NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance

Lack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1high tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance

Aberrant expression of decoy receptor 3 in human breast cancer: relevance to lymphangiogenesis

AbstractBackgroundDecoy receptor 3 (DcR3), a decoy receptor against Fas ligand belonging to the tumor necrosis factor receptor superfamily, is overexpressed in some forms of cancer. It was recently reported that DcR3 could protect endothelial cells from apoptosis, implying a potential role in the development of vessels, whereas its role in the lymphangiogenesis remains unclear. In the present study, we studied the DcR3 expression and its relationship with the lymphatic microvessel density (LMVD) to investigate if it played a role in the lymph metastasis of human breast cancer.Materials and methodsReal-time polymerase chain reaction and immunohistochemistry were performed to measure the messenger RNA and protein expression of DcR3 in the breast cancer tissues, noncancerous counterparts, and axillary lymph node from 63 patients. LMVD in these specimens was assessed by counting the D2-40 labeled–microvessels. Furthermore, the correlations between DcR3 expression and LMVD and other clinicopathologic parameters were analyzed.ResultsDcR3 was overexpressed in the breast cancer tissue of 58 patients (92.1%) and was also expressed in vascular endothelial cells and tumor cells in the lymph nodes. LMVD in cancer tissue and lymph nodes were both positively correlated to the aberrant expression of DcR3.ConclusionsThe relevance between DcR3 overexpression and LMVD revealed the existence of possible links between DcR3 and lymphangiogenesis. Based on these findings, it is important to further explore the regulation of lymphangiogenesis operated by the reverse tumor necrosis factor signaling of DcR3

Association of PDE11A global haplotype with major depression and antidepressant drug response

Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the intracellular second messengers cAMP and cGMP to their corresponding monophosphates. PDEs play an important role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. We have previously shown that the individual haplotype GAACC in the PDE11A gene was associated with major depressive disorder (MDD) based on block-by-block analysis. There are two PDE genes, PDE11A and PDE1A, located in chromosome 2q31–q32. In this study, we have further explored whether the whole region 2q31–q32 contribute to MDD or antidepressant response 278 depressed Mexican-American participants and 321 matched healthy controls. Although there is no significant interaction between the two genes, the remission rate of individual carrying the combination genotype at rs1880916 (AG/AA) and rs1549870 (GG) is significantly increased. We analyzed the global haplotype by examining 16 single-nucleotide polymorphisms (SNPs) in PDE11A and six SNPs in PDE1A. None of the haplotypes consisting of six SNPs in the PDE1A have a significant difference between depressed and control groups. Among haplotypes consisting of 16 SNPs across 440 kb in the PDE11A gene, 18 common haplotypes (with frequency higher than 0.8%) have been found in the studied population. Six haplotypes showed significantly different frequencies between the MDD group and the control group. The phylogenetic network result for the 16 SNPs showed that several historic recombination events have happened in the PDE11A gene. The frequency of one haplotype is significantly lower in the remitter group than in the nonremitter group for the depressed participants treated with either desipramine or fluoxetine. Thus, our data suggest that the PDE11A global haplotype is associated with both MDD and antidepressant drug response

Association between systemic iron status and β-cell function and insulin sensitivity in patients with newly diagnosed type 2 diabetes

ObjectiveAbnormal iron metabolism is related to the risk of diabetes, but the underlying mechanism of this association remains uncertain. This study was conducted to evaluate the contributions of systemic iron status to β-cell function and insulin sensitivity of patients with newly diagnosed T2DM.MethodsA total of 162 patients with newly diagnosed T2DM and 162 healthy controls were enrolled in the study. Basic characteristics, biochemical indicators, and iron metabolism biomarkers, including serum iron (SI), ferritin (SF), transferrin (Trf), and transferrin saturation (TS), were collected. All patients underwent a 75 g oral glucose tolerance test. A series of parameters for assessing β-cell function and insulin sensitivity were calculated. The multivariate stepwise linear regression model was used to investigate the contributions of iron metabolism to β-cell function and insulin sensitivity.ResultsCompared with healthy controls, patients with newly diagnosed T2DM had significantly higher levels of SF. Among the diabetic patients, the SI and TS levels were higher, and the percentage of Trf levels below normal values was lower in men than in women. In all diabetic patients, SF was the independent risk factor associated with impaired β-cell function. Further stratification analysis showed that Trf was an independent protective factor for β-cell function in male patients, while SF was an independent risk factor for impaired β-cell function in female patients. However, systemic iron status did not affect insulin sensitivity.ConclusionElevated SF levels and decreased Trf levels had a profound effect on impaired β-cell function in Chinese patients with newly diagnosed T2DM

An Integrative Pharmacology Model for Decoding the Underlying Therapeutic Mechanisms of Ermiao Powder for Rheumatoid Arthritis

As a systemic inflammatory arthritis disease, rheumatoid arthritis (RA) is complex and hereditary. Traditional Chinese medicine (TCM) has evident advantages in treating complex diseases, and a variety of TCM formulas have been reported that have effective treatment on RA. Clinical and pharmacological studies showed that Ermiao Powder, which consists of Phellodendron amurense Rupr. (PAR) and Atractylodes lancea (Thunb.) DC. (ALD), can be used in the treatment of RA. Currently, most studies focus on the anti-inflammatory mechanism of PAR and ALD and are less focused on their coordinated molecular mechanism. In this research, we established an integrative pharmacological strategy to explore the coordinated molecular mechanism of the two herbs of Ermiao Powder in treating RA. To explore the potential coordinated mechanism of PAR and ALD, we firstly developed a novel mathematical model to calculate the contribution score of 126 active components and 85 active components, which contributed 90% of the total contribution scores that were retained to construct the coordinated functional space. Then, the knapsack algorithm was applied to identify the core coordinated functional components from the 85 active components. Finally, we obtained the potential coordinated functional components group (CFCG) with 37 components, including wogonin, paeonol, ethyl caffeate, and magnoflorine. Also, functional enrichment analysis was performed on the targets of CFCG to explore the potential coordinated molecular mechanisms of PAR and ALD. The results indicated that the CFCG could treat RA by coordinated targeting to the genes involved in immunity and inflammation-related signal pathways, such as phosphatidylinositol 3‑kinase/protein kinase B signaling pathway, mitogen-activated protein kinase signaling pathway, tumor necrosis factor signaling pathway, and nuclear factor-kappa B signaling pathway. The docking and in vitro experiments were used to predict the affinity and validate the effect of CFCG and further confirm the reliability of our method. Our integrative pharmacological strategy, including CFCG identification and verification, can provide the methodological references for exploring the coordinated mechanism of TCM in treating complex diseases and contribute to improving our understanding of the coordinated mechanism

Association of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio with outcomes in stroke patients achieving successful recanalization by endovascular thrombectomy

ObjectiveSerum inflammatory biomarkers play crucial roles in the development of acute ischemic stroke (AIS). In this study, we explored the association between inflammatory biomarkers including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR), and clinical outcomes in AIS patients who achieved successful recanalization.MethodsPatients with AIS who underwent endovascular thrombectomy (EVT) and achieved a modified thrombolysis in the cerebral infarction scale of 2b or 3 were screened from a prospective cohort at our institution between January 2013 and June 2021. Data on blood parameters and other baseline characteristics were collected. The functional outcome was an unfavorable outcome defined by a modified Rankin Scale of 3–6 at the 3-month follow up. Other clinical outcomes included symptomatic intracranial hemorrhage (sICH) and 3-month mortality. Multivariable logistic regression analysis was performed to evaluate the effects of PLR, NLR, and MLR on clinical outcomes.ResultsA total of 796 patients were enrolled, of which 89 (11.2%) developed sICH, 465 (58.4%) had unfavorable outcomes at 3 months, and 168 (12.1%) died at the 3-month follow up. After adjusting for confounding variables, a higher NLR (OR, 1.076; 95% confidence interval [CI], 1.037–1.117; p < 0.001) and PLR (OR, 1.001; 95%CI, 1.000–1.003; p = 0.045) were significantly associated with unfavorable outcomes, the area under the receiver operating characteristic curve of NLR and PLR was 0.622 and 0.564, respectively. However, NLR, PLR, and MLR were not independently associated with sICH and 3-month mortality (all adjusted p > 0.05).ConclusionOverall, our results indicate that higher PLR and NLR were independently associated with unfavorable functional outcomes in AIS patients with successful recanalization after EVT; however, the underlying mechanisms are yet to be elucidated