Changes in Serum Interleukin-8 Levels Predict Response to Immune Checkpoint Inhibitors Immunotherapy in Unresectable Hepatocellular Carcinoma Patients.

Background: Effective biomarkers are needed to predict the efficacy of immune checkpoint inhibitors (ICIs) therapy in hepatocellular carcinoma (HCC). We evaluated the early changes in serum interleukin-8 (IL-8) levels as a biomarker of response to ICIs in patients with unresectable HCC. Methods: Eighty patients who received ICIs therapy alone or in combination with other treatments for unresectable HCC were included. Serum was collected at baseline and 2-4 weeks after the first dose. Serum IL-8 levels were measured using by ELISA. Results: In the progressive disease (PD) group, serum IL-8 levels increased significantly before the second dose of ICIs therapy compared with baseline levels (P < 0.001). Early changes in serum IL-8 levels were significantly associated with the response to ICIs therapy (P < 0.001). A cutoff value of 8.1% increase over the baseline most effectively predicted the response to ICIs. Increases in serum IL-8 levels > 8.1% indicated the uselessness of ICIs immunotherapy in patients with unresectable HCC. Patients with increases in serum IL-8 levels > 8.1% had significantly shorter overall survival (OS) and progression-free survival (PFS) than those with increases in serum IL-8 levels ≤ 8.1% (P < 0.001). Increases in serum IL-8 levels > 8.1% were independent prognosticators of worse OS (P = 0.003) and PFS (P < 0.001). Conclusion: Early changes in serum IL-8 levels, measured only 2-4 weeks after starting therapy, could predict the response to ICIs therapy, as well as OS and PFS of patients with unresectable HCC. Increases in serum IL-8 levels > 8.1% indicated the uselessness of ICIs immunotherapy and predicted worse OS and PFS.

Hsc70 promotes anti-tumor immunity by targeting PD-L1 for lysosomal degradation.

Immune checkpoint inhibition targeting the PD-1/PD-L1 pathway has become a powerful clinical strategy for treating cancer, but its efficacy is complicated by various resistance mechanisms. One of the reasons for the resistance is the internalization and recycling of PD-L1 itself upon antibody binding. The inhibition of lysosome-mediated degradation of PD-L1 is critical for preserving the amount of PD-L1 recycling back to the cell membrane. In this study, we find that Hsc70 promotes PD-L1 degradation through the endosome-lysosome pathway and reduces PD-L1 recycling to the cell membrane. This effect is dependent on Hsc70-PD-L1 binding which inhibits the CMTM6-PD-L1 interaction. We further identify an Hsp90α/ß inhibitor, AUY-922, which induces Hsc70 expression and PD-L1 lysosomal degradation. Either Hsc70 overexpression or AUY-922 treatment can reduce PD-L1 expression, inhibit tumor growth and promote anti-tumor immunity in female mice; AUY-922 can further enhance the anti-tumor efficacy of anti-PD-L1 and anti-CTLA4 treatment. Our study elucidates a molecular mechanism of Hsc70-mediated PD-L1 lysosomal degradation and provides a target and therapeutic strategies for tumor immunotherapy.

Autophagic-lysosomal damage induced by swainsonine is protected by trehalose through activation of TFEB-regulated pathway in renal tubular epithelial cells.

Swainsonine (SW) is the main toxic component of locoweed. Previous studies have shown that kidney damage is an early pathologic change in locoweed poisoning in animals. Trehalose induces autophagy and alleviates lysosomal damage, while its protective effect and mechanism against the toxic injury induced by SW is not clear. Based on the published literature, we hypothesize that transcription factor EB(TFEB) -regulated is targeted by SW and activating TFEB by trehalose would reverse the toxic effects. In this study, we investigate the mechanism of protective effects of trehalose using renal tubular epithelial cells. The results showed that SW induced an increase in the expression level of microtubule-associated protein light chain 3-II and p62 proteins and a decrease in the expression level of ATPase H+ transporting V1 Subunit A, Cathepsin B, Cathepsin D, lysosome-associated membrane protein 2 and TFEB proteins in renal tubular epithelial cells in a time and dose-dependent manner suggesting TFEB-regulated lysosomal pathway is adversely affected by SW. Conversely, treatment with trehalose, a known activator of TFEB promote TFEB nuclear translocation suggesting that TFEB plays an important role in protection against SW toxicity. We demonstrated in lysosome staining that SW reduced the number of lysosomes and increased the luminal pH, while trehalose could counteract these SW-induced effects. In summary, our results demonstrated for the first time that trehalose could alleviate the autophagy degradation disorder and lysosomal damage induced by SW. Our results provide an interesting method for reversion of SW-induced toxicity in farm animals and furthermore, activation of TFEB by trehalose suggesting novel mechanism of treating lysosomal storage diseases.

A novel CSN5/CRT O-GlcNAc/ER stress regulatory axis in platinum resistance of epithelial ovarian cancer.

Background: High levels of COP9 signalosome subunit 5 (CSN5) in epithelial ovarian cancer (EOC) are associated with poor prognosis and are implicated in mediating platinum resistance in EOC cells. The underlying mechanisms, however, remained undefined. This study aimed to elucidate the molecular process and identify potential therapeutic targets. Methods: RNA-sequencing was used to investigate differentially expressed genes between platinum-resistant EOC cells with CSN5 knockdown and controls. O-GlcNAc proteomics were employed to identify critical modulators downstream of CSN5. The omics findings were confirmed through qRT-PCR and immunoblotting. In vitro and in vivo experiments assessed the sensitivity of resistant EOCs to platinum. Results: We demonstrated an involvement of aberrant O-GlcNAc and endoplasmic reticulum (ER) stress disequilibrium in CSN5-mediated platinum resistance of EOC. Genetic or pharmacologic inhibition of CSN5 led to tumor regression and surmounted the intrinsic EOC resistance to platinum both in vitro and in vivo. Integration of RNA-sequencing and O-GlcNAc proteomics pinpointed calreticulin (CRT) as a potential target of aberrant O-GlcNAc modification. CSN5 upregulated O-GlcNAc-CRT at T346 to inhibit ER stress-induced cell death. Blocking T346 O-GlcNAc-CRT through CSN5 deficiency or T346A mutation resulted in Ca2+ disturbances, followed by ER stress overactivation, mitochondrial dysfunction, and ultimately cell apoptosis. Conclusion: This study reveals that CSN5-mediated aberrant O-GlcNAc-CRT acts as a crucial ER stress checkpoint, governing cell fate response to stress, and emphasizes an unrecognized role for the CSN5/CRT O-GlcNAc/ER stress axis in platinum resistance of EOC.

Correlation Analysis of Macrophage Distribution and Pathological Features of Carotid Atherosclerotic Plaque.

BACKGROUND: Macrophages play an important role in maintaining the chronic inflammatory of atherosclerosis (AS) and are hallmark of atherosclerotic plaques. They differentiate into different subpopulations under the influence of oxidized lipids and cytokines and play different roles in the formation and development of plaque. To explore the differences in the amount and distribution of different macrophage subpopulations around different carotid plaque pathological features in human AS, and based on these results, to explore the correlation between some macrophage subpopulations and AS pathological features. METHODS: First, we analyzed the single cells RNA-sequence data from the Gene Expression Omnibus DataSets (GSE159677). Second, we investigated the distribution difference of macrophage subpopulations in 61 surgically resected AS plaques by markers staining include CD68, inducible nitric oxide synthase, Arg-1, CD163 and HO-1. RESULTS: The result of single cells RNA-Sequence analysis showed that there were a large number of macrophages infiltrated in AS and they can be categorized into different subpopulations with different transcriptional features and functions; moreover in different part of AS (calcified AS core versus proximal adjacent), the total number and subpopulation ratios were all different. The result of staining analysis showed that macrophages mainly distributed in some pathological lesions such as necrosis, fibrous tissue degeneration, cholesterol crystallization etc., and different subpopulations were distributed differently in these lesions. CONCLUSIONS: This study confirmed that macrophages were heavily infiltrated in atherosclerotic plaques, and there existed subtype variability in different pathological lesions; meanwhile, these results suggested that different macrophage subpopulations may contribute differently in different pathological lesions.

Biological Evaluation of 8-Methoxy-2,5-dimethyl-5H-indolo[2,3-b] Quinoline as a Potential Antitumor Agent via PI3K/AKT/mTOR Signaling.

Chemotherapy is commonly used clinically to treat colorectal cancer, but it is usually prone to drug resistance, so novel drugs need to be developed continuously to treat colorectal cancer. Neocryptolepine derivatives have attracted a lot of attention because of their good cytotoxic activity; however, cytotoxicity studies on colorectal cancer cells are scarce. In this study, the cytotoxicity of 8-methoxy-2,5-dimethyl-5H-indolo[2,3-b] quinoline (MMNC) in colorectal cells was evaluated. The results showed that MMNC inhibits the proliferation of HCT116 and Caco-2 cells, blocks the cell cycle in the G2/M phase, decreases the cell mitochondrial membrane potential and induces apoptosis. In addition, the results of western blot experiments suggest that MMNC exerts cytotoxicity by inhibiting the expression of PI3K/AKT/mTOR signaling pathway-related proteins. Based on these results, MMNC is a promising lead compound for anticancer activity in the treatment of human colorectal cancer.

Development and validation of two redox-related genes associated with prognosis and immune microenvironment in endometrial carcinoma.

In recent studies, the tumourigenesis and development of endometrial carcinoma (EC) have been correlated significantly with redox. We aimed to develop and validate a redox-related prognostic model of patients with EC to predict the prognosis and the efficacy of immunotherapy. We downloaded gene expression profiles and clinical information of patients with EC from the Cancer Genome Atlas (TCGA) and the Gene Ontology (GO) dataset. We identified two key differentially expressed redox genes (CYBA and SMPD3) by univariate Cox regression and utilised them to calculate the risk score of all samples. Based on the median of risk scores, we composed low-and high-risk groups and performed correlation analysis with immune cell infiltration and immune checkpoints. Finally, we constructed a nomogram of the prognostic model based on clinical factors and the risk score. We verified the predictive performance using receiver operating characteristic (ROC) and calibration curves. CYBA and SMPD3 were significantly related to the prognosis of patients with EC and used to construct a risk model. There were significant differences in survival, immune cell infiltration and immune checkpoints between the low-and high-risk groups. The nomogram developed with clinical indicators and the risk scores was effective in predicting the prognosis of patients with EC. In this study, a prognostic model constructed based on two redox-related genes (CYBA and SMPD3) were proved to be independent prognostic factors of EC and associated with tumour immune microenvironment. The redox signature genes have the potential to predict the prognosis and the immunotherapy efficacy of patients with EC.

Prognostic value of gut microbiota-derived metabolites in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Studies about the prognostic role of gut microbiota-derived metabolites including phenylacetyl glutamine (PAGln), indoxyl sulfate (IS), lithocholic acid (LCA), deoxycholic acid (DCA), trimethylamine (TMA), trimethylamine N-oxide (TMAO), and its precursor trimethyllysine (TML) are limited in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To examine the relationship between plasma metabolite levels and major adverse cardiovascular events (MACEs), including nonfatal MI, nonfatal stroke, all-cause mortality, and heart failure in patients with STEMI. METHODS: We enrolled 1004 patients with STEMI undergoing percutaneous coronary intervention (PCI). Plasma levels of these metabolites were determined by targeted liquid chromatography/mass spectrometry. The associations of metabolite levels with MACEs were assessed with the Cox regression model and quantile g-computation. RESULTS: During a median follow-up of 360 d, 102 patients experienced MACEs. Higher plasma PAGln (hazard ratio [HR], 3.17 [95% CI: 2.05, 4.89]; P < 0.001), IS (2.67 [1.68, 4.24], P < 0.001), DCA (2.36 [1.40, 4.00], P = 0.001), TML (2.66 [1.77,3.99], P < 0.001), and TMAO (2.61 [1.70, 4.00], P < 0.001) levels were significantly associated with MACEs independent of traditional risk factors. According to quantile g-computation, the joint effect of all these metabolites was 1.86 (95% CI: 1.46, 2.27). PAGln, IS and TML had the greatest proportional positive contributions to the mixture effect. Additionally, plasma PAGln and TML combined with coronary angiography scores including the Synergy between PCI with Taxus and cardiac surgery (SYNTAX) score (area under the curve [AUC]: 0.792 vs. 0.673), Gensini score (0.794 vs. 0.647) and Balloon pump-assisted Coronary Intervention Study (BCIS-1) jeopardy score (0.774 vs. 0.573) showed better prediction performance for MACEs. CONCLUSIONS: Higher plasma PAGln, IS, DCA, TML, and TMAO levels are independently associated with MACEs suggesting that these metabolites may be useful markers for prognosis in patients with STEMI.

Identification of CBPA as a New Inhibitor of PD-1/PD-L1 Interaction.

Targeting of the PD-1/PD-L1 immunologic checkpoint is believed to have provided a real breakthrough in the field of cancer therapy in recent years. Due to the intrinsic limitations of antibodies, the discovery of small-molecule inhibitors blocking PD-1/PD-L1 interaction has gradually opened valuable new avenues in the past decades. In an effort to discover new PD-L1 small molecular inhibitors, we carried out a structure-based virtual screening strategy to rapidly identify the candidate compounds. Ultimately, CBPA was identified as a PD-L1 inhibitor with a KD value at the micromolar level. It exhibited effective PD-1/PD-L1 blocking activity and T-cell-reinvigoration potency in cell-based assays. CBPA could dose-dependently elevate secretion levels of IFN-γ and TNF-α in primary CD4+ T cells in vitro. Notably, CBPA exhibited significant in vivo antitumor efficacy in two different mouse tumor models (a MC38 colon adenocarcinoma model and a melanoma B16F10 tumor model) without the induction of observable liver or renal toxicity. Moreover, analyses of the CBPA-treated mice further showed remarkably increased levels of tumor-infiltrating CD4+ and CD8+ T cells and cytokine secretion in the tumor microenvironment. A molecular docking study suggested that CBPA embedded relatively well into the hydrophobic cleft formed by dimeric PD-L1, occluding the PD-1 interaction surface of PD-L1. This study suggests that CBPA could work as a hit compound for the further design of potent inhibitors targeting the PD-1/PD-L1 pathway in cancer immunotherapy.

Fluorescence Imaging-Incorporated Transcriptome Study of Glutathione Depletion-Enhanced Ferroptosis Therapy via Targeting Gold Nanoclusters.

Ferroptosis plays an important role in tumor inhibition and is a new type of programmed cell death. Recent studies have shown that glutathione (GSH) depletion is an effective method to enhance the therapeutic efficacy of ferroptosis; however, a systematic investigation of the phenomenon is limited. Herein, we provide a facile fluorescence imaging-incorporated transcriptome strategy to visualize the process and explore the mechanism of GSH depletion-enhanced ferroptosis. The proposed multifunctional nanoplatform is achieved using simple transferrin receptor aptamer-functionalized fluorescent gold nanoclusters (termed TfRA-AuNCs), which exhibit efficient hydroxyl radical generation and GSH-depleting capabilities. Live cell fluorescence imaging results revealed that TfRA-AuNCs were endocytosed into 4T1 cells and were mostly distributed in lysosomes. In vitro results indicated that TfRA-AuNCs enhanced the ferroptosis effect in 4T1 cells. Importantly, transcriptome analysis indicated that 4T1 cells treated with TfRA-AuNCs regulated the expression change of ferroptosis-related genes, and the Kyoto Encyclopedia of Genes and Genomes pathway identified the GSH metabolism pathway involved in ferroptosis, thus revealing the exact molecular mechanism of ferroptosis induced by TfRA-AuNCs at the RNA level. Furthermore, in vivo results confirmed the tumor inhibition effect, tumor-targeted fluorescence imaging, and long-term biocompatibility after TfRA-AuNC treatment. This study introduces a new possibility for the mechanistic study of nanoagent-induced ferroptosis in tumor treatment.

Human epicardial adipose tissue inflammation correlates with coronary artery disease.

BACKGROUND AND AIMS: This study investigates the expression of novel adipocytokines and inflammatory cells infiltration in epicardial adipose tissue (EAT) and subcutaneous adipose tissue (SAT) between 27 coronary artery disease (CAD) and 21 non-CAD (NCAD) patients enrolled from September 2020 to September 2021. METHODS AND RESULTS: Serum, gene, and protein expression levels of the novel adipocytokines were determined using ELISA, RT-qPCR, and western blot analyses. The number of blood vessels and adipocytes morphology were measured via hematoxylin-eosin staining, and inflammatory cells infiltration was examined via immunohistochemistry. Serum ANGPTL8, CTRP5, and Wnt5a levels were higher in the CAD than in the NCAD group, while serum CTRP3, Sfrp5, and ZAG levels were lower in the CAD than in the NCAD group. Compared to the EAT of NCAD and SAT of CAD patients, the EAT of CAD patients had higher mRNA levels of ANGPTL8, CTRP5, and Wnt5a while lower levels of CTRP3, Sfrp5, and ZAG; higher protein expression levels of ANGPTL8 and CTRP5 but lower levels of CTRP3; more blood vessels; and higher infiltration rates of macrophages (CD68 + ), pro-inflammatory M1 macrophages (CD11c + ), mast cells (Tryptase + ), T lymphocytes (CD3 + ), and B lymphocytes (CD20 + ) but lower infiltration rates of anti-inflammatory M2 macrophages (CD206 + ). CONCLUSION: Novel adipocytokines and inflammatory cells infiltration are dysregulated in human EAT, and could be important pathophysiological mechanisms and novelly promising medicating targets of CAD.

CFNC, a neocryptolepine derivative, inhibited the growth of gastric cancer AGS cells by inhibiting PI3K/AKT signaling pathway.

Gastric cancer is highly heterogeneous and there is still a lack of efficient, low-toxicity small molecule compounds for the treatment of gastric cancer. Natural products are important sources for the development of antitumor compounds. Therefore, it is promising strategy to find the lead compound of anti-gastric cancer agents by structural modification of natural products. The aim of this study was to synthesize a novel neocryptolepine derivative CFNC and explore its potential anti-gastric cancer effect and molecular mechanism. The MTT assay showed that the IC50 of CFNC on AGS cells reached 148 nM. CFNC arrested AGS cells in the G2/M phase of the cell cycle. Furthermore, CFNC inhibited cell proliferation and migration, leading to the loss of membrane potential by causing mitochondrial dysfunction, which induced the apoptosis of AGS cells. Western blot assay suggested that CFNC could inhibit the expression of important proteins in the PI3K/AKT/mTOR signaling pathway. These results showed that CFNC exhibited strong cytotoxic activity in gastric cancer cell lines by regulating the PI3K/AKT/mTOR signaling pathway. Taken together, CFNC could be a promising lead compound for the clinical treatment of gastric cancer.

The Prognostic Value of Hematologic Inflammatory Markers in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

The aggregate index of systemic inflammation (AISI), systemic inflammation response index (SIRI), and neutrophil-to-lymphocyte*platelet ratio (NLRP) are novel indices that simultaneously reflect the inflammatory and immune status. However, the role of these indices in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) remains unclear. We aimed to elucidate the predictive value of AISI, SIRI, and NLRP in patients with ACS undergoing PCI. A total of 1558 patients with ACS undergoing PCI were consecutively enrolled from January 2016 to December 2018. The AISI, SIRI, NLRP, systemic immune-inflammatory index, derived neutrophil-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio cutoff values for predicting major adverse cardiovascular events (MACE) were calculated using receiver-operating characteristic curves, and Spearman's test was used to analyze correlations between these indices. Kaplan-Meier curves and Cox regression models were used for survival analyses, and the endpoint was a MACE, which included all-cause mortality and rehospitalization for severe heart failure during the follow-up period. The Kaplan-Meier curves showed that higher AISI, SIRI, and NLRP values were associated with a higher risk of MACE (all P < .001). The association between AISI, SIRI, and NLRP and ACS prognosis was stable in various subgroups according to sex, age, smoking, dyslipidemia, hypertension, diabetes mellitus, history of stroke, and heart failure (P for interaction > .05). Increasing tertiles of AISI, SIRI, and NLRP significantly increased the MACE risk (P for trend < .05). AISI, SIRI, and NLRP may be suitable laboratory markers for identifying high-risk patients with ACS after PCI.

Design, Synthesis and Biological Evaluation of Neocryptolepine Derivatives as Potential Anti-Gastric Cancer Agents.

Natural products play an important role in drug development and lead compound synthesis. Neocryptolepine is a polycyclic quinoline compound isolated from Cryptolepis sanguinolent. The cytotoxicity of neocryptolepine to gastric cancer cells AGS, MKN45, HGC27, and SGC7901 was not very strong, and it also had certain toxicity to gastric mucosa cells GES-1. Therefore, a series of neocryptolepine derivatives were synthesized by the modification of the structure of neocryptolepine, and their cytotoxicity was evaluated. The results showed that compounds C5 and C8 exhibited strong cytotoxicity to AGS cells. The cell colony formation and cell migration experiments suggested that compounds C5 and C8 could inhibit the proliferation and cell migration of AGS and HGC27 cells. Cell cycle and apoptosis experiments showed that compounds C5 and C8 did not cause the apoptosis of AGS and HGC27 cells but, mainly, caused cell necrosis. Compound C5 had no significant effect on AGS and HGC27 cell cycles at low concentration. After treatment with AGS cells for 24 h at high concentration, compound C5 could significantly arrest the AGS cell cycle in the G2/M phase. Compound C8 had no significant effect on the AGS and HGC27 cell cycles. The results of molecular docking and Western blot showed that compounds C5 and C8 might induce cytotoxicity through the PI3K/AKT signaling pathway. Therefore, compounds C5 and C8 may be promising lead compounds for the treatment of gastric cancer.

Combination of Paclitaxel and PXR Antagonist SPA70 Reverses Paclitaxel-Resistant Non-Small Cell Lung Cancer.

Paclitaxel (PTX) is one of the most efficient drugs for late-stage non-small cell lung cancer (NSCLC) patients. However, most patients gradually develop resistance to PTX with long-term treatments. The identification of new strategies to reverse PTX resistance in NSCLC is crucially important for the treatment. PTX is an agonist for the pregnane X receptor (PXR) which regulates PTX metabolism. Antagonizing PXR, therefore, may render the NSCLC more sensitive to the PTX treatment. In this study, we investigated the PXR antagonist SPA70 and its role in PTX treatment of NSCLC. In vitro, SPA70 and PTX synergistically inhibited cell growth, migration and invasion in both paclitaxel-sensitive and paclitaxel-resistant A549 and H460 lung cancer cells. Mechanistically, we found PTX and SPA70 cotreatment disassociated PXR from ABCB1 (MDR1, P-gp) promoter, thus inhibiting P-gp expression. Furthermore, the combination regimen synergistically enhanced the interaction between PXR and Tip60, which abrogated Tip60-mediated α-tubulin acetylation, leading to mitosis defect, S-phase arrest and necroptosis/apoptosis. Combination of PXT and SPA70 dramatically inhibited tumor growth in a paclitaxel-resistant A549/TR xenograft tumor model. Taken together, we showed that SPA70 reduced the paclitaxel resistance of NSCLC. The combination regimen of PTX and SPA70 could be potential novel candidates for the treatment of taxane-resistant lung cancer.

Role of serum C1q/TNF-related protein family levels in patients with acute coronary syndrome.

Background: The C1q/TNF-related protein (CTRP) family affects inflammation regulation, energy metabolism, and insulin signaling. However, their role in acute coronary syndrome (ACS) development is unclear. In this cross-sectional study, we aimed to investigate the association between CTRP family and ACS. Methods: We enrolled 289 consecutive inpatients with suspected ACS. Serum CTRP family, tumor necrosis factor-α (TNF-α), and adiponectin (ADP) levels were assessed using enzyme-linked immunosorbent assay (ELISA). Multivariate logistic regression and subgroup analyses were used to assess risk factors for ACS. Spearman's tests were used to analyze correlations between CTRP family and continuous variables. Results: Serum CTRP family levels differed significantly between ACS and Control groups (p < 0.05). After adjusting for confounding factors, CTRP family were independently associated with ACS (p < 0.05). The association between serum CTRP family levels and ACS was stable in various subgroups according to sex, age, diabetes mellitus, and dyslipidemia status (p for interaction > 0.05). Increasing tertiles of serum CTRP1 levels, significantly increased ACS risks, which decreased gradually with increasing CTRP2, CTRP12, and CTRP13 tertiles (p for trend < 0.05). Additionally, serum CTRP1, CTRP2, CTRP13, and CTRP15 levels were weakly correlated with the severity of coronary artery stenosis. Conclusion: CTRP1 and CTRP5 were identified as independent ACS risk factors, whereas CTRP2, CTRP3, CTRP9, CTRP12, CTRP13, and CTRP15 were independent protective factors for ACS. CTRP family, especially CTRP1 and CTRP3 could be novel potential clinical biomarkers of ACS.

Oxidant stress-sensitive circRNA Mdc1 controls cardiomyocyte chromosome stability and cell cycle re-entry during heart regeneration.

Targeting cardiomyocyte plasticity has emerged as a new strategy for promoting heart repair after myocardial infarction. However, the precise mechanistic network underlying heart regeneration is not completely understood. As noncoding RNAs, circular RNAs (circRNAs) play essential roles in regulating cardiac physiology and pathology. The present study aimed to investigate the potential roles of circMdc1 in cardiac repair after injury and elucidate its underlying mechanisms. Here, we identified that circMdc1 levels were upregulated in postnatal mouse hearts but downregulated in the regenerative myocardium. The expression of circMdc1 in cardiomyocytes is sensitive to oxidative stress, which was attenuated by N-acetyl-cysteine. Enforced circMdc1 expression inhibited cardiomyocyte proliferation, while circMdc1 silencing led to cardiomyocyte cell cycle re-entry. In vivo, the cardiac-specific adeno-associated virus-mediated knockdown of circMdc1 promoted cardiac regeneration and heart repair accompanied by improved heart function. Conversely, circMdc1 overexpression blunted the regenerative capacity of neonatal hearts after apex resection. Moreover, circMdc1 was able to block the translation of its host gene Mdc1 specifically by binding to PABP, affecting DNA damage and the chromosome stability of cardiomyocytes. Furthermore, overexpression of Mdc1 caused damaged mouse hearts to regenerate and repair after myocardial infarction in vivo. Oxidative stress-sensitive circMdc1 plays an important role in cardiac regeneration and heart repair after injury by regulating DNA damage and chromosome stability in cardiomyocytes by blocking the translation of the host gene Mdc1.

Association Between Novel Pro- and Anti- Inflammatory Adipocytokines in Patients with Acute Coronary Syndrome.

BACKGROUND AND AIMS: Novel pro- and anti-inflammatory adipocytokines affect inflammation, energy metabolism, and insulin signaling. However, their role in acute coronary syndrome (ACS) development is unclear. We evaluated the diagnostic and risk predictive value of such adipocytokines for ACS. METHODS: We enrolled 168 consecutive inpatients with suspected ACS and detected serum PLIN1, PLIN2, PLIN5, CTRP6, CTRP7, CTRP11, WISP1, FAM19A5, TNF-α, and adiponectin levels. Multivariate logistic regression analysis and Spearman's test were used to assess risk factors for ACS and correlations between serum adipocytokines and continuous variables, respectively. RESULTS: Serum levels of the adipocytokines differed between ACS and Non-ACS groups (p < 0.05). After adjusting for confounding factors, serum PLIN1, PLIN2, PLIN5, CTRP6, CTRP7, CTRP11, WISP1, and FAM19A5 levels were independently associated with ACS (p < 0.05). Increasing tertiles of serum PLIN1, PLIN2, CTRP7, CTRP11, and WISP1 levels increased the ACS risk, which decreased gradually with increasing PLIN5 and CTRP6 tertiles (p for trend <0.05). Serum PLIN1, PLIN5, CTRP6, CTRP7, CTRP11, WISP1, and FAM19A5 levels correlated with ACS severity. CONCLUSIONS: PLIN1, PLIN2, CTRP7, CTRP11, and WISP1 were identified as independent ACS risk factors, whereas PLIN5, CTRP6, and FAM19A5 were independent protective factors for ACS. These serum adipocytokines are novel potential clinical biomarkers of ACS.

A Novel Isaindigotone Derivative Displays Better Anti-Proliferation Activities and Induces Apoptosis in Gastric Cancer Cells.

Isaindigotone is an alkaloid containing a pyrrolo-[2,1-b]quinazoline moiety conjugated with a benzylidene group and isolated from the root of Isatis indigotca Fort. However, further anticancer activities of this alkaloid and its derivatives have not been fully explored. In this work, a novel isaindigotone derivative was synthesized and three different gastric cell lines and one human epithelial gastric cell line were used to study the anti-proliferation effects of the novel isaindigotone derivative BLG26. HGC27 cells and AGS cells were used to further explore the potential mechanisms. BLG26 exhibited better anti-proliferation activities in AGS cells with a half-maximal inhibitory concentration (IC50) of 1.45 µM. BLG26 caused mitochondrial membrane potential loss and induced apoptosis in both HGC27 cells and AGS cells by suppressing mitochondrial apoptotic pathway and PI3K/AKT/mTOR axis. Acute toxicity experiment showed that LD50 (median lethal dose) of BLG26 was above 1000.0 mg/kg. This research suggested that BLG26 can be a potential candidate for the treatment of gastric cancer.

Ablation of long noncoding RNA MALAT1 activates antioxidant pathway and alleviates sepsis in mice.

The metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is a long noncoding RNA (lncRNA) and is known for its role in cancer development and prognosis. In this study, we report that MALAT1 plays an important role in regulating acute inflammatory responses in sepsis. In patient samples, MALAT1 expression was positively correlated with severity of sepsis. In cultured macrophages, LPS treatment significantly induced MALAT1 expression, while genetic ablation of MALAT1 greatly reduced proinflammatory cytokine levels. Furthermore, MALAT1-ablated mice had significantly increased survival rates in cecal ligation and puncture (CLP)-induced sepsis and LPS-induced endotoxemia. One novel and salient feature of MALAT1-ablated mice is greatly reduced ROS level in macrophages and other cell types and increased glutathione/oxidized glutathione (GSH/GSSG) ratio in macrophages, suggesting an increased antioxidant capacity. We showed a mechanism for MALAT1 ablation leading to enhanced antioxidant capacity is through activation of methionine cycle by epitranscriptomical regulation of methionine adenosyltransferase 2A (MAT2A). MAT2A 3'UTR can be methylated by METTL16 which was known to directly bind to MALAT1. MALAT1 ablation was found to reduce methylation in MAT2A hairpin1 and increase MAT2A protein levels. Our results suggest a MALAT1-METTL16-MAT2A interactive axis which may be targeted for treatments of sepsis.