Three coordination polymers based on 4,4'-bis(2-methylimidazol-1-yl)diphenyl ether: Synthesis, structure and selective fluorescent sensing properties.

Three CPs [Zn2(PDA)2(BMIOPE)2·3H2O]n (1), [Co(Br-BDC)(BMIOPE)]n (2) and [Co(MIP)(BMIOPE)]n (3) were synthesized by solvothermal method based on dual-ligand strategy (H2PDA, Br-H2BDC, BMIOPE and H2MIP are 1,3-phenylenediacetic acid, 5-bromo-isophthalic acid, 4,4'-bis(2-methylimidazol-1-yl)diphenyl ether and 5-methylisophthalic acid, respectively). Complexes 1 and 3 exhibit twofold parallel interwoven sql nets. Complex 2 is 2D layer structure. The luminescence property investigations showed that complexes 1-3 could act as multi-responsive fluorescent sensors to detect UO22+, Cr2O72- and CrO42- and nitrofurantoin (NFT) through fluorescence turn-off process, presenting excellent sensitivity and selectivity. Finally, the possible fluorescent quenching mechanisms of complexes 1-3 toward the above pollutants are also further investigated by employing spectroscopic methods and quantum chemical calculations. The fluorescence lifetime measurements manifest the mechanism of fluorescence quenching is static quenching process.

Emerging clinical relevance of microbiome in cancer: promising biomarkers and therapeutic targets.

The profound influence of microbiota in cancer initiation and progression has been under the spotlight for years, leading to numerous researches on cancer microbiome entering clinical evaluation. As promising biomarkers and therapeutic targets, the critical involvement of microbiota in cancer clinical practice has been increasingly appreciated. Here, recent progress in this field is reviewed. We describe the potential of tumor-associated microbiota as effective diagnostic and prognostic biomarkers, respectively. In addition, we highlight the relationship between microbiota and the therapeutic efficacy, toxicity, or side effects of commonly utilized treatments for cancer, including chemotherapy, radiotherapy, and immunotherapy. Given that microbial factors influence the cancer treatment outcome, we further summarize some dominating microbial interventions and discuss the hidden risks of these strategies. This review aims to provide an overview of the applications and advancements of microbes in cancer clinical relevance.

Clinical features, genomic profiling, and outcomes of adult patients with unifocal Langerhans cell histiocytosis.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare highly heterogeneous histiocytosis, which can be divided into single system and multiple system disease according to site of involvement. There is a paucity of studies examining unifocal LCH in adults in the molecular era. RESULTS: We retrospectively analysed records from 70 patients with unifocal LCH. The median age at diagnosis was 36 years (18-69). The most common organ involved was the bone (70.0%), followed by pituitary gland (7.1%). Target gene sequencing of lesion tissues was performed on 32 of the 70 patients. MAPK/PI3K pathway alterations were observed in 78.1% of the patients; the most common mutations included BRAFV600E (28.1%), MAP2K1 (18.8%) and PIK3CA (9.4%). After a median follow-up time of 39.4 months (0.7-211.8), 10 (14.3%) patients developed disease progression, of whom 4 had local recurrence, 2 progressed to single-system multifocal and 4 progressed to multiple system LCH. The 3-year progression-free survival (PFS) was 81.9%. Univariate analysis showed that age < 30 years at diagnosis was associated with worse 3-year PFS (52.2% vs. 97.0%, p = 0.005). The 3-year overall survival was 100%. CONCLUSIONS: In our large cohort of adults with unifocal LCH, we found that prognosis of unifocal LCH in adults was very good, and age < 30 years at diagnosis was associated with increased relapse risk.

The clinical spectrum and prognostic factors of Erdheim-Chester disease and mixed Langerhans cell histiocytosis and Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare and probably fatal multisystemic non-Langerhans cell histiocytosis (LCH). To comprehensively investigate the clinical features, genomic analysis, treatments, and prognostic factors of ECD, we retrospectively analyzed the clinical data of 75 ECD patients and 10 mixed LCH and ECD patients in our center. The median age at diagnosis was 46 years (range, 5-70). ECD patients were older at diagnosis (p = 0.006) and had more cardiac involvement (p = 0.011) as well as vascular (p = 0.031) involvement compared to mixed LCH and ECD patients. 64.8% of ECD patients and 87.5% of mixed LCH and ECD patients carried BRAFV600E mutation. The BRAFV600E mutation correlated with a greater number of affected organs (p = 0.030) and was associated with lung involvement (p = 0.033) as well as pleural involvement (p = 0.002). The median follow-up time was 38 months (range, 1-174). The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 48.9% and 84.7%, respectively. In a multivariate analysis, right atrial pseudotumor (p = 0.013) and pancreatic involvement (p = 0.005) predicted worse OS, while pleural (p = 0.042) and central nervous system (CNS) involvement (p = 0.043) predicted worse PFS. Our study described the clinical spectrum of ECD and mixed LCH and ECD, while also revealed the prognostic value of right atrial pseudotumor and pancreatic, pleural, and CNS involvement for worse survival.

Behavioral and ecotoxicology of sulfonamide metabolites in the aquatic environment.

Sulfonamides (SAs) are the first broad-spectrum synthetic antimicrobial agents used in human health and veterinary medicine. The majority of SAs entering human body is discharged into aquatic environment in the form of parent material or metabolites. The residues of SAs and their metabolites in the aquatic environment and the development of drug resistance can be serious threats to ecosystems and human health. We summarized recent advances in the research of SAs. The main metabolite types of SAs and the distribution characteristics of metabolites in different aquatic environments were introduced. The ecotoxicology of SAs metabolites, especially the distribution and hazards of sulfonamide resistance genes (sul-ARGs), were discussed with emphasis. Finally, the future research works were proposed. This paper could provide basic information for further research on SAs.

Identification of prognostic and driver gene mutations in acute myeloid leukemia by a bioinformatics analysis.

Background: The representative gene mutation in the prognostic groups of acute myeloid leukemia (AML) patients is not yet known. The purpose of this study is to identify representative mutations that can help physicians better predict patient prognosis and thus develop better treatment plans. Methods: The Cancer Genome Atlas (TCGA) database was queried for clinical and genetic information, and individuals with AML were classified into 3 groups based on their AML Cancer and Leukemia Group B (CALGB) cytogenetic risk category. Each group's differentially mutated genes (DMGs) were evaluated. Simultaneously, Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to assess the function of DMGs within the 3 distinct groups. We used the driver status and protein impact of DMGs as additional filters to narrow down the list of significant genes. Cox regression analysis was used to examine the survival features of gene mutations in these genes. Results: A cohort of 197 AML patients were divided into 3 groups according to their prognostic subtype: favorable (n=38), intermediate (n=116) and poor (n=43). There were significant differences in age and tumor metastasis rates among the three groups of patients. Patients in the favorable group had the highest rate of tumor metastasis. Different prognosis groups' DMGs were detected. The DMGs were examined for the driver and harmful mutations. We considered the DMGs that had driver and harmful mutations and that affected the survival outcomes in the prognostic groups as the key gene mutations. The group with a favorable prognosis carried specific gene mutations for KIT and WT1. The intermediate prognostic group contained mutations in the genes IDH2, NRAS, NPM1, FLT3, RUNX1, DNMT1A, and MUC16. In the group with a poor prognosis, the representative genes were KRAS, TP53, IDH1, IDH2, and DNMT3A, with TP53 mutations substantially correlated with overall patient survival. Conclusions: We performed the systemic analysis of the gene mutation in patients with AML and identified representative and driver mutations between the prognostic group. identification of representative and driver mutations between the prognostic group can help predict the prognosis of patients with AML and guide treatment decisions.

Preclinical study of LMP1-RNAi-based anti-tumor therapy in EBV-positive nasopharyngeal carcinoma.

RNA interference (RNAi) treatment has been proven to be an important therapeutic approach in cancer based on downregulation of target-oncogenes, but its clinical efficacy still needs further investigation. LMP1 is usually presented by Epstein-Barr virus (EBV)-positive tumor cells like EBV-associated nasopharyngeal carcinoma (NPC) and acts as an oncogene in tumorigenesis. However, the mechanism of LMP1 as a proto-oncogene in nasopharyngeal carcinoma is still unclear. Two sequence-specific shRNAs 1 and 2 were designed to target the different nucleotide loci of EBV latent antigen LMP1 gene and a series of in vivo and in vitro experiments were performed to investigate the therapeutic effect of sequence-specific shRNAs targeting LMP1 and its related molecular mechanisms in EBV-positive NPC. LMP1-shRNA2 generated a truncated LMP1 mRNA and protein, whereas LMP1-shRNA1 completely blocked LMP1 mRNA and protein expression. Both LMP1-shRNAs inhibited the proliferation and migration of NPC cells overexpressing LMP1 (NPC-LMP1) as well as the NPC-associated myeloid-derived suppressor cell (MDSC) expansion in vitro. However, LMP1-shRNA2 maintained the immunogenicity of NPC-LMP1 cells, which provoked MHC-class I-dependent T cell recognition. LMP1-shRNAs inhibited tumor growth in nude mice but did not reach statistical significance compared to control groups, while the LDH nanoparticle loaded LMP1-shRNAs and the antigen-specific T cells induced by NPC-LMP1 cells treated with LMP1-shRNA2 significantly reduced tumor growth in vivo. LMP1-RNAi-based anti-tumor therapy could be a new hope for the clinical efficacy of RNAi treatment of tumors like NPC.

Comparing the effectiveness and safety of Sorafenib plus TACE with Apatinib plus TACE for treating patients with unresectable hepatocellular carcinoma: a multicentre propensity score matching study.

OBJECTIVE: Local combined systemic therapy has been an important method for the treatment of unresectable hepatocellular carcinoma (HCC).The purpose of this study was to compare the effectiveness and safety of transarterial chemoembolization (TACE) plus Sorafenib versus TACE plus Apatinib for treating patients with unresectable HCC. METHODS: The clinical data of patients with unresectable HCC who were treated with TACE plus Sorafenib or TACE plus Apatinib at 5 Chinese medical centers between January 2016 and December 2020 were retrospectively analyzed. Propensity score matching (PSM) was applied to reduce the bias from confounding factors. RESULTS: A total of 380 patients were enrolled, of whom 129 cases were treated with TACE plus Sorafenib and 251 cases with TACE plus Apatinib. After the 1:1 PSM, 116 pairs of patients were involved in this study. The results showed that the PFS and OS in the TACE-Sorafenib group were significantly longer than those in the TACE-Apatinib group (PFS: 16.79 ± 6.45 vs. 14.76 ± 6.98 months, P = 0.049; OS: 20.66 ± 6.98 vs. 17.69 ± 6.72 months, P = 0.013). However, the ORR in the TACE-Apatinib group was markedly higher than that in the TACE-Sorafenib group (70.69% vs. 56.03%, P = 0.021). There were more patients with adverse events (AEs) in the TACE-Apatinib group than those in the TACE-Sorafenib group before dose adjustment (87 vs. 63, P = 0.001); however, the number of patients who suffered from AEs was not significantly different between the two groups after the dose adjustment (62 vs. 55, P = 0.148). No treatment-related death was found in the two groups. Subgroup analysis revealed that patients with unresectable HCC could better benefit from regular doses than reduced doses (Sorafenib, 22.59 vs. 18.02, P < 0.001; Apatinib, 19.75 vs. 16.86, P = 0.005). CONCLUSION: TACE plus either Sorafenib or Apatinib could effectively treat patients with unresectable HCC, the safety of TACE plus Sorafenib was better. and the ORR of TACE plus Apatinib was higher.

Acidity Scale in a Choline Chloride- and Ethylene Glycol-Based Deep Eutectic Solvent and Its Implication on Carbon Dioxide Absorption.

An equilibrium acidity (pKa) scale that comprises 16 Brönsted organic acids, including phenols, carboxylic acids, azoles, and phenylmalononitriles, was established in a choline chloride/EG-based deep eutectic solvent (DES) ([Ch][Cl]:2EG) by ultraviolet-visible (UV-Vis) spectroscopic methods. The established acidity scale spans about 6 pK units in the DES, which is similar to that for these acids in water. The acidity comparisons and linear correlations between the DES and other solvents show that the solvent property of [Ch][Cl]:2EG is quite different from those of amphiphilic protic and dipolar aprotic molecular solvents. The carbon dioxide absorption capabilities as well as apparent absorption kinetics for a series of anion-functionalized DESs ([Ch][X]:2EG) were measured, and the results show that the basicity of comprising anion [X] of choline salt is essential for the maximum carbon dioxide absorption capacity, i.e., a stronger basicity leads to a greater absorption capacity. The possible absorption mechanisms for carbon dioxide absorption in these DESs were also discussed based on the spectroscopic evidence.

Obesity-mediated upregulation of the YAP/IL33 signaling axis promotes aggressiveness and induces an immunosuppressive tumor microenvironment in breast cancer.

Obesity is a well-known risk factor for breast cancer formation and is associated with elevated mortality and a poor prognosis. An obesity-mediated inflammatory microenvironment is conducive to the malignant progression of tumors. However, the detailed molecular mechanism is still needed to be clarified. Herein, we identified that breast cancer cells from mice with diet-induced obesity exhibited increased growth, invasiveness, and stemness capacities. A transcriptome analysis revealed that expressions of interleukin 33 (IL33) signaling pathway-related genes were elevated in obesity-associated breast cancer cells. Importantly, IL33 expression was significantly associated with the yes-associated protein (YAP) signature, and IL33 was transcriptionally regulated by YAP. Suppression of IL33 reduced tumor migration and invasion, while the addition of IL33 activated nuclear factor (NF)-κB signaling and revived tumor mobility in YAP-silenced cells. Furthermore, suppression of YAP attenuated IL33 expression which was accompanied by relief of obesity-mediated immunosuppression. Clinical analyses showed that IL33 expression was markedly associated with macrophage and regulatory T cell infiltration. These findings reveal a crucial role of the YAP/IL33 axis in promoting aggressiveness and immunosuppression of obesity-associated breast cancer progression.

Galectin-9 Facilitates Epstein-Barr Virus Latent Infection and Lymphomagenesis in Human B Cells.

The immune regulator galectin-9 (Gal-9) is commonly involved in the regulation of cell proliferation, but with various impacts depending on the cell type. Here, we revealed that Gal-9 expression was persistently increased in Epstein-Barr virus (EBV)-infected primary B cells from the stage of early infection to the stage of mature lymphoblastoid cell lines (LCLs). This sustained upregulation paralleled that of gene sets related to cell proliferation, such as oxidative phosphorylation, cell cycle activation, and DNA replication. Knocking down or blocking Gal-9 expression obstructed the establishment of latent infection and outgrowth of EBV-infected B cells, while exogenous Gal-9 protein promoted EBV acute and latent infection and outgrowth of EBV-infected B cells at the early infection stage. Mechanically, stimulator of interferon gene (STING) activation or signal transducer and activator of transcription 3 (STAT3) inhibition impeded the outgrowth of EBV-infected B cells and promotion of Gal-9-induced lymphoblastoid cell line (LCL) transformation. Accordingly, Gal-9 expression was upregulated by forced EBV nuclear antigen 1 (EBNA1) expression in 293T cells in vitro. Clinical data showed that Gal-9 expression in B-cell lymphomas (BCLs) correlated positively with EBNA1 and disease stage. Targeting Gal-9 slowed LCL tumor growth and metastasis in xenografted immunodeficient mice. These findings highlight an oncogenic role of Gal-9 in EBV-associated BCLs, indicating that Gal-9 boosts the transformation of EBV-infected B cells. IMPORTANCE The cross talk between Epstein-Barr virus (EBV) and the host cell transcriptome assumes important roles in the oncogenesis of EBV-associated malignancies. Here, we first observed that endogenous Gal-9 expression was persistently increased along with an overturned V-type change in antivirus signaling during the immortalization of EBV-transformed B cells. Upregulation of Gal-9 promoted the outgrowth and latent infection of EBV-infected B cells, which was linked to B-cell-origin tumors by suppressing STING signaling and subsequently promoting STAT3 phosphorylation. EBV nuclear antigen EBNA1 induced Gal-9 expression and formed a positive feedback loop with Gal-9 in EBV-infected B cells. Tumor Gal-9 levels were positively correlated with disease stage and EBNA1 expression in patients with B-cell lymphomas (BCLs). Targeting Gal-9 slowed the growth and metastases of LCL tumors in immunodeficient mice. Altogether, our findings indicate that Gal-9 is involved in the lymphomagenesis of EBV-positive BCLs through cross talk with EBNA1 and STING signals.

The anti-TMV potency of the tobacco-derived fungus Aspergillus versicolor and its active alkaloids, as anti-TMV activity inhibitors.

Nicotiana tabacum (tobacco) has attracted interest as one of the most economically important industrial crops widely cultivated in China, whose dried leaves are popularly consumed medicinally and recreationally by human societies. In this study, five undescribed alkaloids derivatives, isoaspergillines A-E, together with eight known alkaloids, notoamide D, (1R,4S)-4-benzyl-1-isopropyl-2,4-dihydro-1H-pyrazino-[2,1-b]quinazoline-3,6-dione, protuboxepin K, notoamide C, notoamide M, deoxybrevianamide E, cyclo (D-Pro-L-Trp), and versicolamide B, were obtained from the culture of the Nicotiana tabacum-derived fungus Aspergillus versicolor. Their structures were mainly elucidated through comprehensive analyses of spectroscopic data. Bioactivity evaluation of all isolated compounds revealed that isoaspergilline A and notoamide M exhibited anti-TMV activities with IC50 values of 20.0 and 22.8 µM, respectively. Molecular docking suggested that isoaspergilline A and notoamide M were well located into the active site of anti-TMV by interacting with SER138, SER143, and ASN73 residues. This study enlightens the therapeutic potential of the endophytic fungus A. versicolor and it is helpful to find undescribed anti-TMV activity inhibitors, as well as searching for new anti-TMV candidates from natural sources.

Isochromenes from the Nicotiana tabacum-derived endophytic fungus Aspergillus versicolor and their anti-tobacco mosaic virus activities.

Three new isochromenes, (5-methoxy-7-prenyl-1H-isochromen-3-yl)methanol (1), 3-(3-(hydroxymethyl)-5-methoxy-1H-isochromen-7-yl)propan-1-ol (2), and (5-methoxy-7-methyl-1H-isochromen-3-yl)methanol (3), along with three known analogues (4-6) were isolated from the fermentation products of a Nicotiana tabacum-derived endophytic fungus Aspergillus versicolor. Their structures were elucidated by spectroscopic methods, including extensive 1 D and 2 D NMR techniques. Compounds 1-3 and 6 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities. The results showed that compound 2 exhibited high anti-TMV activity with inhibition rate of 46.4%, and this rate is higher than that of positive control. Compounds 1, 3, and 6 also showed potential anti-TMV activity with inhibition rates of 28.6, 30.5, and 26.2%, respectively. The IC50 of compounds 1-3 and 6 were also tested, and showed IC50 values of 49.3, 22.4, 42.2, and 54.1 µM, respectively.

Preclinical study of LMP1-RNAi-based anti-tumor therapy in EBV-positive nasopharyngeal carcinoma

RNA interference (RNAi) treatment has been proven to be an important therapeutic approach in cancer based on downregulation of target-oncogenes, but its clinical efficacy still needs further investigation. LMP1 is usually presented by Epstein-Barr virus (EBV)-positive tumor cells like EBV-associated nasopharyngeal carcinoma (NPC) and acts as an oncogene in tumorigenesis. However, the mechanism of LMP1 as a proto-oncogene in nasopharyngeal carcinoma is still unclear. Two sequence-specific shRNAs 1 and 2 were designed to target the different nucleotide loci of EBV latent antigen LMP1 gene and a series of in vivo and in vitro experiments were performed to investigate the therapeutic effect of sequence-specific shRNAs targeting LMP1 and its related molecular mechanisms in EBV-positive NPC. LMP1-shRNA2 generated a truncated LMP1 mRNA and protein, whereas LMP1-shRNA1 completely blocked LMP1 mRNA and protein expression. Both LMP1-shRNAs inhibited the proliferation and migration of NPC cells overexpressing LMP1 (NPC-LMP1) as well as the NPC-associated myeloid-derived suppressor cell (MDSC) expansion in vitro. However, LMP1-shRNA2 maintained the immunogenicity of NPC-LMP1 cells, which provoked MHC-class I-dependent T cell recognition. LMP1-shRNAs inhibited tumor growth in nude mice but did not reach statistical significance compared to control groups, while the LDH nanoparticle loaded LMP1-shRNAs and the antigen-specific T cells induced by NPC-LMP1 cells treated with LMP1-shRNA2 significantly reduced tumor growth in vivo. LMP1-RNAi-based anti-tumor therapy could be a new hope for the clinical efficacy of RNAi treatment of tumors like NPC.

Awareness of hazards due to tobacco among people aged 15 years and older in Chongqing, China, in 2020: A cross-sectional analysis.

INTRODUCTION: Tobacco smoke contains a large number of harmful substances and carcinogens. Smoking and secondhand smoke cause a variety of cancers and diseases, seriously endangering human health. However, the status and characteristics of the awareness of hazards due to tobacco among people aged ≥15 years in Chongqing, China, are still unknown. METHODS: A multistage stratified cluster random sampling method was used to select ten districts and counties in Chongqing Municipality, China and a total of 6622 people were investigated between August and October 2020. The chi-squared test was used to analyze the awareness of hazards due to tobacco in various populations after the data had been cleaned and weighted. RESULTS: In 2020, the awareness rates of people aged ≥15 years in Chongqing, China, about a specific disease caused by smoking were lung cancer (77.1%), heart disease (45.1%), stroke (40.1%), and penile erectile dysfunction (24.2%). However, only 22.1% of the respondents knew that smoking could simultaneously lead to all four diseases mentioned above. Adult lung cancer was the disease with the highest awareness rating (72.5%), followed by children's lung disease (54.2%) and adult heart disease (46.1%). A total of 42.0% of respondents knew that secondhand smoke could cause the three diseases simultaneously. Only 22.0% of those correctly understood the harm of low-tar cigarettes. The logistic regression results showed that education level and occupation were risk factors for lack of awareness of hazards due to tobacco. In contrast, media campaigns on tobacco control were a protective factor. CONCLUSIONS: The awareness of hazards due to tobacco among people aged ≥15 years in Chongqing, China, still needs to be improved. More graphic health warning labels and mass media campaigns about the hazards of tobacco should be carried out to raise people's awareness and warn about the health risks of smoking.

Reconstruction and analysis of potential biomarkers for hypertrophic cardiomyopathy based on a competing endogenous RNA network.

Hypertrophic cardiomyopathy (HCM) is a common heritable cardiomyopath. Although considerable effort has been made to understand the pathogenesis of HCM, the mechanism of how long noncoding RNA (lncRNA)-associated competing endogenous RNA (ceRNA) network result in HCM remains unknown. In this study, we acquired a total of 520 different expression profiles of lncRNAs (DElncRNAs) and 371 messenger RNAs (mRNA, DEGs) by microarray and 33 microRNAs (DEmiRNAs) by sequencing in plasma of patients with HCM and healthy controls. Then lncRNA-miRNA pairs were predicted using miRcode and starBase and crossed with DEmiRNAs. MiRNA-mRNA pairs were retrieved from miRanda and TargetScan and crossed with DEGs. Combined with these pairs, the ceRNA network with eight lncRNAs, three miRNAs, and 22 mRNAs was constructed. lncRNA RP11-66N24.4 and LINC00310 were among the top 10% nodes. The hub nodes were analyzed to reconstruct a subnetwork. Furthermore, quantitative real-time polymerase chain reaction results showed that LINC00310 was significantly decreased in patients with HCM. For LINC00310, GO analysis revealed that biological processes were enriched in cardiovascular system development, sprouting angiogenesis, circulatory system development, and pathway analysis in the cGMP-PKG signaling pathway. These results indicate that the novel lncRNA-related ceRNA network in HCM and LINC00310 may play a role in the mechanism of HCM pathogenesis, which could provide insight into the pathogenesis of HCM.

Isoindolin-1-ones from the stems of Nicotiana tabacum and their antiviral activities.

In previous studies, several isoindolin-1-one analogs that exhibited significant anti-tobacco mosaic virus (anti-TMV) activities were isolated from Nicotiana tabacum. Since gene-editing mutants provide a new sample for the discovery of active metabolites, we focused on the stems of YN-18-23 (a mutant N. tabacum for gene editing with the alkaloid metabolic pathway cultivated by Yunnan Tobacco Company), which led to the isolation of four new (1-4) and four known (5-8) isoindolin-1-ones. To the best of our knowledge, nicindole C (3) is the first subclass of isoindolin-1-one bearing a pentacyclic ketone, while nicindole D (4) is the first example of isoindolin-1-one bearing a methyl-pyridin-2-(1H)-one moiety. Compounds 1-4 were tested for their anti-TMV activities, and the results revealed that compounds 1, 3, and 4 exhibited high anti-TMV activities at concentrations of 20 µM with inhibition rates of 48.6, 42.8, and 71.5%, respectively. These rates are higher than the inhibition rate of the positive control (33.2%). The mechanistic study of compound 4, which had the highest anti-TMV activity revealed that increased potentiation of defense-related enzyme activities and downregulation of expression of the NtHsp70 protein may induce resistance in tobacco against the viral pathogen TMV. Molecular docking studies also revealed that the isoindolin-1-one substructure is fundamental for anti-TMV activity. The methyl-pyridin-2-(1H)-one moiety in compound 4 and the 2-oxopropyl groups in compounds 1 and 3 at the N-2 position may increase inhibitory activities. This study of the structure-activity relationship is helpful for finding new anti-TMV activity inhibitors. To study whether the isoindolin-1-ones have broader antiviral activities, compounds 1-4 were also tested for their anti-rotavirus activities. Compound 4 exhibited high anti-rotavirus activity with a therapeutic index (TI) value of 20.7. This TI value is close to that of the positive control (20.2).

Pancreatic involvement in Erdheim-Chester disease: a case report and review of the literature.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis characterized by infiltration of lipid-laden foamy macrophages within different tissues. Clinical manifestations of ECD are highly heterogeneous. Bone lesions are found in 80%-95% of patients, while extraosseous lesions usually involve the cardiovascular system, retroperitoneum, central nervous system (CNS), and skin. Pancreatic involvement in ECD has barely been reported. CASE PRESENTATION: A 29-year-old female initially presented with menoxenia, diabetes insipidus and diabetes mellitus. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) revealed hypermetabolic foci in the bilateral frontal lobe, saddle area, and pancreas. A 99mTc-MDP bone scrintigraphy scan revealed symmetrical increased uptake in distal femoral and proximal tibial metaphysis, which was confirmed to be osteosclerosis by high-resolution peripheral quantitative computed tomography. The patient underwent incomplete resection of the sellar mass. Histological examination of biopsies showed histiocytic aggregates, which were positive for S100 and negative for CD1a and CD207 on immunohistochemistry. Enhanced abdominal CT scan showed hypointense nodules within the body and tail of the pancreas. Endoscopic ultrasonography guided fine-needle aspiration (EUS-FNA) found no evidence of malignancy. She was diagnosed with ECD and treated with high-dose IFN-α. Repeated examinations at three-and eight-months post treatment revealed markedly reduction of both intracranial and pancreatic lesions. CONCLUSIONS: ECD is a rare histiocytic neoplasm that can involve almost every organ, whereas pancreatic involvement has barely been reported to date. Here, we present the rare case of pancreatic lesions in ECD that responded well to interferon-α. We further reviewed reports of pancreatic involvement in histiocytic disorders and concluded the characteristics of such lesions to help diagnosis and treatment, in which these lesions mimicked pancreatic adenocarcinoma and caused unnecessary invasive surgeries.

MicroRNA expression profiles in familial hypertrophic cardiomyopathy with myosin-binding protein C3 (MYBPC3) gene mutations.

Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant inherited disease caused by mutations in genes encoding cardiac sarcomere proteins. MicroRNAs (miRNAs) play an important role in the pathogenesis of FHCM. In the present study, we aimed to determine the miRNA profile in FHCM patients with myosin-binding protein C3 (MYBPC3) gene mutations. We recruited three FHCM patients and age- and sex-matched controls. The three probands all had hypertrophic obstructive cardiomyopathy with severe myocardial hypertrophy, and two of the three had a history of sudden cardiac death, representing a "malignant" phenotype. We then compared the miRNA expression profiles of three FHCM patients carrying MYBPC3 gene mutations with those of the normal control group using miRNA sequencing technology. Differentially expressed miRNAs were verified using real-time polymerase chain reaction (qPCR). Target genes and signaling pathways of the identified differentially expressed miRNAs were predicted using bioinformatics analysis. A total of 33 significantly differentially expressed miRNAs were detected in the peripheral blood of the three probands, of which 28 were upregulated, including miR-208b-3p, and 5 were downregulated. Real-time PCR confirmed the upregulated expression of miR-208b-3p in FHCM patients (P < 0.05). Bioinformatics analysis showed that miR-208b-3p was mainly enriched in 79 target genes including UBE2V2, MED13, YBX1, CNKSR2, GATA4, andSOX5/6, et al. Gene ontology (GO) analysis of target genes showed that miR-208b was mainly involved in the processes of negative regulation of transcription from RNA polymerase II promoter, and regulation of transcription, DNA templated. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the target genes regulated by miR-208b-3p were mainly involved in the Wnt signaling pathway. These findings suggest that FHCM patients with MYBPC3 gene mutations have a specific miRNA expression profile, and that miR-208b-3p is significantly upregulated in cardiac hypertrophy. Our results also indicate that miRNA-208b-3p activates the Wnt signaling pathway through its target gene to promote cardiac hypertrophy.

Indole Alkaloids and Chromones from the Stem Bark of Cassia alata and Their Antiviral Activities.

The Cassia (Leguminosae) genus has attracted a lot of attention as a prolific source of alkaloids and chromones with diverse structures and biological properties. The aim of this study is to screen the antiviral compounds from Cassia alata. The extract of the stem bark of this plant was separated using silica gel, MCI, ODS C18, and Sephadex LH-20 column chromatography, as well as semi-preparative HPLC. As a result, three new indole alkaloids, alataindoleins A-C (1-3); one new chromone, alatachromone A (4); and a new dimeric chromone-indole alkaloid, alataindolein D (5) were isolated. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Interestingly, alataindolein D (5) represents a new type of dimeric alkaloid with an unusual N-2-C-16' linkage, which is biogenetically derived from a chromone and an indole alkaloid via an intermolecular nucleophilic substitution reaction. Compounds 1-5 were tested for their anti-tobacco mosaic virus (TMV) and anti-rotavirus activities, and the results showed that compounds 2-4 showed high anti-TMV activities with inhibition rates of 44.4%, 66.5%, and 52.3%, respectively. These rates were higher than those of the positive control (with inhibition rate of 32.8%). Compounds 1 and 5 also showed potential anti-TMV activities with inhibition rates of 26.5% and 31.8%, respectively. In addition, compounds 1-5 exhibited potential anti-rotavirus activities with therapeutic index (TI) values in the range of 9.75~15.3. The successful isolation and structure identification of the above new compounds provided materials for the screening of antivirus drugs, and contributed to the development and utilization of C. alata.