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Hepatocellular carcinoma (HCC) is a common malignancy with poor prognosis. In recent years, immune checkpoint inhibitors (ICIs) have enabled breakthroughs in the clinical treatment of patients with HCC, but the overall response rate to ICIs in HCC patients is still low, and no validated biomarker is available to guide clinical decision making. Here, we demonstrated that the long non-coding RNA Lnc-CCNH-8 is highly expressed in HCC and correlates with poor prognosis. Functionally, elevated Lnc-CCNH-8 inactivated co-cultured T cells in vitro and compromised antitumor immunity in an immunocompetent mouse model. Mechanistically, up-regulated Lnc-CCNH-8 can sponge microRNA (miR)-217 to regulate the expression of PD-L1. In addition, Lnc-CCNH-8 can also stabilize PD-L1 through miR-3173/PKP3 axis. Furthermore, mice bearing tumors with high Lnc-CCNH-8 expression had significant therapeutic sensitivity to anti-PD-L1 monoclonal antibody treatment. More important, HCC patients with high levels of plasma exosomal Lnc-CCNH-8 had a better therapeutic response to ICIs. Taken together, our results reveal the function of Lnc-CCNH-8 in inducing immune escape from CD8+ T-cell-mediated killing by up-regulating PD-L1 in a miR-217/miR-3173-dependent manner, which also reveals a novel mechanism of PD-L1 regulation in HCC, and exosomal Lnc-CCNH-8 can serve as a predictive marker for immunotherapy response in HCC.

Objective: This study aimed to establish and validate a dynamic online nomograph for predicting the risk of frailty in older patients hospitalized with heart failure in China. Methods: A total of 451 older adults with heart failure hospitalized were selected between December 2021 and November 2022 at the Department of Cardiovascular Medicine in a Class A tertiary hospital in Shandong, China. The data of patients were obtained by using Barthel Index, instrumental activity of daily living scale, mini nutrition assessment-short form, Pittsburgh sleep quality index scale, Morse fall risk assessment scale and general information scale. The brain natriuretic peptide and echocardiographic indexes of patients were collected by electronic medical records. All participants were randomly divided into the training set (n = 319) and the validation set (n = 132) at the ratio of 7:3. The training set is used for model construction, and the validation set is used for internal validation. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression method to filter modeling variables, while the multivariable logistic regression was used to establish the nomogram based on the screened optimal variables. The performance of the model was evaluated by the area under the curve (AUC) of the receiver operator characteristic (ROC) curve, Hosmer-Lemeshow test, calibration plot, and decision curve analysis (DCA). Results: The prevalence of frailty in 451 patients was 50.6%, 51.4%, and 48.5% in the training and validation sets, respectively. Drinking, grip strength, New York Heart Association (NYHA) class, multimorbidity, hospitalization history of heart failure, Barthel Index, the instrumental activities of daily living, nutritional status, sleep, fall, and left atrial end-diastolic diameter were used for LASSO regression analysis as the significant predictors of frailty. According to internal validation, the AUC of the ROC curve for the nomogram was 0.920, with a sensitivity of 86.8% and specificity of 84.4%. Moreover, in the validation set, the P-values of the H-L test were 0.742, and the calibration curve had good concordance between the estimated frailty risk and actual observation, indicating the model was well-calibrated. The DCA results confirmed that the nomogram had a well-performance in clinical suitability. Conclusions: An online dynamic nomogram predicting frailty for older patients hospitalized for heart failure in China was well-established and identified in this study. This model benefits medical professionals in identifying high-risk frailty in older hospitalized patients with heart failure, which could reduce the medical and disease burden of heart failure to a certain extent. However, further verification is needed in the future.

Summary: Hypoxic microenvironment is clinically associated with metastasis and poor prognosis of numerous cancers. The mechanisms by which intratumoral hypoxia regulates metastasis are not fully understood. Our study identifies a downregulation of Lnc-CSMD1-7 in hepatocellular carcinoma (HCC) and correlated with poor prognosis of HCC patients. Lnc-CSMD1-7 negatively regulated HCC cell migration and invasion in vitro and suppressed lung metastasis in vivo. Mechanistically, Lnc-CSMD1-7 directly binds to RBFOX2, thereby affecting RBFOX2-regulated alternative splicing in epithelial and mesenchymal-specific events. More importantly, hypoxic microenvironment and m6A methylation mediate the downregulation of Lnc-CSMD1-7 expression. Specifically, hypoxia transcriptionally upregulates the expression of the m6A methyltransferase METTL16 via HIF-1α, and METTL16 directly binds to Lnc-CSMD1-7 and downregulates the RNA stability of Lnc-CSMD1-7 via m6A methylation, ultimately promoting HCC metastasis. Our findings highlight the regulatory function of the METTL16/Lnc-CSMD1-7/RBFOX2 axis in modulating hypoxia-induced HCC progression, which may provide potential prognostic and therapeutic targets for HCC treatment.

Xuanfeibaidu Formula (XFBD) is a Chinese medicine used in the clinical treatment of coronavirus disease 2019 (COVID-19) patients. Although XFBD has exhibited significant therapeutic efficacy in clinical practice, its underlying pharmacological mechanism remains unclear. Here, we combine a comprehensive research approach that includes network pharmacology, transcriptomics, and bioassays in multiple model systems to investigate the pharmacological mechanism of XFBD and its bioactive substances. High-resolution mass spectrometry was combined with molecular networking to profile the major active substances in XFBD. A total of 104 compounds were identified or tentatively characterized, including flavonoids, terpenes, carboxylic acids, and other types of constituents. Based on the chemical composition of XFBD, a network pharmacology-based analysis identified inflammation-related pathways as primary targets. Thus, we examined the anti-inflammation activity of XFBD in a lipopolysaccharide-induced acute inflammation mice model. XFBD significantly alleviated pulmonary inflammation and decreased the level of serum proinflammatory cytokines. Transcriptomic profiling suggested that genes related to macrophage function were differently expressed after XFBD treatment. Consequently, the effects of XFBD on macrophage activation and mobilization were investigated in a macrophage cell line and a zebrafish wounding model. XFBD exerts strong inhibitory effects on both macrophage activation and migration. Moreover, through multimodal screening, we further identified the major components and compounds from the different herbs of XFBD that mediate its anti-inflammation function. Active components from XFBD, including Polygoni cuspidati Rhizoma, Phragmitis Rhizoma, and Citri grandis Exocarpium rubrum, were then found to strongly downregulate macrophage activation, and polydatin, isoliquiritin, and acteoside were identified as active compounds. Components of Artemisiae annuae Herba and Ephedrae Herba were found to substantially inhibit endogenous macrophage migration, while the presence of ephedrine, atractylenolide I, and kaempferol was attributed to these effects. In summary, our study explores the pharmacological mechanism and effective components of XFBD in inflammation regulation via multimodal approaches, and thereby provides a biological illustration of the clinical efficacy of XFBD.

The reusable launch vehicle (RLV) presents a new avenue for reducing cost of space transportation. The landing mechanism, which provides landing support and impact absorption, is a vital component of the RLV at final stage of recovery. This study proposes a novel legged deployable landing mechanism (LDLM) for RLV. The Watt-II six-bar mechanism is adopted to obtain the preferred configuration via the application of the linkage variation approach. To endow the proposed LDLM with advantages of large landing support region, lightweight, and reasonable linkage internal forces, a multi-objective optimization paradigm is developed. Furthermore, the optimal scale parameters for guiding the LDLM prototype design is obtained numerically using the non-dominated sorting genetic algorithm-II (NSGA-II) evolutionary algorithm. A fully-functional scaled RLV prototype is developed by integrating the gravity-governed deploying scheme to facilitate unfolding action to avoid full-range actuation, a dual-backup locking mechanism to enhance reliability of structure stiffening as fully deployed, and a shock absorber (SA) with multistage honeycomb to offer reliable shock absorbing performance. The experimental results demonstrate that the proposed LDLM is capable of providing rapid and smooth deployment (duration less than 1.5 s) with mild posture disturbance to the cabin (yaw and pitch fluctuations less than 6°). In addition, it provides satisfactory impact attenuation (acceleration peak less than 10g (g is the gravitational acceleration)) in the 0.2 m freefall test, which makes the proposed LDLM a potential alternative for developing future RLV archetype.

Aberrant expression of long non-coding RNAs (lncRNAs) is associated with progression of multiple human cancers including hepatocellular carcinoma (HCC). However, the role of lncRNAs in HCC is not been fully understood. Our study aimed to investigate the biological function and potential molecular mechanism of Lnc-PAL2G4A-4 in HCC. In the current study, we show that Lnc-PLA2G4A-4 was significantly up-regulated in HCC tissues and high Lnc-PLA2G4A-4 expression was remarkably associated with tumor size, microvascular invasion and poor prognosis of HCC patients. Functionally, Lnc-PLA2G4A-4 positively regulated cell proliferation, invasion and migration in vitro, and facilitated lung metastasis of HCC in vivo. Mechanistically, Lnc-PLA2G4A-4 functioned as a competing endogenous RNA (ceRNA) to bind to miR-23b-3p and subsequently facilitate miR-23b-3p's target gene versican (VCAN) expression in HCC cells. Over-expression of miR-23b-3p could reverse Lnc-PLA2G4A-4 induced cell phenotypes in HCC and suppress versican expression of by rescue analysis. Collectively, Lnc-PLA2G4A-4 promotes HCC progression by targeting the miR-23b-3p/versican axis, which may be a potential biomarker and therapeutic target for HCC.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Natural compounds extracted from medicinal plants characterized by diverse biological activities and low toxicity or side effects, are increasingly taking center stage in the search for new drugs. Currently, preclinical evaluation of natural products relies mainly on the use of immortalized cell lines of human origin or animal models. Increasing evidence indicates that cardiomyopathy models based on immortalized cell lines do not recapitulate pathogenic phenotypes accurately and a substantial physiological discrepancy between animals and humans casts doubt on the clinical relevance of animal models for these studies. The newly developed human induced pluripotent stem cell (hiPSC) technology in combination with highly-efficient cardiomyocyte differentiation methods provides an ideal tool for modeling human cardiomyopathies in vitro. Screening of drugs, especially screening of natural products, based on these models has been widely used and has shown that evaluation in such models can recapitulate important aspects of the physiological properties of drugs. The purpose of this review is to provide information on the latest developments in this area of research and to help researchers perform screening of natural products using the hiPSC-CM platform.

Fusobacterium nucleatum (F. nucleatum) is enriched in colorectal cancer (CRC) tissues and a high amount of F. nucleatum was associated with an immunosuppressive tumor environment. PD-L1 is an important immune checkpoint expressed on tumor cells and promotes tumor immune escape. Whether PD-L1 is regulated by F. nucleatum is still unclear. We demonstrated that F. nucleatum promoted CRC progression and upregulated PD-L1 protein expression in CRC cell lines. Combined m6A-seq and RNA-seq identified m6A-modified IFIT1 mediating F. nucleatum induced PD-L1 upregulation. IFIT1 mRNA was modified with m6A modifications in 3’UTR and the m6A levels were altered by F. nucleatum treatment. Our results also indicated that IFIT1 served as a potential oncogene in CRC and regulated PD-L1 protein levels through altering PD-L1 ubiquitination. Clinical CRC data confirmed the correlation among F. nucleatum abundance, IFIT1 and PD-L1 expressions. Our work highlighted the function of F. nucleatum in stimulating PD-L1 expression through m6A-modified IFIT1 and provided new aspects for understanding F. nucleatum mediated immune escape.

Ischemic stroke is a leading cause of death worldwide, and it remains an urgent task to develop novel and alternative therapeutic strategies for the disease. We previously reported the positive effects of Guhong injection (GHI), composed of safflower extract and aceglutamide, in promoting functional recovery in ischemic stroke mice. However, the active substances and pharmacological mechanism of GHI is still elusive. Aiming to identify the active anti-stroke components in GHI, here we conducted a multi-phenotypic screening in zebrafish models of phenylhydrazine-induced thrombosis and ponatinib-induced cerebral ischemia. Peripheral and cerebral blood flow was quantified endogenously in erythrocytes fluorescence-labeled thrombosis fish, and baicalein and rutin were identified as major anti-thrombotic substances in GHI. Moreover, using a high-throughput video-tracking system, the effects of locomotion promotion of GHI and its main compounds were analyzed in cerebral ischemia model. Chlorogenic acid and gallic acid showed significant effects in preventing locomotor dyfunctions. Finally, GHI treatment greatly decreased the expression levels of coagulation factors F7 and F2, NF-κB and its mediated proinflammatory cytokines in the fish models. Molecular docking suggested strong affinities between baicalein and F7, and between active substances (baicalein, chlorogenic acid, gallic acid, and rutin) and NF-κB p65. In summary, our findings established a novel drug discovery method based on multi-phenotypic screening of zebrafish, provided endogenous evidences of GHI in preventing thrombus formation and promoting behavioral recovery after cerebral ischemia, and identified baicalein, rutin, chlorogenic acid, and gallic acid as active compounds in the management of ischemic stroke.

MOFs (Metal-Organic Framework), as promising crystalline materials of adsorption and separation, has been the subject of many recent investigations. However, the H2O stability of MOFs and the variation of adsorption selectivity in humid environments largely hinder attempts as excellent adsorbents in numerous scenarios. This study employs hydro-thermal synthesis [Cd0.5(DPETA)0.5]n using 2,3′,5,5′-Diphenyl tetracarboxylic acid (DPETA) and Cd(NO3)2·4H2O as ligands and metal ions, respectively. And it is modified by adding auxiliary ligands 4-4′-bipyridyl (bpy) and 1,2-bis (4-pyridyl) ethylene(bpe) to obtain [Cd1.5bpy2(DPETA)]n and [Cd2bpe2(DPETA)]n.The phase purity of the MOFs is examined using PXRD and FT-IR spectrum. The adsorption capacities of three MOFs are tested separately for water, ethanol and methanol using vapor adsorption. Their adsorption conformations and hydrogen bond lengths are also calculated by the GCMC method. The adsorption selection ratios of methanol and ethanol are deduced in combination with the IAST method under three components of water, methanol and ethanol. The results shows a methanol/ethanol adsorption separation ratio of 45 for [Cd1.5bpy2(DPETA)]n at 297 K, which is consistent with the of GCMC demonstrated. These results suggest that the methanol/ethanol adsorption selectivity ratio can be improved by increasing the adsorption force on methanol through by adding of auxiliary pyridyl ethylene. It can be used for efficient methanol/ethanol separation in humid environments.

Cardiac fibrosis occurs in most cardiac diseases, which reduces cardiac muscle compliance, impairs both systolic and diastolic heart function and, ultimately, leads to heart failure. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of a variety of biological processes; however, little is known about the expression and function of lncRNAs in cardiac fibrosis. Using unbiased transcriptome profiling in a mouse model of myocardial infarction (MI), we identified a cardiac fibroblast-enriched lncRNA (AK048087) named cardiac fibroblast-associated transcript (Cfast), which is significantly elevated after MI. Silencing Cfast expression by small interfering RNAs (siRNAs) or lentiviral short hairpin RNAs (shRNAs) resulted in suppression of fibrosis-related gene expression and transdifferentiation of myofibroblasts into cardiac fibroblasts. Depletion of Cfast by lentiviral shRNAs in mouse hearts significantly attenuated cardiac fibrosis induced by MI or isoproterenol-infusion. Importantly, inhibition of Cfast ameliorated cardiac function following cardiac injury. RNA pull-down followed by mass spectrometry analyses identified COTL1 (coactosin-like 1) as one of the Cfast interacting proteins. Mechanistically, Cfast competitively inhibits the COTL1 interaction with TRAP1 (transforming growth factor-β receptor-associated protein 1), which enhances TGF-β signaling by augmenting SMAD2/SMAD4 complex formation. Therefore, our study identifies Cfast as a novel cardiac fibroblast-enriched lncRNA that regulates cardiac fibroblast activation in response to pathophysiological stress. Cfast could serve as a potential therapeutic target for the prevention of cardiac fibrosis and cardiac diseases.

To study the strength properties and evolution laws of cracked sandstone samples in re-loading tests, strength and damage evolution properties of intact sandstone samples were first analyzed through the triaxial compression tests carried on TAW-2000 microcomputer control electro-hydraulic servo rock triaxial test system. Damage evolution models were established based on dilatancy properties realizing the real-time and quantitative evaluation of samples damage state in loading process. On this basis, samples with different damage were obtained by pre-peak, peak point, post-peak and residual strength stage unloading tests in the loading process of intact samples. The characteristics of the stress-strain curves and strength evolution laws were studied through the re-loading tests of samples with different damage under different stress states. The experimental results showed that the slope of stress-strain curves, peak strength and residual strength of cracked samples increased linearly with confining pressure and decreased linearly with damage. The equivalent cohesion decreased with damage in the exponential decay curves. The mechanics properties of samples transformed from strain softening to strain hardening with damage. Keywords: Rock mechanics, Damage, Re-loading, Strength characteristics, Strain hardening

Increasing evidence has demonstrated the essential role of inflammatory micro-environment in tumorigenesis and tumor progression. Some cancer cells in tumor maintain typical stemness properties and, with the capacity of self-renewal, are thought to be crucial for the initiation and maintenance of tumors as well as their metastasis. Although both inflammatory micro-environment and stemness properties played crucial roles in tumor initiation and development, currently it is still unclear whether and how the inflammatory micro-environment promotes cancer stemness properties. Here, we show the first evidence that the inflammatory micro-environment promotes the stemness properties and metastatic potential of hepatocellular carcinoma (HCC) via the NF-κB/miR-497/SALL4 axis. We discover that miR-497 directly targets SALL4, negatively regulates its expression, and further inhibits the self-renewal and metastasis of HCC; more importantly, inflammatory factor TNF-α inhibits the expression of miR-497 via NF-kB-mediated negative transcriptional regulation and simultaneously upregulates the expression of SALL4 and promotes the self-renewal and metastasis phenotypes of HCC cells. Moreover, lower expression of miR-497 is significantly associated with poor prognosis in HCC patients. Taken together, our findings not only revealed a novel signaling pathway (NF-κB/miR-497/SALL4 axis) to connect inflammation with stemness properties, and clarified the molecular mechanisms underlying the inflammation-mediated self-renewal and metastasis phenotypes, but also provided novel molecular targets for developing new anticancer strategies. Keywords: miR-497, SALL4, stemness, metastasis, inflammation, hepatocellular carcinoma, NF-κB

Background: Hongjingtian injection (HJT) has been widely used in the clinic to treat coronary heart disease in China. However, the underlying mechanisms of therapies still need to be illustrated. The present study aims to determine whether HJT protects against myocardial ischemia reperfusion injury via Reactive Oxygen Species (ROS)-induced autophagic flux and apoptosis and, if so, to explore the underlying mechanisms. Methods: In vivo myocardial protection and autophagy regulation of HJT in myocardial ischemia reperfusion injury in C57BL/6 J and CAG-RFP-EGFP-LC3 transgenic C57BL/6 J mice were investigated. In vitro, the effects of HJT on apoptosis, autophagic flux, oxidative stress and mitochondrial function were observed in H2O2-induced H9c2 cells. In addition, apoptosis-related proteins and autophagy-related proteins were assessed to explore the underlying mechanisms. Results: HJT significantly decreased the infarct area and cell apoptosis after myocardial ischemia reperfusion injury in C57BL/6 J mice. Autophagic flux was reduced by HJT treatment after myocardial ischemia reperfusion injury in CAG-RFP-EGFP-LC3 transgenic C57BL/6 J mice. HJT inhibited H2O2-induced cell apoptosis by significantly decreasing the levels of cleaved caspase 3 and increasing the Bcl-2/Bax ratio. HJT inhibited autophagic flux after H2O2 stimulation by significantly decreasing LC3-Ⅱ and p-AMPK expression and increasing p-mTOR. HJT inhibited ROS production and improved mitochondrial function in H2O2-induced cells by significantly increasing the mitochondrial membrane potential, intracellular ATP contents and oxygen consumption. Conclusion: The beneficial effects of HJT in treating myocardial ischemia reperfusion are partially due to improved mitochondrial function and regulated autophagy to inhibit cell apoptosis through the AMPK/mTOR pathway.

Myocardial ischemia reperfusion (MI/R) injury is a severe pathological process that threatens human health all over the world. The role of microRNAs (miRNAs) in the pathogenesis of MI/R injury has been increasingly recognized in recent years. Here, we conducted a miRNA profiling of the hearts of MI/R injured rat model, and identified 46 miRNAs which were differentially expressed between the MI/R injury and the control groups. With a special focus on one of the most significantly changed miRNA, miR-30c-5p, we demonstrated its protective role against cardiomyocyte injury in tBHP-treated H9c2 cells. Overexpression of miR-30c-5p increased cell viability, decreased LDH release, and reduced cell apoptosis of cardiomyocytes after tBHP stimulation, accompanied with downregulated p53 expression. Noticeably, the level of miR-30c-5p was markedly upregulated in MI/R injury cells treated with panax notoginseng saponins (PNS), a traditional Chinese Medicine with significant clinical effects in the treatment of human MI/R injury. Moreover, miR-30c-5p inhibitor is sufficient to block the protection of PNS, as well as its active ingredient ginsenoside Re, against tBHP induced cardiomyocyte injury. The expression of p53 protein was also reduced in PNS treated cells. In summary, our study identified novel miRNA hits of MI/R injury, revealed a pivotal role of miR-30c-5p in cardiomyocyte damage and apoptosis after MI/R, and illustrated a miR-30c-5p-dependent therapeutic mechanism of PNS of this pathologic process. Future studies are warranted to examine the endogenous significance of miR-30c-5p, along with multiple other miRNA hits, in the pathogenesis and treatment of MI/R injury.