cause mortality of DKA as well as an increased incidence of DKA-related infections. RA is a potential prognostic marker for DKA.

Association Between Systemic Immune-Inflammation Index and Diabetic Depression.

BACKGROUND: Depression is highly prevalent in patients with diabetes mellitus (DM). Diabetic depression has been shown to be associated with low-grade systemic inflammation. In recent years, the systemic immune-inflammation (SII) index has been developed as an integrated and novel inflammatory indicator. The aims of this study were to investigate the relationship between diabetic depression and SII levels, adjusting for a wide range of potential confounding factors, to examine the potential of SII in predicting diabetic depression. METHODS: The present cross-sectional study was conducted among adults with DM in the National Health and Nutrition Examination Survey between 2009 and 2016, the SII level was calculated as the platelet counts × neutrophil counts/lymphocyte counts. Patient Health Questionnaire-9 was used to measure depression in patients with DM. Multivariable logistic regression and propensity score-matched analysis were used to analyze the association between SII levels and depression. RESULTS: A total of 2566 patients with DM were included in the study, of which 370 (13.3%) were diagnosed with depression. Multivariable logistic regression showed that high SII level was an independent risk factor for diabetic depression (OR = 1.347, 95% CI: 1.031-1.760, P = 0.02882) after adjusting for covariates. The relationship between SII and diabetic depression was further verified by propensity score-matched analysis. CONCLUSION: Our data suggest that SII is a risk factor for depression in patients with DM. The SII may be an easily accessible and cost-effective strategy for identifying depression in patients with DM. More studies are warranted to further analyze the role of SII in depression in diabetic patients.

Vagus nerve plays a pivotal role in CD4+ T cell differentiation during CVB3-induced murine acute myocarditis.

Abnormalities in CD4+ T cell (Th cell) differentiation play an important role in the pathogenesis of viral myocarditis (VMC). Our previous studies demonstrated that activation of the cholinergic anti-inflammatory pathway (CAP) alleviated the inflammatory response. In addition, we observed that right cervical vagotomy aggravates VMC by inhibiting CAP. However, the vagus nerve's effect on differentiation of CD4+ T cells has not been studied in VMC mice to date. In this study, we investigated the effects of cervical vagotomy and the α7nAChR agonist pnu282987 on CD4+ T cell differentiation in a murine myocarditis model (BALB/c) infected with coxsackievirus B3 (CVB3). Splenic CD4+ T cells from CVB3-induced mice obtained and cultured to investigate the potential mechanism of CD4+ T cell differentiation. Each Th cell subset was analyzed by flow cytometry. Our results showed that right cervical vagotomy increased proportions of Th1 and Th17 cells and decreased proportions of Th2 and Treg cells in the spleen. Vagotomy-induced upregulation of T-bet, Ror-γ, IFN-γ, and IL-17 expression while downregulating the expression of Gata3, Foxp3, and IL-4 in the heart. In addition, we observed upregulated levels of proinflammatory cytokines, aggravated myocardial lesions and cellular infiltration, and worsened cardiac function in VMC mice. Pnu282987 administration reversed these outcomes. Furthermore, vagotomy inhibited JAK2-STAT3 activation and enhanced NF-κB activation in splenic CD4+ T cells. The CD4+ T cell differentiation was related to JAK2-STAT3 and NF-κB signal pathways. In conclusion, vagus nerve modulates the inflammatory response by regulating CD4+ T cell differentiation in response to VMC.

The Association between Neutrophil-to-Lymphocyte Ratio and Diabetic Depression in U.S. Adults with Diabetes: Findings from the 2009-2016 National Health and Nutrition Examination Survey (NHANES).

OBJECTIVE: To determine the association between neutrophil-to-lymphocyte ratio (NLR) and clinically relevant depressive symptoms in people with diabetes. METHODS: This cross-sectional study was conducted among adults (age >18) with diabetes in the National Health and Nutrition Examination Survey (NHANES) between 2009 and 2016. NLR was calculated from complete blood count. Nine-item Patient Health Questionnaire (PHQ-9) was used to measure depression, with scores ≥10 indicating the presence of clinically relevant symptoms. Multivariable logistic regression was used to calculate the odds ratio (OR) with 95% confidence interval (CI) of clinically relevant depressive symptoms in relation to the NLR. We performed the smooth curve fitting and established a weighted generalized additive model to identify the nonlinearity of NLR and depression in diabetes patients. To account for the nonlinear relationship between NLR and depression in diabetes patients, weighted two-piecewise linear model was applied. RESULTS: We included 2,820 eligible participants, of which 371 (12.4%) had clinically relevant depressive symptoms. In the unadjusted model, the OR (95% CI) of clinically relevant depressive symptoms for the second (NLR 1.75-2.57) and third (NLR >2.57) were 1.24 (0.90, 1.70) and 1.68 (1.23, 2.30), respectively, compared to the reference group (NLR < 1.75). After controlling for potential confounding factors, NLR was significantly associated with clinically relevant symptoms (odds ratio = 1.57, 95% confidence interval: 1.13-1.87; P for trend = .0078). Nonlinear relationships were observed, and a two-piecewise linear regression model was established. The inflection point of NLR was 2.87. To the left of the inflection point (NLR ≤ 2.87), the OR (95% CIs) was 1.33 (1.07-1.66) (P < .031). CONCLUSIONS: Elevated levels of NLR are independently associated with increased odds of clinically relevant depressive symptoms in people with diabetes. Prospective study is needed to further analyze the role of NLR in depression in diabetic patients.

Erratum: The WW domains dictate isoform-specific regulation of YAP1 stability and pancreatic cancer cell malignancy: Erratum.

[This corrects the article DOI: 10.7150/thno.42795.].

The WW domains dictate isoform-specific regulation of YAP1 stability and pancreatic cancer cell malignancy.

YAP1 is a key mediator of the Hippo pathway capable of exerting a profound effect on organ size as well as tumorigenesis. Alternative mRNA splicing of human YAP1 results in at least 8 protein isoforms that differ within the 2nd WW motif and the transcriptional activation domain. Methods: To investigate the isoform-specific differences in their mRNA expression, transcriptional activity and tumor-promoting function, we cloned cDNA encoding all of the eight YAP1 protein isoforms. Then, we examined their mRNA expression, subcellular localization, transcriptional regulation properties, interactions with key regulatory partners, and protein stability in response to changes in cell density, as well as their effects on pancreatic cancer cell malignancy both in vitro and in vivo. Results: Multiple YAP1 mRNA isoforms are expressed in commonly used pancreatic cancer lines as well as human pancreatic cancer PDX lines. Based on the analysis of heterologous reporter and endogenous target genes, all YAP1 isoforms are capable of activating transcription, albeit to a different extent. Importantly, we unveiled a marked discrepancy between the mRNA and protein expression levels of the YAP1-1 and YAP1-2 isoforms. We further discovered that the YAP1-2 isoform, which contains two tandem WW motifs, is less stable at the protein level, particularly at high cell densities. Mechanistically, we found that the presence of the 2nd WW motif in YAP1-2 facilitates the de novo formation of the YAP1-2/AMOT/LATS1 complex and contributes to a stronger binding of YAP1-2 to LATS1 and subsequently increased YAP1-2 ubiquitination and degradation by ß-TRCP. Conclusion: Our data reveals a potent effect of YAP1-1 on pancreatic cancer malignancy in vitro and in vivo and provides novel mechanistic insight into isoform-specific and cell density-dependent regulation of YAP1 stability, as well as its impact on cancer malignancy.

Legume Consumption and All-Cause and Cardiovascular Disease Mortality.

BACKGROUND: Legume consumption is suggested to have protective effects against cardiovascular disease (CVD) mortality in the general population, but the results have been equivocal. We conducted a meta-analysis of prospective cohort studies to assess the association between legume consumption and risk of CVD mortality and all-cause mortality. METHODS AND RESULTS: Medline (via Ovid) and EMBASE (via Ovid) databases were searched through April 2017 to identify eligible studies. The two authors independently extracted the data and the adjusted relative risks (RRs) and 95% confidence intervals (CIs) were pooled by using a random-effects model. A total of 6 studies were identified, including the sizes of participants ranging from 23,601 to 59,485 with a sum of 21,8997. Comparing the highest category with the lowest, the pooled RR (95% CI) was 0.96 (0.86-1.06) for CVD mortality and 0.93 (0.87-0.99) for all-cause mortality. CONCLUSIONS: Results from the current study show that high legume intakes are associated with lower risk of all-cause mortality. In consideration of the small number of studies, the evidence for assessing relationship between legumes intake and risk of all-cause mortality remains inclusive and warrants further study in the future. Further, consuming legumes does not increase the risk of CVD mortality.

Approach selection of radiofrequency catheter ablation for ventricular arrhythmias originating from the left ventricular summit: potential relevance of Pseudo Delta wave, Intrinsicoid deflection time, maximal deflection index.

BACKGROUND: Ventricular arrhythmias (VAs) originating from the left ventricular summit is a challenge for radiofrequency catheter ablation (RFCA). The present study aimed to investigate the appropriate RFCA strategy for VAs originating from the left ventricular summit. METHODS: Forty-five consecutive patients with VAs arising from the left ventricular summit were successfully ablated at our cardiac electrophysiology center and reviewed in the study. RESULTS: Thirty-two cases of VAs were eliminated in the left ventricular endocardium by retrograde transaortic (n = 22, 22/45, 48.9%) or antegrade transseptal (n = 10, 10/45, 22.2%) approaches, the other 13 cases were eliminated in the left ventricular epicardium by distal great cardiac vein (DGCV) approach (n = 13, 13/45, 28.9%). Though these VAs were similar in electrocardiographic (ECG) morphology, the pseudo delta waves (PDW), intrinsicoid deflection time (IDT), maximal deflection index (MDI) differed among them, PDW >53 ms, IDT > 74 ms, MDI > 0.45 strongly indicated that ablating left ventricular summit VAs by DGCV approach. During mean follow-up of 19.5 ± 13.2 (range, 3-60) months, 2 (4.4%) patients experienced VAs recurrence. CONCLUSION: This retrospective study showed that VAs of left ventricular summit origin can be effectively cured with RFCA. For these VAs, prolonged PdW, IDT, MDI indicating RFCA by DGCV approach can be attempted firstly.

Origins location of the outflow tract ventricular arrhythmias exhibiting qrS pattern or QS pattern with a notch on the descending limb in lead V1.

BACKGROUND: Ventricular outflow tract(VOT) ventricular arrhythmias(VAs) presenting qrS pattern or QS pattern with a notch on the descending limb in lead V1 were consistently thought of arising from the commissure between left and right coronary cusp (L-RCC) by previous studies. However, we found they could originate from other anatomic structures in VOT. This study aimed to investigate the exact origin of this kind VAs. METHODS: Forty-nine patients of VOT premature ventricular contrations/ventricular tachycardia(PVCs/VT) with lead V1 presenting qrS pattern or QS pattern with a notch on the descending limb undergoing successful radiofrequency catheter ablation(RFCA) in our center were analyzed. RESULTS: 12-lead electrocardiogram(ECG) of these PVCs/VT were summarized. Among these PVCs/VT, 37 cases exhibited qrS morphology in lead V1, 12 cases presented QS pattern with a notch on the descending limb in the same lead. Based on the successful ablation sites, these PVCs/VT were divided into 2 groups: (1)Right ventricular outflow tract(RVOT) group (26 cases), and (2) Left ventricular outflow tract (LVOT) group(23 cases, 4 cases originating from the left coronary cusp(LCC), 2 from the right coronary cusp(RCC), 16 from the L-RCC, 1 from the area inferior to LCC(ILCC)). The ECG characteristics of each PVCs/VT were analyzed. Among these PVCs/VT, applying the precordial transitional zone index(TZ index) < 0 to predict LVOT origin was demonstrated with sensitivity of 95.65%, specificity of 96.15%, positive predicting value(PPV) of 95.65% and negative predicting value(NPV) of 96.15%. In LVOT group, further applying the r, R, m,or Rs morphology in lead I to predict L-RCC and RCC origin was demonstrated with sensitivity of 94.44%, specificity of 60.00%, PPV of 89.47% and NPV of 75.00%. CONCLUSIONS: Ventricular outflow tract PVCs/VT with lead V1 presenting qrS pattern or QS pattern with a notch on descending limb not only arising from L-RCC, but also RVOT, LCC, RCC and ILCC. Combining TZ index and QRS morphology in lead I to predict origin site of these kind VAs is a convenient, simple and reliable method and facilitates the RFCA procedure.