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Patients with relapsed/refractory acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) have poor outcomes compared with newly diagnosed, treatment-naïve patients. The phase 2, open-label DELPHINUS study evaluated daratumumab (16 mg/kg intravenously) plus backbone chemotherapy in children with relapsed/refractory B-cell ALL (n=7) after ≥2 relapses and children and young adults with T-cell ALL (children, n=24; young adults, n=5) or LL (n=10) after first relapse. The primary endpoint was complete response (CR) in the B-cell ALL (end of Cycle 2) and T-cell ALL (end of Cycle 1) cohorts, after which patients could proceed off study to allogeneic hematopoietic stem cell transplant (HSCT). Seven patients with advanced B-cell ALL received daratumumab with no CRs achieved; this cohort was closed due to futility. For the childhood T-cell ALL, young adult T-cell ALL, and T-cell LL cohorts, the CR (end of Cycle 1) rates were 41.7%, 60.0%, and 30.0%, respectively; overall response rates (any time point) were 83.3% (CR+CR with incomplete count recovery [CRi]), 80.0% (CR+CRi), and 50.0% (CR+partial response); minimal residual disease-negativity (<0.01%) rates were 45.8%, 20.0%, and 50.0%; observed 24-month event-free survival rates were 36.1%, 20.0%, and 20.0%; observed 24-month overall survival rates were 41.3%, 25.0%, and 20.0%; and allogeneic HSCT rates were 75.0%, 60.0%, and 30.0%. No new safety concerns with daratumumab were observed. In conclusion, daratumumab was safely combined with backbone chemotherapy in children and young adults with T-cell ALL/LL and contributed to successful bridging to HSCT. This trial was registered at www.ClinicalTrials.gov as NCT03384654., (Copyright © 2024 American Society of Hematology.)

Epithelial mesenchymal transition (EMT) is a critical process implicated in the pathogenesis of retinal fibrosis and the exacerbation of diabetic retinopathy (DR) within retinal pigment epithelium (RPE) cells. Apigenin (AP), a potential dietary supplement for managing diabetes and its associated complications, has demonstrated inhibitory effects on EMT in various diseases. However, the specific impact and underlying mechanisms of AP on EMT in RPE cells remain poorly understood. In this study, we have successfully validated the inhibitory effects of AP on high glucose-induced EMT in ARPE-19 cells and diabetic db/db mice. Notably, our findings have identified CBP/p300 as a potential therapeutic target for EMT in RPE cells and have further substantiated that AP effectively downregulates the expression of EMT-related genes by attenuating the activity of CBP/p300, consequently reducing histone acetylation alterations within the promoter region of these genes. Taken together, our results provide novel evidence supporting the inhibitory effect of AP on EMT in RPE cells, and highlight the potential of specifically targeting CBP/p300 as a strategy for inhibiting retinal fibrosis in the context of DR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The alleviating effect of paeoniflorin (Pae) on liver fibrosis has been established; however, the molecular mechanism and specific target(s) underlying this effect remain elusive., Purpose: This study was to investigate the molecular mechanism underlying the regulatory effect of Pae on hepatic stellate cells (HSCs) activation in liver fibrosis, with a specific focus on the role of Pae in modulating histone methylation modifications., Methods: The therapeutic effect of Pae was evaluated by establishing in vivo and in vitro models of carbon tetrachloride (CCl 4 )-induced mice and transforming growth factor β 1 (TGF-β 1 )-induced LX-2 cells, respectively. Molecular docking, surface plasmon resonance (SPR), chromatin immunoprecipitation-quantitative real time PCR (ChIP-qPCR) and other molecular biological methods were used to clarify the molecular mechanism of Pae regulating HSCs activation., Results: Our study found that Pae inhibited HSCs activation and histone trimethylation modification in liver of CCl 4 -induced mice and LX-2 cells. We demonstrated that the inhibitory effect of Pae on the activation of HSCs was dependent on peroxisome proliferator-activated receptor γ (PPARγ) expression and enhancer of zeste homolog 2 (EZH2). Mechanistically, Pae directly binded to EZH2 to effectively suppress its enzymatic activity. This attenuation leaded to the suppression of histone H3K27 trimethylation in the PPARγ promoter region, which induced upregulation of PPARγ expression., Conclusion: This investigative not only sheds new light on the precise targets that underlie the remission of hepatic fibrogenesis induced by Pae but also emphasizes the critical significance of EZH2-mediated H3K27 trimethylation in driving the pathogenesis of liver fibrosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Herein, a novel ratiometric sensor for fluorimetric and smartphone-assisted visual detection of Al 3+ in environmental water was developed based on the target-regulated formation of Eu metal-organic frameworks (Eu MOFs). By employing 2-[4-(2-hydroxyethyl) piperazin-1-yl] ethanesulfonic acid (Hepes), Eu 3+ and tetracycline (TC) as raw materials, Eu MOFs with red emission were facilely synthesized through the coordination of Eu 3+ with Hepes and TC. However, upon the introduction of Al 3+ , a higher affinity of TC towards Al 3+ resulted in the formation of a TC-Al 3+ complex with green fluorescence and inhibited the generation of Eu MOFs. This led to an increase in green fluorescence and a decrease in red fluorescence accompanied by the fluorescence color of the solution changing from red to green under the illumination of the UV lamp. Thus, a ratiometric sensor for fluorimetric and the smartphone-assisted visual detection of Al 3+ was established. The ratiometric sensor exhibited high sensitivity for Al 3+ detection with a detection limit of 0.14 μM for fluorescence detection and 1.21 μM for visual detection. Additionally, the proposed strategy was successfully applied to detect Al 3+ in the environmental water samples with satisfactory results, indicating great application prospects for environmental monitoring.

Background: One-fourth of Parkinson's disease (PD) patients suffer from cognitive impairment. However, few neuroimaging markers have been identified regarding cognitive impairment in PD., Objective: This study aimed to explore the association between third ventricular width by transcranial sonography (TCS) and cognitive decline in PD., Method: Participants with PD were recruited from one medical center in China. Third ventricular width was assessed by TCS, and cognitive function was analyzed by the Mini-Mental State Examination (MMSE). Receiver operating characteristic (ROC) analysis and Cox model analysis were utilized to determine the diagnostic and predictive accuracy of third ventricular width by TCS for cognitive decline in PD patients., Result: A total of 174 PD patients were recruited. Third ventricular width was negatively correlated with MMSE scores. ROC analysis suggested that the optimal cutoff point for third ventricular width in screening for cognitive impairment in PD was 4.75 mm (sensitivity 62.7%; specificity 75.6%). After 21.5 (18.0, 26.0) months of follow-up in PD patients without cognitive impairment, it was found that those with a third ventricular width greater than 4.75 mm exhibited a 7.975 times higher risk of developing cognitive impairment [hazard ratio = 7.975, 95% CI 1.609, 39.532, p = 0.011] compared with patients with a third ventricular width less than 4.75 mm., Conclusion: Third ventricular width based on TCS emerged as an independent predictor of developing cognitive impairment in PD patients., (© 2023 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

Background: Soothing the liver and regulating qi is one of the core ideas of traditional Chinese medicine (TCM) in the treatment of fatty liver. Si-Ni-San (SNS) is a well-known herbal formula in TCM for liver soothing and qi regulation in fatty liver treatment. However, its efficacy lacks modern scientific evidence., Purpose: This study was aimed to investigate the impact of SNS on metabolic associated fatty liver disease (MAFLD) in mice and explore the underlying molecular mechanisms, particularly its effects on lipid metabolism in hepatocytes., Methods: The therapeutic effect of SNS was evaluated using in vivo and in vitro models of high-fat/high-cholesterol (HFHC) diet-induced mice and palmitic acid (PA)-induced hepatocytes, respectively. Molecular biological techniques such as RNA-sequencing (RNA-seq), co-immunoprecipitation (co-IP), and western blotting were employed to elucidate the molecular mechanism of SNS in regulating lipid metabolism in hepatocytes., Results: Our findings revealed that SNS effectively reduced lipid accumulation in the livers of HFHC diet-induced mice and PA-induced hepatocytes. RNA-seq analysis demonstrated that SNS significantly down-regulated the expression of fatty acid synthase (Fasn) in the livers of HFHC-fed mice. Mechanistically, SNS inhibited Fasn expression and lipid accumulation by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK). Activation of AMPK suppressed the activity of the transcriptional coactivator p300 and modulated the protein stability of sterol regulatory element-binding protein-1c (SREBP-1c). Importantly, p300 was required for the inhibition of Fasn expression and lipid accumulation by SNS. Furthermore, SNS activated AMPK by decreasing adenosine triphosphate (ATP) production in hepatocytes., Conclusion: This study provided novel evidence on the regulatory mechanisms underlying the effects of SNS on Fasn expression. Our findings demonstrate, for the first time, that SNS exerts suppressive effects on Fasn expression through modulation of the AMPK/p300/SREBP-1c axis. Consequently, this regulatory pathway mitigates excessive lipid accumulation and ameliorates MAFLD in mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Quzhou Aurantii Fructus (QAF) has a long history as a folk medicine and food for the treatment of liver diseases. While our earlier study provided evidence of hepatoprotective properties contained within the flavonoids and limonins constituents in QAF, the potential preventative effects afforded by essential oil components present within QAF remains enigmatic. In this study, we prepared Quzhou Aurantii Fructus essential oil (QAFEO) and confirmed its anti-inflammatory effects on liver inflammation through experimentation on lipopolysaccharide and D-galactosamine (LPS/D-GalN) induced acute liver failure (ALF) mouse models. Using RNA-sequence (RNA-seq) analysis, we found that QAFEO prevented ALF by systematically blunting the pathways involved in response to LPS and toll-like receptor signaling pathways. QAFEO effectively suppressed the phosphorylation of tank-binding kinase 1 (TBK1), TGF-beta activated kinase 1 (TAK1), interferon regulatory factor 3 (IRF3), and the activation of mitogen activated kinase-like protein (MAPK) and nuclear factor-kappa B (NF-κB) pathways in vivo and in vitro. Importantly, QAFEO substantially reduced myeloid differentiation primary response gene 88 (MyD88)- toll-like receptor 4 (TLR4) interaction levels. Moreover, 8 compounds from QAFEO could directly bind to REAL, TAK1, MyD88, TBK1, and IRF3. Taken together, the results of our study support the notion that QAFEO exerts a hepatoprotective effect through inhibiting LPS-mediated inflammatory response., (© 2023. Kunming Institute of Botany, CAS.)

Ferroptosis is a type of nonapoptotic necrotic cell death characterized by iron-dependent lipid peroxidation. Saikosaponin A (SsA), a natural bioactive triterpenoid saponin extracted from Radix Bupleuri, has shown potent antitumor activity against various tumors. However, the underlying mechanism of the antitumor activity of SsA remains unclear. Here, we discovered that SsA induced HCC cell ferroptosis in vitro and in vivo. Using RNA-sequence analysis, we found that SsA mainly affected the glutathione metabolic pathway and inhibited the expression of cystine transporter solute carrier family 7 member 11 (SLC7A11). Indeed, SsA increased intracellular malondialdehyde (MDA) and iron accumulation, while it decreased the levels of reduced glutathione (GSH) in HCC. Deferoxamine (DFO), ferrostatin-1 (Fer-1) and GSH could rescue SsA-induced cell death, whereas Z-VAD-FMK was found ineffective in inhibiting SsA-induced cell death in HCC. Importantly, our result indicated that SsA induced the expression of activation transcription factor 3 (ATF3). SsA-induced cell ferroptosis and suppression of SLC7A11 are dependent on ATF3 in HCC. Moreover, we revealed that SsA induced ATF3 upregulation via activation of endoplasmic reticulum (ER) stress. Taken together, our findings support that ATF3-dependent cell ferroptosis mediated the antitumor effects of SsA, opening the possibility to explore SsA as a ferroptosis inducer in HCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Backgrounds: The relationship between kidney function and cognitive impairment in Parkinson's disease (PD) is poorly understood and underexplored. This study aims to explore whether renal indices can serve as indicators to monitor the cognitive impairment of PD., Methods: A total of 508 PD patients and 168 healthy controls from the Parkinson's Progression Markers Initiative (PPMI) were recruited, and 486 (95.7%) PD patients underwent longitudinal measurements. The renal indicators including serum creatinine (Scr), uric acid (UA), and urea nitrogen, as well as UA/Scr ratio and estimated glomerular filtration rate (eGFR), were measured. Cross-sectional and longitudinal associations between kidney function and cognitive impairment were evaluated using multivariable-adjusted models., Results: eGFR was associated with lower levels of cerebrospinal fluid (CSF) A β 1-42 ( p  = 0.0156) and α-synuclein ( p  = 0.0151) and higher serum NfL ( p  = 0.0215) in PD patients at baseline. Longitudinal results showed that decreased eGFR predicted a higher risk of cognitive impairment (HR = 0.7382, 95% CI = 0.6329-0.8610). Additionally, eGFR decline was significantly associated with higher rates of increase in CSF T-tau ( p  = 0.0096), P-tau ( p  = 0.0250), and serum NfL ( p  = 0.0189), as well as global cognition and various cognitive domains ( p  < 0.0500). The reduced UA/Scr ratio was also linked to higher NfL levels ( p  = 0.0282) and greater accumulation of T-tau ( p  = 0.0282) and P-tau ( p  = 0.0317). However, no significant associations were found between other renal indices and cognition., Conclusion: eGFR is altered in PD subjects with cognitive impairment, and predict larger progression of cognitive decline. It may assist identifying patients with PD at risk of rapid cognitive decline and have the potential to monitoring responses to therapy in future clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Qu, Qin, Wang, Li, Zhao, An, Li, Mao, Min, Xiong and Xue.)

Objectives: The aim of this study is to assess the influence of cardiopulmonary coupling (CPC) based on RCMSE on the prediction of complications and death in patients with acute type A aortic dissection (ATAAD)., Background: The cardiopulmonary system may be nonlinearly regulated, and its coupling relationship with postoperative risk stratification in ATAAD patients has not been studied., Methods: This study was a single-center, prospective cohort study (ChiCTR1800018319). We enrolled 39 patients with ATAAD. The outcomes were in-hospital complications and all-cause readmission or death at 2 years., Results: Of the 39 participants, 16 (41.0%) developed complications in the hospital, and 15 (38.5%) died or were readmitted to the hospital during the two-year follow-up. When CPC-RCMSE was used to predict in-hospital complications in ATAAD patients, the AUC was 0.853 ( p  < 0.001). When CPC-RCMSE was used to predict all-cause readmission or death at 2 years, the AUC was 0.731 ( p  < 0.05). After adjusting for age, sex, ventilator support (days), and special care time (days), CPC-RCMSE remained an independent predictor of in-hospital complications in patients with ATAAD [adjusted OR: 0.8 (95% CI, 0.68-0.94)]., Conclusion: CPC-RCMSE was an independent predictor of in-hospital complications and all-cause readmission or death in patients with ATAAD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Mao, Wen, Han, Dong, Shen, Huang and Xie.)

Backgrounds: Apathy is common in Parkinson's disease (PD) but difficult to identify. Growing evidence suggests that abnormal iron metabolism is associated with apathy in PD. We aimed to investigate the clinical features and iron metabolism of apathetic patients with PD, and construct a nomogram for predicting apathy in PD., Methods: Data of 201 patients with PD were analyzed. Demographic data, Apathy Scale (AS) assessments, and serum iron metabolism parameters were obtained. Spearman correlations were used to assess relationships between AS scores and iron metabolism parameters, separately for male and female patients. Additionally, a nomograph for detecting apathetic patients with PD was built based on the results of logistic regression analysis., Results: The serum transferrin (TRF, p  < 0.0024) concentration and total iron binding capacity (TIBC, p  < 0.0024) were lower in the apathetic group after Bonferroni correction, and they were negatively associated with AS scores in male participants with PD (TRF, r  = -0.27, p  = 0.010; TIBC, r  = -0.259, p  = 0.014). The nomogram was developed by incorporating the following five parameters: age, sex, serum iron concentration, TIBC and Hamilton Depression Rating Scale (HAMD) scores, which showed good discrimination and calibration, with a consistency index of 0.799 (95% confidence interval = 0.732-0.865)., Conclusion: Abnormal iron metabolism may contribute to apathy in PD, especially among men. TIBC levels in combination with HAMD scores can be effectively used for the prediction of apathetic patients with PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Qu, Gao, Li, Qin, Wang, Zhao, Mao, Min, Xiong and Xue.)

Background : Yunpi-Huoxue-Sanjie (YP-SJ) formula is a Chinese herbal formula with unique advantages for the treatment of diabetic cardiovascular complications, such as Diabetic cardiomyopathy (DCM). However, potential targets and molecular mechanisms remain unclear. Therefore, our research was designed to evaluate rat myocardial morphology, fat metabolism and oxidative stress to verify myocardial protective effect of YP-SJ formula in vivo . And then to explore and validate its probable mechanism through network pharmacology and experiments in vitro and in vivo . Methods: In this study, DCM rats were randomly divided into five groups: control group, model group, and three YP-SJ formula groups (low-dose, middle-dose, and high-dose groups). Experimental rats were treated with 6 g/kg/d, 12 g/kg/d and 24 g/kg/d YP-SJ formula by gavage for 10 weeks, respectively. Cardiac function of rats was measured by high-resolution small-animal imaging system. The cells were divided into control group, high glucose group, high glucose + control serum group, high glucose + dosed serum group, high glucose + NC-siRNA group, high glucose + siRNA-FoxO1 group. The extent of autophagy was measured by flow cytometry, immunofluorescence, and western blotting. Results: It was found that YP-SJ formula could effectively improve cardiac systolic function in DCM rats. We identified 46 major candidate YP-SJ formula targets that are closely related to the progression of DCM. Enrichment analysis revealed key targets of YP-SJ formula related to environmental information processing, organic systems, and the metabolic occurrence of reactive oxygen species. Meanwhile, we verified that YP-SJ formula can increase the expression of forkhead box protein O1 (FoxO1), autophagy-related protein 7 (Atg7), Beclin 1, and light chain 3 (LC3), and decrease the expression of phosphorylated FoxO1 in vitro and in vivo . The results showed that YP-SJ formula could activate the FoxO1 signaling pathway associated with DCM rats. Further experiments showed that YP-SJ formula could improve cardiac function by regulating autophagy. Conclusion: YP-SJ formula treats DCM by modulating targets that play a key role in autophagy, improving myocardial function through a multi-component, multi-level, multi-target, multi-pathway, and multi-mechanism approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, You, Zhang, Jiang, Qiu, Ruan and Mao.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is frequently diagnosed and treated in advanced tumor stages with poor prognosis. More effective screening programs and novel therapeutic means are urgently needed. Recent studies have regarded tight junction protein claudin 18.2 (CLDN18.2) as a candidate target for cancer treatment, and zolbetuximab (formerly known as IMAB362) has been developed against CLDN18.2. However, there are few data reported thus far related to the clinicopathological characteristics of CLDN18.2 expression for PDAC., Aim: To investigate the expression of CLDN18.2 in PDAC patients and subsequently propose a new target for the treatment of PDAC., Methods: The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus, and European Genome-phenome Archive databases were first employed to analyze the CLDN18 gene expression in normal pancreatic tissue compared to that in pancreatic cancer tissue. Second, we analyzed the expression of CLDN18.2 in 93 primary PDACs, 86 para-cancer tissues, and 13 normal pancreatic tissues by immunohistochemistry. Immunostained tissues were assessed applying the histoscore. subsequently, they fell into two groups according to the expression state of CLDN18.2. Furthermore, the correlations between CLDN18.2 expression and diverse clinicopathological characteristics, including survival, were investigated., Results: The gene expression of CLDN18 was statistically higher ( P < 0.01) in pancreatic tumors than in normal tissues. However, there was no significant correlation between CLDN18 expression and survival in pancreatic cancer patients. CLDN18.2 was expressed in 88 (94.6%) of the reported PDACs. Among these tumors, 50 (56.8%) cases showed strong immunostaining. The para-cancer tissues were positive in 81 (94.2%) cases, among which 32 (39.5%) of cases were characterized for strong staining intensities. Normal pancreatic tissue was identified solely via weak immunostaining. Finally, CLDN18.2 expression significantly correlated with lymph node metastasis, distant metastasis, nerve invasion, stage, and survival of PDAC patients, while there was no correlation between CLDN18.2 expression and localization, tumor size, patient age and sex, nor any other clinicopathological characteristic., Conclusion: CLDN18.2 expression is frequently increased in PDAC patients. Thus, it may act as a potential therapeutic target for zolbetuximab in PDAC., Competing Interests: Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: In the current era of big data, it is critical to address people's demand for health literacy. At present, the traditional mode of communicating scientific health knowledge and information technology is interchangeable, resulting in the emergence of a new mode of communicating health literacy. To publicize health education and health literacy in a targeted way, to meet the public's needs, and to understand how the public's demand for subjects, contents, and forms of health literacy service has changed in the era of COVID-19, the investigation of public's demand for health information and health literacy was conducted., Objective: This study aims to understand the differences in demand for health literacy service providers, contents, channels, forms, and facilities among Chinese citizens with different genders, ages, education levels, economic conditions, and living environments, and to provide reasonable recommendations for developing public health literacy., Methods: Questionnaire Star was used to conduct a large sample of random online surveys. In Wuhan, Hubei Province, 2184 questionnaires were issued, 8 invalid questionnaires were eliminated, and 2176 were recovered, with an effective rate of 99.6%. IBM SPSS Statistics 20 was utilized to analyze the survey data., Results: (1) In health literacy service providers selected by the public, the proportion of government departments or government collaboration with other institutions exceeded 73%, indicating that health literacy services are public goods; (2) access to health literacy services was lower in township areas than in urban areas (P < 0.001, 3) internet media and communicating with acquaintances, which have the highest popularity rate, were also the two channels that were least trusted by the public; and (4) the differences in contents and service channels of health literacy among residents with different genders, ages, education levels, economic status, and living environments were statistically significant., Conclusions: (1) It is recommended to establish an integrated health literacy service model with multi-center supply. Government departments, medical institutions, and media should cooperate effectively to provide health literacy services. (2) The government should pay attention to the fairness of health education and strengthen the supply of health literacy services in township areas. (3) It is critical to strengthen the public's ability to discriminate network information and pay attention to scientific thinking cultivation. (4) Health literacy service providers must focus on the differences between public demands and improve the connotation of health literacy services., (© 2022. The Author(s).)

Background: The newly identified betacoronavirus SARS-CoV-2 is the causative pathogen of the 2019 coronavirus disease (COVID-19), which has killed more than 4.5 million people. SARS-CoV-2 causes severe respiratory distress syndrome by targeting the lungs and also induces myocardial damage. Shenshao Ningxin Yin (SNY) has been used for more than 700 years to treat influenza. Previous randomized controlled trials (RCTs) have demonstrated that SNY can improve the clinical symptoms of viral myocarditis, reverse arrhythmia, and reduce the level of myocardial damage markers., Methods: This work uses a rational computational strategy to identify existing drug molecules that target host pathways for the treatment of COVID-19 with myocarditis. Disease and drug targets were input into the STRING database to construct proteinɃprotein interaction networks. The Metascape database was used for GO and KEGG enrichment analysis., Results: SNY signaling modulated the pathways of coronavirus disease, including COVID-19, Ras signaling, viral myocarditis, and TNF signaling pathways. Tumor necrosis factor (TNF), cellular tumor antigen p53 (TP53), mitogen-activated protein kinase 1 (MAPK1), and the signal transducer and activator of transcription 3 (STAT3) were the pivotal targets of SNY. The components of SNY bound well with the pivotal targets, indicating there were potential biological activities., Conclusion: Our findings reveal the pharmacological role and molecular mechanism of SNY for the treatment of COVID-19 with myocarditis. We also, for the first time, demonstrate that SNY displays multi-component, multi-target, and multi-pathway characteristics with a complex mechanism of action.

To investigate aldo-keto reductase 1C3 (AKR1C3) expression in T and B acute lymphoblastic leukemia/lymphoma (ALL) patients. Three commercial antibodies were evaluated for AKR1C3 immunohistochemistry (IHC) staining performance: Polyclonal Thermofisher scientific (Clone#PA523667), rabbit monoclonal Abcam [EPR16726] (ab209899) and Sigma/Millipore anti-AKR1C3 antibody, mouse monoclonal, clone NP6.G6.A6, purified from hybridoma cell culture. Initial optimization was performed on cell line controls: HCT116 (negative control); genetically modified cell line HCT116 with AKR1C3 overexpression; Nalm and TF1 cell lines. Twenty normal bone marrows from archival B and T-ALL patient samples were subsequently examined. AKR1C3 expression levels in these samples were evaluated by immunohistochemistry, Protein Wes and quantitative RT-PCR. Sigma/Millipore Anti-AKR1C3 antibody (mouse monoclonal, clone NP6.G6.A6) showed higher specificity compared to rabbit polyclonal antibody by immunohistochemistry. H-score was used to quantify percent of nuclear immunoreactivity for AKR1C3 with varying disease involvement. T-ALL samples had a higher H-score (172-190) compared to B-ALL cases (H-score, 30-160). The AKR1C3 expression in peripheral blood by Protein Wes and RT-qPCR showed concordance in relapsed/refractory and/or minimal residual T-ALL cases. Sigma/Millipore Anti-AKR1C3 antibody and mouse monoclonal, clone NP6.G6.A6 can be used to aid in AKR1C expression of T-ALL and in cases of relapsed/refractory and/or minimal residual disease., (© 2022. The Author(s).)

Background: Ganoderma (Lingzhi in Chinese) has shown good clinical outcomes in the treatment of insomnia, restlessness, and palpitation. However, the mechanism by which Ganoderma ameliorates insomnia is unclear. We explored the mechanism of the anti-insomnia effect of Ganoderma using systems pharmacology from the perspective of central-peripheral multi-level interaction network analysis., Methods: The active components and central active components of Ganoderma were obtained from the TCMIP and TCMSP databases, then screened to determine their pharmacokinetic properties. The potential target genes of these components were identified using the Swiss Target Prediction and TCMSP databases. The results were matched with the insomnia target genes obtained from the GeneCards, OMIM, DisGeNET, and TCMIP databases. Overlapping targets were subjected to multi-level interaction network analysis and enrichment analysis using the STRING, Metascape, and BioGPS databases. The networks analysed were protein-protein interaction (PPI), drug-component-target gene, component-target gene-organ, and target gene-extended disease; we also performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses., Results: In total, 34 sedative-hypnotic components (including 5 central active components) were identified, corresponding to 51 target genes. Multi-level interaction network analysis and enrichment analysis demonstrated that Ganoderma exerted an anti-insomnia effect via multiple central-peripheral mechanisms simultaneously, mainly by regulating cell apoptosis/survival and cytokine expression through core target genes such as TNF, CASP3, JUN, and HSP90αA1; it also affected immune regulation and apoptosis. Therefore, Ganoderma has potential as an adjuvant therapy for insomnia-related complications., Conclusion: Ganoderma exerts an anti-insomnia effect via complex central-peripheral multi-level interaction networks., (© 2021. The Author(s).)

The aim of this study is to assess serum human epididymis protein 4 (HE-4) levels as a biomarker for predicting the recurrence of atrial fibrillation (AF) after catheter ablation. This was a prospective observational study that enrolled one hundred eighty-four consecutive nonvalvular AF patients (65 persistent, 119 paroxysmal) who were eligible for their first ablation. Multiple Cox proportional hazards models and Kaplan-Meier curve analyses were used to test the association between serum HE-4 levels and AF recurrence after catheter ablation. During the 12-month follow-up, we observed that 47 patients (25.5%) experienced AF recurrence. Patients were divided into tertiles of HE-4 level (T1: < 50 pmol/L; T2: ≥ 50 pmol/L). The AF recurrence rate of higher serum HE-4 level patients was significantly increased (34.6% vs 13.8%, P < 0.001). Generalized additive models were used to visually assess functional relationships between the serum HE-4 levels and the risk of AF recurrence. When stratified with serum levels as the cut-off value, Kaplan-Meier analysis showed that patients with serum HE-4 levels (> 50 pmol/L) had a significantly increased risk of AF recurrence. In addition, multivariate Cox proportional hazard modelling revealed that HE-4 (≥ 50 pmol/L) (HR 2.65; 95% CI 1.34, 5.27, P = 0.005) was independent predictors of AF recurrence. Serum HE-4 levels in patients with AF are associated with postoperative recurrence of AF, and high HE-4 levels are an independent predictor of AF recurrence after ablation.

Ethnopharmacological Relevance: Diabetes is a serious chronic metabolic disorder, and type 2 diabetes mellitus (T2DM) accounts for more than 90% of all diabetes cases. Insulin resistance (IR) is an early symptom, typical feature and main pathogenesis of T2DM due to the combined effects of genetic and environmental factors. Current evidence shows that IR is mainly caused by nutrient overload, systemic fatty acid excess, fatty tissue inflammation, endoplasmic reticulum stress, oxidative stress and abnormal autophagy. Autophagy plays an important role in the development of IR and decreased autophagy activity can cause IR through various ways., Aim of the Study: Yunpiheluo (YPHL) decoction is a Chinese herbal formula with unique advantages for the treatment of T2DM. The aim of the present study was to investigate the regulatory mechanism of YPHL on the autophagy pathway in the skeletal muscle of IR Zucker diabetic fatty (ZDF) rats., Methods: T2DM ZDF rats were treated with YPHL or transfected with SIRT1 adeno-associated virus. Serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), insulin resistance index (IRI) and skeletal muscle TG levels were detected in a T2DM ZDF rat model. The skeletal muscle morphology was observed by histological analysis and Oil Red O Staining. Autophagosomes were observed by transmission electron microscopy (TEM). The skeletal muscle morphology and fat deposition were observed by histological examination and Oil Red O Staining. A rat skeletal muscle IR cell model was established and transfected with SIRT1 overexpression plasmids. Cell apoptosis was observed by DAPI staining. SIRT1 levels in skeletal muscle tissues and cells were detected by qRT-PCR. The protein expressions of SIRT1, FOXo1, LC3B and P62 were detected by Western blotting., Results: Large numbers of lipid droplets and swollen mitochondria were observed in the skeletal muscle in both model group and negative control (NC) group receiving blank plasmid. Autophagosomes were seen in the skeletal muscle of YPHL and SIRT1 groups, with no significant structural abnormality. In addition, the protein expression of LC3B was decreased and the protein expression of p62 was increased significantly in the model group as compared with the NC group. After intervention with YPHL and SIRT1 overexpression, the protein expression of LC3B was significantly increased and p62 was significantly decreased. However, there was no significant difference in cell apoptosis between the two groups., Conclusion: The SIRT1-FoxO1 autophagy pathway may play a significant role in the pathogenesis of IR. YPHL could increase the autophagy level by regulating the SIRT1-FoxO1 signaling pathway in the skeletal muscle and improving the lipid metabolism, thereby attenuating IR., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Resistance to cytarabine is an important cause of therapy failure in persons with acute myeloid leukemia (AML). Deoxycytidine kinase, encoded by DCK, catalyzes phosphorylation of cytarabine to cytarabine monophosphate, a necessary step for eventual incorporation of cytarabine triphosphate into DNA and for clinical efficacy. Whether DCK mutations make AML cells resistant to cytarabine is controversial. We studied DCK mutations and messenger RNA (mRNA) concentrations in leukemia cells from 10 subjects with AML who received cytarabine-based therapy and relapsed and in 2 artificially induced cytarabine-resistant AML cell lines. DCK mutations were detected in 4 subjects with AML relapsing after achieving a complete remission and receiving high-dose cytarabine postremission therapy. Most mutations were in exons 4-6 and were not present before therapy. DCK was also mutated in cytarabine-resistant but not parental AML cell lines. DCK mRNA concentrations were significantly decreased in cytarabine-resistant K562 and SHI-1 cells compared with cytarabine-sensitive parental cells. Mutation frequency of DCK and mRNA concentration did not correlate with the extent of cytarabine resistance indicating other factors operate. Overexpression of wild-type DCK restored cytarabine sensitivity to previously resistant leukemia cell lines. Our data contribute to the understanding of cytarabine resistance in persons with AML., (© 2021 S. Karger AG, Basel.)

Aims: Myocardial reperfusion damage after severe ischemia was an important issue during a clinical practice. However, the exacted pathogenesis involved remained unclear and also lacks effective interventions. Melatonin was identified to exert protective effects for alleviating the myocardial I/R injury. This meta-analysis was determined to evaluate the efficacy of melatonin treatment against reperfusion insult and further summarize potential molecular and cellular mechanisms., Methods and Results: 15 eligible studies with 211 animals (108 received melatonin and 103 received vehicle) were included after searching the databases of PubMed, MEDLINE, Embase, and Cochrane. Pretreatment with melatonin was associated with a significant lower infarct size in comparison with vehicle in myocardial I/R damage (WMD: -20.45, 95% CI: -25.43 to -15.47, p < 0.001; I 2 = 91.4%, p < 0.001). Evidence from subgroup analyses and sensitivity analysis indicated the robust and consistent cardioprotective effect of melatonin, while the metaregression also did not unmask any significant interactions between the pooled estimates and covariates (i.e., sample size, state, species, study type, route of administration, and duration of reperfusion, along with timing regimen of pretreatment). Accordingly, melatonin evidently increased EF (WMD: 17.19, 95% CI: 11.08 to 23.29, p < 0.001; I 2 = 77.0%, p < 0.001) and FS (WMD: 14.18, 95% CI: 11.22 to 17.15, p < 0.001; I 2 = 3.5%, p = 0.387) in the setting of reperfusion damage., Conclusions: Melatonin preadministration conferred a profound cardioprotection against myocardial I/R injury in preclinical studies., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Zhi-Jie Mao et al.)

Silibinin is a traditional medicine and utilized for liver protection with antioxidant, anti-inflammation and anti-apoptosis properties. However, its role in myocardial I/R injury and the mechanism involved is currently unknown. In the present study, Silibinin treatment improves cardiac function and limits infarct size, and subsequently inhibits fibrotic remodeling in mice with myocardial I/R injury. Mechanistically, silibinin reduces cardiomyocytes apoptosis, attenuates mitochondrial impairment and endoplasmic reticulum (ER) stress, alleviates ROS generation, neutrophil infiltration and cytokines release. Consistently, silibinin prevents H9C2 cells from hypoxia/reperfusion-induced cell death, oxidative stress and inflammation in vitro . Furthermore, H9C2 cells treated with silibinin blocks NF-κB signaling activation by inhibiting IKKα phosphorylation, IκBα degradation and p65 NF-κB nuclear translocation during hypoxia/ reperfusion. In addition, silibinin plus BAY 11-7082 (a selected NF-κB inhibitor) do not provide incremental benefits in improving myocytes apoptosis, oxidative stress and inflammation in comparison with NF-κB signaling inhibition only. Thus, silibinin-mediated cardioprotection in myocardial I/R injury is associated with decreased apoptosis, oxidative stress and inflammatory response through deactivation of NF-κB pathway., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Gastric cancer (GC) is one of the most common malignancies of the digestive system worldwide. Multiple long noncoding RNAs (lncRNAs) participate in the regulation of GC development and metastasis. In this study, we aimed to elucidate the expression and function of lncRNA IGFL2-AS1 in GC. We found that IGFL2-AS1 was highly expressed in GC tissues and cell lines. Knockdown of IGFL2-AS1 suppressed GC cell proliferation, migration, and invasion in vitro. Furthermore, we identified that IGFL2-AS1 exerted its function as a molecular sponge of miR-802. MiR-802 was demonstrated to be a tumor suppressor, and overexpression of miR-802 suppressed GC cell growth, migration, and invasion. Mechanistically, we revealed that the cAMP-regulated phosphoprotein 19 (ARPP19) was a direct target of miR-802 and could reverse the inhibitory function of miR-802. Moreover, our results confirmed that knockdown of IGFL2-AS1 inhibited GC tumor development in an in vivo GC tumor xenograft model. In summary, our data suggest that the IGFL2-AS1/miR-802/ARPP19 axis plays a critical role in the progression and metastasis of GC. Therapies targeting the IGFL2-AS1/miR-802/ARPP19 axis can potentially improve GC treatment., (© 2020 Wiley Periodicals, Inc.)

Background: Radix Astragali (Astragalus membranaceus var. mongholicus (Bunge)) and Coptis chinensis (Coptis chinensis var. angustiloba) are two commonly prescribed traditional Chinese herbs for diabetes. Astragalus Polysaccharide (AP) and Berberine (BBR) are active ingredients of these two herbs respectively and they are scientifically proved to have immunomodulatory and anti-inflammatory effects. They are also known for their antidiabetic potential by ameliorating insulin resistance (IR). AP and BBR have shown different advantages in treating diabetes according to previous reports. However, very few studies focus on the combined activities of the two potential antidiabetic ingredients. In this study, we discovered that reactive oxygen species (ROS) accumulated in IR-hepG2 cells and APBBR can decrease ROS level in model group significantly. We conjectured that APBBR can ameliorate IR in hepG2 cells by decreasing ROS level. In order to verify this hypothesis, we obtained phenotype and transcriptome information of IR-HepG2 cells and explore the underlying mechanism of the combination of AP and BBR(APBBR) activity on the relationship between ROS change in IR at whole-transcriptome level, so as to shed new light to efficacy and application of APBBR in treating diabetes., Methods: The IR cell model was established with high-level insulin intervention. Glucose content, HepG2 cell viability as well as ROS level was detected to study the effect of IR-hepG2 cell phenotype. Unbiased genome-wide RNA sequencing was used to investigate alterations in experimental groups. Then, GO and KEGG functional enrichment was performed to explore the function and pathway of target genes. Venn analysis found out the differentially expressed lncRNAs that had close relationship with IR and ROS. Finally, we screened out candidate lncRNAs and these target genes to construct interaction network of differentiated lncRNA-miRNA-mRNA by according to the principle of competitive endogenous RNA (ceRNA)., Results: The biochemical experiments showed that APBBR administration could improve the proliferation activity of IR-HepG2 cells and decrease ROS level in model cells. The GO and KEGG functional enrichment analyses demonstrated several mRNAs remarkably enriched in biological processes and signaling pathways related to ROS production and IR progression. Interaction network suggest that APBBR ameliorates IR in HepG2 cells by regulating the expression of multiple genes and activating relevant signaling pathway to decrease ROS level. Thus, we demonstrated that APBBR ameliorated IR in hepG2 cells via the ROS-dependent pathway., Competing Interests: Zhu-Jun Mao is a co-inventor of patent no. CN108478591A., (©2020 Lin and Mao.)

Insulin resistance (IR) is likely to induce metabolic syndrome and type 2 diabetes mellitus (T2DM). Gluconeogenesis (GNG) is a complex metabolic process that may result in glucose generation from certain non-carbohydrate substrates. Chinese herbal medicine astragalus polysaccharides and berberine have been documented to ameliorate IR, and combined use of astragalus polysaccharide (AP) and berberine (BBR) are reported to synergistically produce an even better effect. However, what change may occur in the GNG signaling pathway of IR-HepG2 cells in this synergistic effect and whether AP-BBR attenuates IR by regulating the GNG signaling pathway remain unclear. For the first time, we discovered in this study that the optimal time of IR-HepG2 cell model formation was 48 h after insulin intervention. AP-BBR attenuated IR in HepG2 cells and the optimal concentration was 10 mg. AP-BBR reduced the intracellular H 2 O 2 content with no significant effect on apoptosis of IR-HepG2 cells. In addition, a rapid change was observed in intracellular calcium current of the IR-HepG2 cell model, and AP-BBR intervention attenuated this change markedly. The gene sequencing results showed that the GNG signaling pathway was one of the signaling pathways of AP-BBR to attenuate IR in IR-Hepg2 cells. The expression of p-FoxO1 Ser256 and PEPCK protein was increased, and the expression of GLUT2 protein was decreased significantly in the IR-HepG2 cell model, and both of these effects could be reversed by AP-BBR intervention. AP-BBR attenuated IR in IR-HepG2 cells, probably by regulating the GNG signaling Pathway., (Copyright © 2019 Mao, Lin, Zhang and Qin.)

The lipid metabolism relationship between non-alcoholic fatty pancreas disease (NAFPD) and type 2 diabetes mellitus (T2DM) is poorly defined. We aim to identify novel T2DM-related lipid biomarkers in addition to previous studies and provide the evidence for elucidating the relationship between NAFPD and T2DM in a lipid perspective. In this study, multi-dimensional mass spectrometry-based shotgun lipidomics (MDMS-SL) was used to investigate the potential discriminating lipid profile of the fasting plasma of 105 Chinese individuals (39 NAFPD patients, 38 T2DM patients and 30 healthy controls). Then multivariate statistical analysis combined with pathway analysis was performed to identify the lipid biomarker and explore the potential relationship of these two important diseases. The results described a marked reduction of plasmalogen and a significant 4-hydroxynonenal increase in the two diagnostic group, which indicated increased oxidative stress and peroxisomal dysfunction in patients. 60 discriminating metabolites were identified by multivariate statistical analysis of the lipidomics data. In addition, ingenuity pathway analysis (IPA) and a metabolic network constructed by prediction of IPA indicated that lipid metabolism, molecular transport, carbohydrate metabolism and small molecule biochemistry were correlated with disease progression. Our results revealed that the profile of plasma lipid alteration characteristic of NAFPD was similar to that of T2DM, especially during the period prior to the onset of T2DM., Competing Interests: We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced the outcome., (This journal is © The Royal Society of Chemistry.)

Background and Objective: Yunpiheluo (YPHL) decoction is a Chinese herbal formula with unique advantages for the treatment of type 2 diabetes mellitus (T2DM). The aim of the present study was to investigate changes in miRNA expression and downstream gene expression in Zucker diabetic fatty (ZDF) rats treated with YPHL to determine whether YPHL could be used as an adjuvant treatment of T2DM., Methods: Serum and liver total cholesterol (TC) and triglycerides (TG) levels, insulin resistance index (IR) and differentially expressed miRNAs were detected in a T2DM ZDF rat model. miRNA target prediction was based on bioinformatic algorithms and dual luciferase reporter assay. Protein expression of genes in the insulin receptor signaling pathway was detected by Western blot. The IR cell model was established and the effects of lyophilized YPHL powder on the protein expressions were observed by transfecting specific miRNA mimics and inhibitors., Results: The miR-29a-3p expression level was significantly increased in the liver of ZDF rats. Insulin receptor substrate 1 (IRS1) was the target gene of miR-29a-3p. IRS1 mRNA and protein expressions of IRS1, IRS1 (phospho S307), protein kinase B (Akt), Akt (phosphor ser473) and pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK1) were decreased significantly. miR-29a-3p over-expression decrease IRS1 and the others protein expressions in the HepG2 IR cell model while anti-miR-29a-3p showed the opposite result. The miR-29a-3p level was decreased, and the expressions of IRS1 mRNA and the above proteins were all increased after YPHL treatment., Conclusion: miR-29a-3p played a functional role in insulin receptor signaling in the liver of ZDF rats. YPHL decoction attenuated IR in T2DM probably by down-regulating or maintaining the miR-29a-3p level, increasing the expression of IRS1 mRNA and its phosphorylated proteins, and regulating the expression of insulin receptor signaling-related proteins. YPHL may prove to be an alternative treatment for T2DM., (Copyright © 2019. Published by Elsevier B.V.)

Aims: Myocardial ischemia/reperfusion (I/R) injury is a leading cause of cardiomyocyte loss and subsequent ventricular dysfunction after restoring the coronary blood flow and contributes to considerable increase in morbidity and mortality. Resveratrol has been declared to confer cardioprotection against in vivo and ex vivo myocardial I/R injury. Here, we have sought to investigate the effects of preconditioning with resveratrol on myocardial I/R damage across the small animal studies., Methods and Results: The MEDLINE, Google Scholar, PubMed, and Cochrane databases were searched for preclinical studies investigating resveratrol vs. vehicle published from the inception to July 2018. Eventually, 10 in vivo and 7 ex vivo studies with 261 animals (130 for resveratrol; 131 for vehicle) were included for meta-analysis. Pooled estimates for primary outcomes demonstrated that pretreatment with resveratrol significantly reduced the infarct size after myocardial I/R injury irrespective of in vivo (weighted mean difference (WMD): -13.42, 95% CI: -16.63 to -10.21, P ≤ 0.001) or ex vivo (WMD: -15.05, 95% CI: -18.23 to -11.86, P ≤ 0.001) studies. Consistently, stratified analysis according to the reperfusion duration, route of administration, or timing regimen of pretreatment all showed the infarct-sparing benefit of resveratrol. Metaregression did not indicate any difference in infarct size based on species, sample size, state, route of administration, reperfusion duration, and timing regimen of pretreatment. Meanwhile, sensitivity analysis also identified the cardioprotection of resveratrol with robust results in spite of significant heterogeneity., Conclusions: Preconditioning with resveratrol appears to prevent the heart from I/R injury in comparison with vehicle, as evidenced by limited infarct size in a preclinical setting. Studies with large animals or randomized controlled trials will add more evidence and provide the rationale for clinical use.

Dendrochronological techniques were used to study the response of radial growth of Pinus koraiensis with different diameter classes to climate change throughout the natural range of broad-leaved Korean pine forests, including Baishilazi Nature Reserve (40.9° N), Changbai Mountain Nature Reserve (42.4° N), Liangshui Nature Reserve (47.2° N), and Shengshan Nature Reserve (49.4° N). We investigated the similarities and differences of growth responses of different diameter classes to climate factors and clarified the key climate factors affecting the growth of P. koraiensis at different latitude sites. We explored the dynamic changes of the radial growth of P. koraiensis from the latitudinal gradient over the past 40 years. The results showed many similarities in the response of two diameter classes to local climate factors. Small diameter (diameter at breast height of 10-20 cm) trees were more sensitive to the changes of average minimum temperature of the current growing season and the meteorological factors of the previous year, whereas large diameter (diameter at breast height >40 cm) trees were more sensitive to the changes of average maximum temperature and average relative humidity of the current growing season. The key meteorological factors that affecting radial growth of P. koraiensis differed along the latitude gradient. In Baishilazi Nature Reserve, the southernmost plot, the key climate factors were the average maximum temperature and the average maximum temperature in the current growing season. In Shengshan Nature Reserve, the northernmost sample plot, the key climate factors were low temperature factors, such as the minimum temperature in all seasons, the average maximum temperature in winter, the average temperature of all seasons except for the end of previous growing season and the current growing season. The Palmer drought severity index (PDSI) in the current growth season and the end of the current growth season and the precipitation in the current growth season were the key climate factors in Changbai Mountain Nature Reserve. The average temperature of the current growing season was the key climate factor of Liangshui Nature Reserve. In recent four decades, with the rising of temperature, the radial growth of P. koraiensis of two diameter classes significantly decreased in the southernmost point, significantly increased in the northernmost point, and had no significant variation in middle latitudes.

The effects of soil moisture variation on the litter decomposition of main tree species Betula platyphylla, Abies nephrolepis and Pinus koraiensis were evaluated in a primary forest of Korean pine (P. koraiensis) in Fenglin National Nature Reserve of the Northeast China, based on the measurements of surface (0-10 cm) soil moisture from 1998 to 2017. The results showed that litter decomposition rates increased with the increase of litter quality. The order of litter decomposition rate was B. platyphylla > A. nephrolepis > P. koraiensis at the same soil moisture. The litter decomposition rates decreased with the decrease of soil moisture. The sensitivity index of litter decomposition rates on soil moisture (M 10 ) were 0.782, 0.789 and 0.827, respectively, for B. platyphylla, A. nephrolepis and P. koraiensis. The initial litter decomposition rate decreased by 21.8%, 21.1% and 17.3% for B. platyphylla, A. nephrolepis and P. koraiensis, respectively, when soil moisture decreased by 10%. The decomposition rates of high-quality litter (high nitrogen content, low carbon to nitrogen ratio, and low lignin content) were more sensitive to the variation of soil moisture. The difference in decomposition rate among different litter types was reduced with the decrease of soil moisture. In the recent 20 years, the average soil moisture presented a significantly decreasing trend, which would inhibit litter decomposition in the primary Korean pine forest. Under the scena-rios of global change, soil moisture would further decrease with the increase of air temperature. It would definitely intensify the inhibitory effect on litter decomposition, and partly offset the enhanced effects of increased air temperature.

Shenfu Injection (SFI) is a classical Chinese medicine used to treat heart failure. Our previous study demonstrated that miRNAs underwent changes in rats with myocardial hypertrophy induced by abdominal aortic constriction. Interestingly, there was a significant change in miR-19a-3p, whose target gene is known to be associated with MEF2 signaling. However, whether and how SFI regulates miR-19a-3p in the treatment of myocardial hypertrophy has not been investigated. The purpose of the present study was to investigate the regulatory effect of SFI on miR-19a-3p in MEF2 signaling in the rat hypertrophic myocardium. We found that the miR-19a-3p expression level was significantly decreased in the hypertrophic myocardium, and MEF2A was the target gene of miR-19a-3p. The protein expressions of MEF2A, β-MHC, BNP and TRPC1 were significantly increased in hypertrophic cardiomyocytes. MiR-19a-3p was up-regulated after SFI treatment, and the protein expressions of these genes were significantly decreased. In addition, miR-19a-3p over-expression in hypertrophic cardiomyocytes could decrease MEF2A mRNA and protein expressions, and anti-miR-19a-3p showed the opposite result. Our study provided substantial evidence that miR-19a-3p played a functional role in MEF2 signaling in myocardial hypertrophy. SFI attenuated cardiomyocyte hypertrophy probably through up-regulating or maintaining the miR-19a-3p levels and regulating the MEF2 signaling pathway.

In order to investigate the sleep quality and influencing factors in patients with Parkinson's disease (PD), 201 PD patients were enrolled and underwent extensive clinical evaluations. Subjective sleep evaluation was assessed using the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS). It was found that poor sleep quality (77.11%) and excessive daytime sleepiness (32.34%) were commonly seen in PD patients and positively correlated with disease severity. Then 70 out of the 201 PD patients and 70 age- and sex-matched controls underwent a polysomnographic recording. The parameters were compared between PD group and control group and the influencing factors of sleep in PD patients were analyzed. The results showed that sleep efficiency (SE) was significantly decreased (P<0.01), and sleep latency (SL) and the arousal index (AI) were increased (P<0.05) in the PD group as compared with those in the control group. SE and total sleep time (TST) were positively correlated with the Hoehn and Yahr (H&Y) stage. There was significant difference in the extent of hypopnea and hypoxemia between the PD group and the control group (P<0.05). Our results indicate that PD patients have an overall poor sleep quality and a high prevalence of sleep disorder, which may be correlated with the disease severity. Respiratory function and oxygen supply are also affected to a certain degree in PD patients.

Chronic myeloid leukemia (CML) has chronic and acute phases. In chronic phase myeloid differentiation is preserved whereas in acute phase myeloid differentiation is blocked. Acute phase CML resembles acute myeloid leukemia (AML). Chronic phase CML is caused by BCR-ABL1. What additional mutation(s) cause transition to acute phase is unknown and may differ in different persons with CML. BCL11A encodes a transcription factor and is aberrantly-expressed in several haematological and solid neoplasms. We analyzed BCL11A mRNA levels in subjects with chronic and acute phase CML. BCL11A transcript levels were increased in subjects with CML in acute phase compared with those in normals and in subjects in chronic phase including some subjects studied in both phases. BCL11A mRNA levels were correlated with percent bone marrow blasts and significantly higher in lymphoid versus myeloid blast crisis. Differentiation of K562 with butyric acid, a CML cell line, decreased BCL11A mRNA levels. Cytology and flow cytometry analyses showed that ectopic expression of BCL11A in K562 cells blocked differentiation. These data suggest BCL11A may operate in transformation of CML from chronic to acute phase in some persons., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Histone deacetylase inhibitors, which have also received attention in AIDS and other diseases, are a new class of anticancer drugs developed in recent years. However, there is still a lack of a unified and reliable method for detecting histone acetylation levels in basic and clinical research. In this study, we developed a flow cytometry-based method to detect histone acetylation levels by comparing different sample processing temperature (on ice vs. room temperature), permeabilization method (intracellular vs. nuclear), antibody dose (antibody titration) and antibody incubation time (time gradient) using whole blood and peripheral blood mononuclear cells. In addition, we applied this optimized method in in vitro experiment and clinical trial of Chidamide (the only China FDA approved HDACi), the result of which confirmed that the flow cytometry-based method for detecting histone acetylation levels is a reliable, fast and convenient method which can be used in basic and clinical research.

To reveal the radial growth trends of Pinus koraiensis and the differences in their responses to climate factors among different latitudes, and to assess the dynamic characteristics, adaptabi-lity and sensitivity of P. koraiensis under the influence of climate change, dendrochronological techniques were used to study the relationships between the climatic variables and the radial growth of P. koraiensis in broad-leaved Korean pine forests with different latitudes. The results showed that there were differences in the responses of the radial growth of P. koraiensis in four different latitudes to local climatic factors. In Baishilazi Nature Reserve, the southernmost sample plot, the radial growth of P. koraiensis was significantly positively correlated to the average relative humidity but significantly negatively correlated to the average maximum temperature of growing season. In low altitude of Changbai Mountain Nature Reserve, the intermediate sample plot, it was significantly positively correlated with precipitation, average relative humidity and PDSI, and significantly negatively correlated with the average maximum temperature in growing season. In Liangshui Nature Reserve, the intermediate sample plot, significantly positive correlations occurred for average relative humidity and PDSI in growing season, while significantly negative correlations occurred for the average temperature and the average maximum temperature in growing season. Nevertheless, in Shengshan Nature Reserve, the northernmost sample plot, it was positively correlated to the tempe-rature factors of most months. The climatic variables in June of current year were the main factors limiting the radial growth of P. koraiensis in all latitudes, and the average maximum temperature in June of current year was highly negatively correlated with radial growth for P. koraiensis measured at all sites. In recent four decades, with the rising of temperature, the radial growth of P. koraiensis decreased significantly in the southernmost point, increased significantly in the northernmost point, and did not change significantly in middle latitudes. The distribution area of P. koraiensis would be reduced if the temperature increased and precipitation remained unchanged in the future.

Objectives: Maintenance therapy for patients with advanced non-small-cell lung cancer (NSCLC) is an increasingly hot topic in the field of clinical NSCLC research. This study aimed to evaluate the effects of Traditional Chinese Medicine (TCM) treatment as maintenance therapy on time to progression (TTP), quality of life (QOL), overall survival (OS) and 1-year survival rate in patients with advanced NSCLC., Methods: This study was conducted as a randomized, controlled, open-label trial. 64 non-progressive patients who responded to initial therapy were randomized 1:1 to the TCM arm (treated with herbal injection (Cinobufacini, 20ml/d, d1-d10), herbal decoction (d1-d21) and Chinese acupoint application (d1-d21), n=32) or to the chemotherapy arm (treated with pemetrexed (non-squamous NSCLC, 500mg/m(2), d1), docetaxel (75mg/m(2), d1) or gemcitabine (1250mg/m(2), d1 and d8), n=32). Each therapy cycle was 21 days. They were repeated until disease progression, unacceptable toxicity, or until the patients requested therapy discontinuation. The primary end point was TTP; the secondary end points were QOL, OS and 1-year survival rate. "Intention-to-treat" analysis included all randomized participants., Results: TCM treatment prolonged median TTP for 0.7 months compared with chemotherapy, but it was not statistically significant (3.0 months vs. 2.3 months, P=0.114). Median OS time for TCM treatment did not offer a significant advantage over for chemotherapy (21.5 months vs. 18.8 months, P=0.601). 1-year survival rate of TCM treatment significantly improved than that of chemotherapy (78.1% vs. 53.1%, P=0.035). TCM treatment can significantly improve QOL when compared to chemotherapy as assessed by EORTC QLQ-C30 and EORTC QLQ-LC13 QOL instruments., Conclusions: TCM maintenance treatment had similar effects on TTP and OS compared with maintenance chemotherapy, but it improved patients' QOL and had higher 1-year survival rate. TCM Maintenance treatment is a promising option for advanced NSCLC patients without progression following first-line chemotherapy., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: BCL11A encodes a C2H2 type zinc-finger protein. During normal haematopoietic cell differentiation BCL11A expression is down-regulated. Data in mice suggest up-regulation of BCL11A is involved in the pathogenesis of myeloid leukaemias. BCL11A expression in persons with acute myeloid leukaemia (AML) is not systematically studied., Objective: Interrogate associations between BCL11A expression at diagnosis and clinical and laboratory valuables and outcomes in newly-diagnosed persons with AML., Methods: We determined BCL11A mRNA levels in bone marrow and blood mononuclear cells in 292 consecutive newly-diagnosed subjects with AML by reverse transcript and real-time polymerase chain reaction. Data were compared to mRNA levels in bone marrow cells of normals., Results: Subjects with BCL11A transcript levels at diagnosis exceeding the median value of 2.434 (±3.423 SD; 25th-75th inter-quartile range, 1.33-4.29) had higher WBC levels, a greater proportion of bone marrow myeloblasts, were more likely to be FAB M0 subtype, less likely to be FAB M3 subtype, more likely to be in the intermediate cytogenetic risk cohort, less likely to have a complex karyotype and more likely to have DNMT3A(R882) and FLT3-ITD mutations than subjects with transcript levels below the median value. In 89 subjects receiving conventional induction chemotherapy the complete remission rate was 54% (95% confidence interval [CI]; 33, 75%) in the lower BCL11A cohort and 65% (45, 85%; P=0.26) in the higher BCL11A cohort. 3 year survival was 33% (2, 65%) in the lower BCL11A cohort and 15% (0, 39%; P=0.35) in the high BCL11A cohort., Conclusion: BCL11A transcript levels at diagnosis was significantly associated with several clinical and laboratory variables. There were also non-significant associations with complete remission rate and survival. These data suggest a possible role for BCL11A expression in AML biology., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: Analysis for 24 variable regions of the T-cell-receptor beta chain by flow cytometry (Vbeta) is a new technique to detect clonal alpha-beta T lymphocytes and is characteristically performed on peripheral blood. Angioimmunoblastic T-cell lymphoma (AITL) has increased neoplastic follicular-helper T cells (FHT), which often express CD10; but nonneoplastic, CD10-positive T cells may be associated with reactive lymphadenopathy and with B-cell lymphomas. This study documents the utility of Vbeta analysis of FHT in specimens of AITL from blood, from marrow, and from lymph nodes., Methods: The electronic medical record in the flow cytometry laboratory was searched for specimens that were analyzed by flow cytometry for Vbeta and that were involved by AITL. Flow cytometry was performed for the following antigens: T-cell-associated proteins, CD10, CD56, CD94, CD161, killer-cell immunoglobulin-like receptors, alpha-beta T-cell receptor, gamma-delta T-cell receptor, and Vbeta., Results: Five patients had six specimens of blood (two), of bone marrow (one), or of lymph nodes (three). Immunophenotypic aberrances were detected for antigens: CD2 (2/6), CD3 (6/6), CD4 (1/6), CD5 (1/6), CD7 (5/6), and CD45 (2/6). All abnormal T-cell populations expressed CD4, and most expressed CD10 (5/6). Four specimens were clonally restricted for Vbeta. Two specimens lacked the alpha-beta T-cell receptor and Vbeta., Conclusions: Vbeta analysis by flow cytometry can be used to detect clonal alpha-beta FHT in AITL, which may be difficult to diagnose with early involvement. Abnormal Vbeta expression on CD10-positive T cells confirms that FHT are the neoplastic cells., (© 2015 International Clinical Cytometry Society.)

The mechanisms underlying acute myeloid leukemia (AML) treatment failure are not clear. Here, we established a mouse model of AML by syngeneic transplantation of BXH-2 derived myeloid leukemic cells and developed an efficacious Ara-C-based regimen for treatment of these mice. We proved that leukemic cell load was correlated with survival. We also demonstrated that the susceptibility of leukemia cells to Ara-C could significantly affect the survival. To examine the molecular alterations in cells with different sensitivity, genome-wide expression of the leukemic cells was profiled, revealing that overall 366 and 212 genes became upregulated or downregulated, respectively, in the resistant cells. Many of these genes are involved in the regulation of cell cycle, cellular proliferation, and apoptosis. Some of them were further validated by quantitative PCR. Interestingly, the Ara-C resistant cells retained the sensitivity to ABT-737, an inhibitor of anti-apoptosis proteins, and treatment with ABT-737 prolonged the life span of mice engrafted with resistant cells. These results suggest that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C. Incorporation of apoptosis inhibitors, such as ABT-737, into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C. This work provided direct in vivo evidence that leukemic load and intrinsic cellular resistance can affect the outcome of AML treated with Ara-C, suggesting that incorporation of apoptosis inhibitors into traditional cytotoxic regimens merits consideration for the treatment of AML in a subset of patients with resistance to Ara-C.

Dendrochronological techniques including correlation functions and single-years analysis were used to study the relationship between the two kinds of Korean pine radial growth in Liangshui Natural Reserve and climatic variables, and to assess the similarities and differences between Korean pine with coarse bark (Pinus koraiensis forma pachidermis) and fine bark (Pinus koraiensis forma leptodermis) in response to climate factors, the main affecting factors and whether the response relationship could be of long-term stability. The results showed that the Korean pine with fine bark was more suitable for dendrochronological study. The radial growth of the two kinds of Korean pine was very sensitive to environmental variables and their climate responses had no significant differ- ences. From 1902 to 2009, meteorological factors in the growing season, especially in June were the primary factors affecting the radial growth of the two kinds of Korean pine in the study area. The temperature showed a significant negative correlation and the precipitation showed a significant positive correlation. The Korean pine growing in different periods had a significantly different iresponse to meteorological factors. With the rapid rise of temperature and drought after 1970, the radial growth of the two kinds of Korean pine was more sensitive to the meteorological factors than before, which was especially more sensitive to temperature in growing season and PDSI in many seasons.

The difficulty in manipulation of leukemia cells has long hindered the dissection of leukemia pathogenesis. We have introduced a non-genetic approach of marking blood cells, using quantum dots. We compared quantum dots complexed with different vehicles, including a peptide Tat, cationic polymer Turbofect and liposome. Quantum dots-Tat showed the highest efficiency of marking hematopoietic cells among the three vehicles. Quantum dots-Tat could also label a panel of leukemia cell lines at varied efficiencies. More uniform intracellular distributions of quantum dots in mouse bone marrow and leukemia cells were obtained with quantum dots-Tat, compared with the granule-like formation obtained with quantum dots-liposome. Our results suggest that quantum dots have provided a photostable and non-genetic approach that labels normal and malignant hematopoietic cells, in a cell type-, vehicle-, and quantum dot concentration-dependent manner. We expect for potential applications of quantum dots as an easy and fast marking tool assisting investigations of various types of blood cells in the future.

Six new acylphloroglucinol derivatives, sampsonols A-F (1-6), were isolated from the petroleum ether extract of the aerial parts of Hypericum sampsonii. The structures and relative configurations of sampsonols A-F were elucidated by extensive spectroscopic analyses. All these compounds were tested for their in vitro cytotoxic and anti-inflammatory activities. Sampsonols A and B (1 and 2) showed significant cytotoxicity against four human tumor cell lines with IC(50) values in the range of 13-28μM, whereas sampsonols C and F (3 and 6) showed potent inhibitory activities against LPS-induced NO production in RAW 264.7 macrophages with IC(50) values of 27.3 and 29.3μM, respectively., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Drug resistance is a major factor for the limited efficacy of chemotherapy in gastric cancer treatment. Hypoxia-inducible factor-1α (HIF-1α), a central transcriptional factor in hypoxia, is suggested to participate in the resistance. Here, we identified a hypoxia-mimic (cobalt chloride) sensitive gastric cell line BGC-823 to explore whether diosgenin, an aglycone of steroidal saponins, can inhibit cancer cell invasion and survival of solid tumor in a hypoxic mimic microenvironment. We have shown that diosgenin is a potent candidate for decreasing the ability of invasion and survival in cobalt chloride treated BGC-823 cells. In addition, when combined with HIF-1α specific short hairpin RNA (shRNA), diosgenin can inhibit BGC-823 cells more effectively. The anti-invasion role of diosgenin may be related to E-cadherin, integrinα5 and integrin β6. These results suggest that diosgenin may be a useful compound in controlling gastric cancer cells in hypoxia condition, especially when combined with down-regulated HIF-1α.

Objective: To observe the effects of ethanol extract of Rhizome Pinelliae Preparata on the intracellular pH value of human gastric cancer SGC7901 cells., Methods: After coculturing SGC7901 cells with ethanol extract of Rhizome Pinelliae Preparata (1, 0.5, 0.25 and 0.125 mg/mL), cell viability was evaluated by chromatometry with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) staining. Intracellular pH value of SGC7901 cells was measured in the monolayer by using the pH-sensitive fluorescent probe 2,7-bis-(2-carboxyethyl)-5-carboxyfluorescein-acetoxymethyl ester. The extracellular pH value of culture medium was measured by a pH211 Calibration Check Microprocessor pH Meter. Half-inhibitory concentration (IC(50)) of ethanol extract culture to SGC7901 cells was decided by the MTT method and expressions of vacuolar-H(+)-ATPase (V-ATPase) and Na(+)/H(+) exchanger isoform 1 (NHE1) mRNAs were examined by the method of fluorescence quantitative-polymerase chain reaction after 72 h of drug treatment., Results: Ethanol extract of Rhizome Pinelliae Preparata at different concentrations significantly inhibited the proliferation of SGC7901 cells, lowered the intracellular pH values and heightened the extracellular pH values. The IC(50) of 72 h culture was 0.5mg/mL and it inhibited the expressions of V-ATPase and NHE1 mRNAs., Conclusion: Ethanol extract of Rhizome Pinelliae Preparata can lower down the intracellular pH value of SGC7901 cells. The mechanism may be related to inhibiting the expressions of V-ATPase and NHE1 mRNAs.

Two new triterpenoid saponins, namely caraganoside C (1) and caraganoside D (2), were isolated from the seeds of Caragana microphylla. Their structures were elucidated on the basis of spectroscopic analyses, including homo- and hetero-nuclear correlation NMR experiments (COSY, HSQC and HMBC). Both 1 and 2 exhibited moderate inhibitory activity against NO production in LPS-stimulated RAW264.7 cells with IC(50) values of 26.4 μM and 32.2 μM, respectively. In addition, 1 showed weak cytotoxicity against MCF-7, HL-60, HCT116, and A549 cell lines.