The potential health effects associated with electronic-cigarette.

A good old gateway theory that electronic-cigarettes (e-cigarettes) are widely recognized as safer tobacco substitutes. In actuality, demographics also show that vaping cannibalizes smoking, the best explanation of the data is the "common liability". However, the utilization of e-cigarette products remains a controversial topic at present. Currently, there has been a widespread and substantial growth in e-cigarette use worldwide owing to their endless new flavors and customizable characteristics. Furthermore, e-cigarette has grown widespread among smokers as well as non-smokers, including adolescents and young adults. And some studies have shown that e-cigarette users are at greater risk to start using combustible cigarettes while e-cigarettes use was also observed the potential benefits to people who want to quit smoking or not. Although it is true that e-cigarettes generally contain fewer toxic substances than combustible cigarettes, this does not mean that the chemical composition in e-cigarettes aerosols poses absolutely no risks. While concerns about toxic substances in e-cigarettes and their widespread use in the population are reasonable, it is also crucial to consider that e-cigarettes have been associated with the potential for promoting smoking cessation and the clinically relevant improvements in users with smoking-related pathologies. Meanwhile, there is still short of understanding of the health impacts associated with e-cigarette use. Therefore, in this review, we discussed the health impacts of e-cigarette exposure on oral, nasal, pulmonary, cardiovascular systems and brain. We aspire for this review to change people's previous perceptions of e-cigarettes and provide them with a more balanced perspective. Additionally, we suggest appropriate adjustments on regulation and policy for e-cigarette to gain greater public health benefits.

OCTN2- and ATB0,+-targeted nanoemulsions for improving ocular drug delivery.

Traditional eye drops are administered via topical instillation. However, frequent dosing is needed due to their relatively rapid precorneal removal and low ocular bioavailability. To address these issues, stearoyl L-carnitine-modified nanoemulsions (SC-NEs) were fabricated. The physicochemical properties of SC-NEs in terms of size, morphology, zeta potential, encapsulation efficiency, and in vitro drug release behavior were characterized. The cellular uptake and mechanisms of SC-NEs were comprehensively studied in human corneal epithelial cells and the stearoyl L-carnitine ratio in SC-NEs was optimized. The optimized SC-NEs could target the novel organic cation/carnitine transporter 2 (OCTN2) and amino acid transporter B (0 +) (ATB0,+) on the corneal epithelium, which led to superior corneal permeation, ocular surface retention ability, ocular bioavailability. Furthermore, SC-NEs showed excellent in vivo anti-inflammatory efficacy in a rabbit model of endotoxin-induced uveitis. The ocular safety test indicated that the SC-NEs were biocompatible. In general, the current study demonstrated that OCTN2 and ATB0,+-targeted nanoemulsions were promising ophthalmologic drug delivery systems that can improve ocular drug bioavailability and boost the therapeutic effects of drugs for eye diseases.

MicroRNA-588 regulates the invasive, migratory and vasculogenic mimicry-forming abilities of hypoxic glioma cells by targeting ROBO1.

BACKGROUND: The microenvironment of hypoxia is an important factor contributing to the development of glioblastoma (GBM). MicroRNA-588 and its potential target Roundabout-directed receptor 1 (ROBO1) have been reported to promote tumor invasion and proliferation in diseases such as gastric, pancreatic and hepatocellular carcinoma, while their function in GBM and response to hypoxic states remain elusive. METHODS: A microarray was leveraged to identify differentially expressed microRNAs in U251 glioma cells cultured under normoxic and hypoxic conditions. The expression of miR-588 was assessed using quantitative real-time PCR (qRT‒PCR). Gain- and loss-of-function studies were used to evaluate the role of miR-588 under hypoxic and normoxic conditions. Cell invasion, migration, proliferation, and vasculogenic mimicry (VM) formation experiments were performed. The relationship between miR-588 and ROBO1 was confirmed using western blot and luciferase reporter assays. Intracranial xenograft tumor mouse models were used to study the function of miR-588 in vivo. RESULTS: The expression of miR-588 was significantly upregulated in hypoxic glioma cells relative to normoxic glioma cells. miR-588 inhibited the invasive, migratory and VM-forming abilities of glioma cells in vitro and in vivo. Mechanistically, roundabout guidance receptor 1 (ROBO1) is a direct, functionally relevant target of miR-588 in glioma. ROBO1 knockdown suppressed the expression of matrix metallopeptidase 2 (MMP2) and matrix metallopeptidase 9 (MMP9), thereby inhibiting the invasive, migratory and VM-forming abilities of glioma. CONCLUSIONS: MiR-588 regulated the behaviors of hypoxic glioma cells by targeting ROBO1. miR-588 can be used as a prognostic marker for glioma and has potential implications in glioma gene therapy.

Surface-sealing encapsulation of phosphotungstic acid in microporous UiO-66 as a bifunctional catalyst for transfer hydrogenation of levulinic acid to γ-valerolactone.

The efficient production of γ-valerolactone (GVL) from renewable lignocellulose that is synthesized in plants by photosynthesis to replace the declining fossil resources conforms to the principles of circular economy. Compared to direct hydrogenation by H2 molecules, catalytic transfer hydrogenation (CTH) of levulinic acid (LA) and/or its esters to GVL with organic alcohols as a hydrogen source is a much milder route. The synergistic catalysis between Lewis and Brønsted acids is indispensable in the CTH process. Considering that unsaturated coordinated Zr species could act as Lewis acid sites and phosphotungstic acid (PTA) could dissociate protons as Brønsted acid sites, UiO-66 (Zr) was thus "acidified" by encapsulating PTA in its channels to tune the ratio of Brønsted to Lewis acid sites as a bifunctional catalyst so as to better understand the catalytic structure-performance relationship in the CTH process. To address the dilemma of encapsulated PTA that is prone to leach, a rapid surface sealing strategy was adopted to establish a polyimide (PI) coating over the surface of UiO-66 introducing a space confinement effect via an anhydride-amine coupling reaction. The as-synthesized PTA/UiO-66@PI catalyst exhibited 100% of LA conversion, a 93.2% of GVL yield and high recyclability for at least five consecutive cycles. Moreover, a reaction pathway followed by esterification, hydrogenation and dealcoholization as well as a catalytic hydrogenation mechanism based on intermolecular hydride ß-H transfer were proposed. Current work not only provides a high-performance and high-stability catalytic system to selectively produce GVL from LA or its esters, but also sheds light on the catalytic mechanism of the CTH process at the molecular level.

Cu/SiO2 synthesized with HKUST-1 as precursor: high ratio of Cu+/(Cu+ + Cu0) and rich oxygen defects for efficient catalytic hydrogenation of furfural to 2-methyl furan.

Cu/SiO2 is one of the most promising catalysts for the furfural (FF) hydrogenation reaction but suffers from the difficulty of tailoring the microstructure and surface properties. Herein, we developed a MOF-derived Cu/SiO2 catalyst (Cu/SiO2-MOF) for FF hydrogenation to 2-methyl furan (2-MF). In comparison with Cu/SiO2 catalysts prepared from ammonia evaporation (Cu/SiO2-AE) and traditional impregnation (Cu/SiO2-TI), the copper species in Cu/SiO2-MOF could not only be anchored on the silica surface via forming Cu-O-Si bonds but also exposed many more active sites. In this way, a higher ratio of Cu+/(Cu+ + Cu0) and richer oxygen defects were constructed via strong metal-support interactions, which were responsible for the superior catalytic performance. In addition, it was found that the solvent effect on product distribution played an important role in adjusting the selectivity to 2-MF and cyclopentanone (CPO). The present work not only provides a deep insight into the catalytic mechanism of Cu/SiO2-MOF for the FF hydrogenation reaction but also sheds light on the design and synthesis of highly efficient catalysts for other heterogeneous catalysis fields.

Knockout of UBE2S inhibits the proliferation of gastric cancer cells and induces apoptosis by FAS-mediated death receptor pathway.

Ubiquitin binding enzyme E2S (UBE2S) is a member of ubiquitin binding enzyme family involved in a variety of biological functions, including cell cycle regulation, apoptosis, and regulation of the ubiquitination of proteins, which are closely correlated with the development of various tumors. However, its role in gastric cancer (GC) remains unknown. In this study, we found that UBE2S was upregulated in GC tissues and cells. Further, its high expression positively correlated with the tumor stage and indicated a poor prognosis. Knockout of UBE2S by CRISPR/Cas9-mediated strategy suppressed the growth of GC in vitro and in vivo. Moreover, RNA-Seq-based transcriptome analysis and tandem mass tag (TMT)-based quantitative proteomics analysis was performed for exploring the underlying mechanism. The multi-omics and verification results showed that UBE2S knockout-induced apoptosis and proliferation inhibition of GC cells was related to upregulation of FAS and the activation of the FAS-mediated apoptotic pathway. Moreover, a negative correlation between UBE2S and FAS expression was observed in GC tissue samples. Finally, the ubiquitination assay confirmed that knockout of UBE2S might activate endogenous FAS by inhibiting ubiquitination and degradation of p53 in GC cells. Collectively, UBE2S is expected to be a novel prognostic biomarker and potential therapeutic target for GC.

Mesenchymal stem cells, as glioma exosomal immunosuppressive signal multipliers, enhance MDSCs immunosuppressive activity through the miR-21/SP1/DNMT1 positive feedback loop.

BACKGROUND: The immunosuppressive microenvironment in glioma induces immunotherapy resistance and is associated with poor prognosis. Glioma-associated mesenchymal stem cells (GA-MSCs) play an important role in the formation of the immunosuppressive microenvironment, but the mechanism is still not clear. RESULTS: We found that GA-MSCs promoted the expression of CD73, an ectonucleotidase that drives immunosuppressive microenvironment maintenance by generating adenosine, on myeloid-derived suppressor cells (MDSCs) through immunosuppressive exosomal miR-21 signaling. This process was similar to the immunosuppressive signaling mediated by glioma exosomal miR-21 but more intense. Further study showed that the miR-21/SP1/DNMT1 positive feedback loop in MSCs triggered by glioma exosomal CD44 upregulated MSC exosomal miR-21 expression, amplifying the glioma exosomal immunosuppressive signal. Modified dendritic cell-derived exosomes (Dex) carrying miR-21 inhibitors could target GA-MSCs and reduce CD73 expression on MDSCs, synergizing with anti-PD-1 monoclonal antibody (mAb). CONCLUSIONS: Overall, this work reveals the critical role of MSCs in the glioma microenvironment as signal multipliers to enhance immunosuppressive signaling of glioma exosomes, and disrupting the positive feedback loop in MSCs with modified Dex could improve PD-1 blockade therapy.

EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3.

BACKGROUND: Gliomas are the most common malignant primary brain tumours with a highly immunosuppressive tumour microenvironment (TME) and poor prognosis. Circular RNAs (circRNA), a newly found type of endogenous noncoding RNA, characterized by high stability, abundance, conservation, have been shown to play an important role in the pathophysiological processes and TME remodelling of various tumours. METHODS: CircRNA sequencing analysis was performed to explore circRNA expression profiles in normal and glioma tissues. The biological function of a novel circRNA, namely, circNEIL3, in glioma development was confirmed both in vitro and in vivo. Mechanistically, RNA pull-down, mass spectrum, RNA immunoprecipitation (RIP), luciferase reporter, and co-immunoprecipitation assays were conducted. RESULTS: We identified circNEIL3, which could be cyclized by EWS RNA-binding protein 1(EWSR1), to be upregulated in glioma tissues and to correlate positively with glioma malignant progression. Functionally, we confirmed that circNEIL3 promotes tumorigenesis and carcinogenic progression of glioma in vitro and in vivo. Mechanistically, circNEIL3 stabilizes IGF2BP3 (insulin-like growth factor 2 mRNA binding protein 3) protein, a known oncogenic protein, by preventing HECTD4-mediated ubiquitination. Moreover, circNEIL3 overexpression glioma cells drives macrophage infiltration into the tumour microenvironment (TME). Finally, circNEIL3 is packaged into exosomes by hnRNPA2B1 and transmitted to infiltrated tumour associated macrophages (TAMs), enabling them to acquire immunosuppressive properties by stabilizing IGF2BP3 and in turn promoting glioma progression. CONCLUSIONS: This work reveals that circNEIL3 plays a nonnegligible multifaceted role in promoting gliomagenesis, malignant progression and macrophage tumour-promoting phenotypes polarization, highlighting that circNEIL3 is a potential prognostic biomarker and therapeutic target in glioma.

miR-3184-3p enriched in cerebrospinal fluid exosomes contributes to progression of glioma and promotes M2-like macrophage polarization.

Liquid biopsy is a novel strategy for tumour diagnosis. The contents of cerebrospinal fluid (CSF) exosomes could reflect glioma status, hence sampling exosomes from CSF is a means of liquid biopsy for glioma. However, few studies have focused on the function of microRNAs in CSF exosomes. In this study, we found that miR-3184-3p was enriched in CSF exosomes in glioma patients and was downregulated after tumour resection. We found that miR-3184 facilitates glioma progression in two ways. On the one hand, miR-3184 directly promotes proliferation, migration, and invasion while inhibiting apoptosis in glioma. On the other hand, miR-3184 in glioma-derived exosomes polarizes macrophages to an M2-like phenotype, which further aggravates tumour progression. Overall, the current findings uncovered a new mechanism and highlighted the significant role of miR-3184 in glioma progression. Furthermore, exosomal miR-3184 could be a considerable factor with potential applications in glioma diagnosis and treatment in the future.

Pancancer landscape analysis of the thymosin family identified TMSB10 as a potential prognostic biomarker and immunotherapy target in glioma.

BACKGROUND: Thymosin family genes (TMSs), biologically important peptides with diverse intracellular and extracellular functions, have been shown to promote the progression of multiple cancers. However, multiomics characterization of TMSs and their role in human cancer prognosis has not been systematically performed. METHODS: We performed a comprehensive analysis of TMSs and thymosin ß10 (TMSB10) using multiomics data from more than 10,000 tumor samples of 33 cancer types from The Cancer Genome Atlas (TCGA). We used single-sample gene set enrichment analysis (ssGSEA) and the gene set variation analysis (GSVA) algorithm to investigate the differences in tumor microenvironment (TME) cell infiltration and functional annotation for individual tumor samples, respectively. The role of TMSB10 in the malignant progression of glioma, the promotion of macrophage infiltration,and immunosuppressive polarization, and the combination drug efficacy were assessed via biological function assays. RESULTS: We comprehensively assessed genomic mutations, expression dysregulation, prognosis and immunotherapeutic response across 33 human cancer samples and showed that TMSB10 is specifically overexpressed in almost all types of cancer tissues. Further pan-cancer analysis showed that TMSB10 is closely related to the biological function, immune regulation and prognosis of glioma. Similar results were also found in several public glioma cohorts and our Qilu local cohort. Further integration with other biological experiments revealed the key roles of TMSB10 in the malignant progression of glioma, the promotion of macrophage infiltration and immunosuppressive polarization. We also identified multiple drugs targeting cells with high TMSB10 expression and validated that knockdown of TMSB10 improved the efficacy of selumetinib (a MEK1/2 inhibitor approved by the FDA for the treatment of neurofibromatosis-associated tumors) and anti-PD1 treatment in glioma. CONCLUSION: These results indicate that TMSB10 holds promise as a novel prognostic marker and therapeutic target, providing a theoretical basis for the development of more effective and targeted clinical treatment strategies for glioma patients.

Exosomal miR-1246 from glioma patient body fluids drives the differentiation and activation of myeloid-derived suppressor cells.

Glioma is a heterogeneous cellular environment in which immune cells play critical roles in tumor progression. Myeloid-derived suppressor cells (MDSCs) contribute to the formation of the immunosuppressive microenvironment of glioma; however, how glioma cells interact with MDSCs and how this interaction affects the function of other immune cells are unclear. Glioma cells can systemically communicate with immune cells via the secretion of exosomes, which contain microRNAs (miRNAs). Leveraging miRNA sequencing of exosomes, we identified enrichment of miR-1246 in glioma-derived exosomes and exosomes isolated from the cerebrospinal fluid (CSF) of glioma patients. We demonstrated that miR-1246 drives the differentiation and activation of MDSCs in a dual specificity phosphatase 3 (DUSP3)/extracellular signal­regulated kinase (ERK)-dependent manner. In addition, postoperative CSF exosomal miR-1246 expression was found to be associated with the glioma recurrence rate. Hypoxia, a well-recognized feature of the glioblastoma microenvironment, increased miR-1246 levels in glioma-derived exosomes by enhancing miR-1246 transcription and selective packaging via upregulation of POU class 5 homeobox 1 (POU5F1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Importantly, we identified a mechanism of 2-methoxyestradiol, a microtubule inhibitor currently undergoing clinical trials for glioblastoma. 2-Methoxyestradiol suppresses MDSC activation by inhibiting hypoxia-driven exosomal miR-1246 expression in glioma cells and PD-L1 expression in MDSCs.

Role of annexin A family in tumorigenesis and chemoresistance of gastric cancer.

Gastric cancer (GC) is one of the most common cancer types and the fourth leading cause of cancer-related mortality among all malignant tumors worldwide. Due to insidious onset and lack of reliable early diagnostic markers, most GC patients are at an advanced stage at the time of diagnosis. Annexin is an evolutionally-conserved Ca2+-dependent phospholipid-binding protein superfamily, including five members (A, B, C, D, and E). Annexins in the cells of vertebrates comprised the annexin A family, consisting of 12 members in humans. The biological functions of annexin A are Ca2+-signal transduction, vesicle transport, cell proliferation, cell division, cell apoptosis, signal transduction, anti-inflammatory, proangiogenesis, and anticoagulation, most of which overlap with the basic characteristics of tumors. Accumulating evidence indicated that members of the annexin A family are correlated with tumorigenesis and chemoresistance and can be used as potential tumor prognostic factors and targets for biological therapy. Thus, the current review focused on the role and relative mechanisms of the annexin A family in GC.

Organocatalytic Enantioselective Michael Reaction of Aminomaleimides with Nitroolefins Catalyzed by Takemoto's Catalyst.

Known as electrophiles, maleimides are often used as acceptors in Michael additions to produce succinimides. However, reactions with maleimides as nucleophiles for enantioselective functionalization are only rarely performed. In this paper, a series of bifunctional Takemoto's catalysts were used to organocatalyze the enantioselective Michael reaction of aminomaleimides with nitroolefins. The resulting products were obtained in good yields (76-86%) with up to 94% enantiomer excess (ee). The catalyst type and the substrate scope were broadened using this methodology.

Exosomes derived from hypoxic glioma deliver miR-1246 and miR-10b-5p to normoxic glioma cells to promote migration and invasion.

Hypoxia is an important feature of the tumor microenvironment and is associated with glioma progression and patient outcome. Exosomes have been implicated in the intercellular communication in the tumor microenvironment. However, the effects of hypoxic glioma exosomes on glioma migration and invasion and the underlying mechanisms remain poorly understood. In this study, we found that exosomes derived from hypoxic glioma cells (H-GDEs) promoted normoxic glioma migration and invasion in vitro and in vivo. Given that exosomes can regulate recipient cell functions by delivering microRNAs, we further revealed miR-1246 and miR-10b-5p were upregulated significantly in H-GDEs and delivered to normoxic glioma cells by H-GDEs. Moreover, we determined the clinical relevance of miR-1246 and miR-10b-5p in glioma patients. Subsequent investigations indicated that miR-1246 and miR-10b-5p markedly induced glioma migration and invasion in vitro and in vivo. Finally, we demonstrated that miR-1246 and miR-10b-5p induced glioma migration and invasion by directly targeting FRK and TFAP2A respectively. In conclusion, our findings suggest that the hypoxic microenvironment stimulates glioma to generate miR-1246- and miR-10b-5p-rich exosomes that are delivered to normoxic glioma cells to promote their migration and invasion; treatment targeting miR-1246 and miR-10b-5p may impair the motility of gliomas, providing a novel direction for the development of antitumor therapy.

Anti-Psoriatic Effects of Middle Fragment of Chlamydial Plasmid-Encoded Protein pGP3 in an Imiquimod-Induced Psoriasis Mouse Model.

BACKGROUND Previously, we demonstrated that the chlamydial protein pGP3 forms a stable complex with LL-37 to neutralize its proinflammatory activity during the pathogenesis of psoriasis. The middle domain of pGP3 (pGP3M) is critical for the binding and neutralization of LL-37. Here, we further examined the mechanism underlying pGP3-mediated inhibition of psoriasis progression and evaluated the inhibitory effect of pGP3M on the development of psoriasis-like skin lesions in mice. MATERIAL AND METHODS Stock solutions of pGP3M and pGP3 (100 µg/mL) were prepared using sterile ultrapure water and intramuscularly injected into the left leg of the imiquimod (IMQ)-induced psoriasis mouse model. The severity of skin lesions was evaluated based on the psoriasis area and severity index score and ear skin thickness. The skin biopsy and blood samples were collected on the 8th day for histological analysis and inflammatory cytokines detection. RESULTS Erythema, scaling, and thickening were observed on the dorsal skin and the right ear skin of IMQ-treated mice. Treatment with pGP3 and pGP3M alleviated the IMQ-induced erythema, inflammatory cell infiltration, and scaly plaques. Compared with IMQ-treated and PBS-treated mice, pGP3- and PGP3M-treated mice had less inflammatory cell infiltration in skin tissues and had significantly reduced IL-17A, IFN-γ, and IL-22 levels in serum. CONCLUSIONS The anti-psoriatic efficacy of exogenous pGP3M was similar to that of pGP3. This indicated that pGP3M attenuated the IMQ-induced inflammatory and psoriatic symptoms in mice by binding and inhibiting LL-37. Further research is needed to examine the toxicity of pGP3 and pGP3M before clinical trial evaluation.

Internal Mammary Sentinel Lymph Node Biopsy in Clinically Axillary Lymph Node-Positive Breast Cancer: Diagnosis and Implications for Patient Management.

BACKGROUND: Routine performance of internal mammary sentinel lymph node biopsy (IM-SLNB) remains a subject of debate due to no clinical relevance in breast cancer, because it was performed only in clinically axillary lymph node (ALN)-negative patients. In this study, IM-SLNB was performed in clinically ALN-positive patients, and its impact on nodal staging and therapeutic strategy were subsequently analyzed. METHODS: Clinically ALN-positive patients who underwent IM-SLNB were enrolled in this prospective study. Statistical analysis was performed using Chi square test, Mann-Whitney U and logistic regression models with a significance level of 0.05. RESULTS: Among the 352 recruited patients, the internal mammary sentinel lymph node (IMSLN) visualization rate of patients who received initial surgery and neoadjuvant systemic therapy (NST) was 71.9% (123/171) and 33.1% (60/181), respectively. The 183 patients who underwent IM-SLNB successfully had the average time duration of 7 min and the median IMSLN number of 2. There were 87 positive IMSLNs in all the 347 removed IMSLNs, which were mainly concentrated in the second (50.6%) and third (34.5%) intercostal space. The IMSLN metastasis rate was 39.8% (initial surgery) and 13.3% (NST), respectively. All of the 183 IM-SLNB patients received more accurate nodal staging, 57 of whom had stage elevated, which might have prompted modifications to the therapeutic strategy. CONCLUSIONS: IM-SLNB should be routinely performed in clinically ALN-positive patients, and thus more accurate nodal staging and perfect pathologic complete response definition could be put forward. The identification of IMLN metastases by IM-SLNB might potentially influence therapeutic strategies.

Correction to: Internal Mammary Sentinel Lymph Node Biopsy in Clinically Axillary Lymph Node-Positive Breast Cancer: Diagnosis and Implications for Patient Management.

The authors' affiliations are corrected as reflected here.

Targeting Chondroitin Sulfate Glycosaminoglycans to Treat Cardiac Fibrosis in Pathological Remodeling.

BACKGROUND: Heart failure is a leading cause of mortality and morbidity, and the search for novel therapeutic approaches continues. In the monogenic disease mucopolysaccharidosis VI, loss-of-function mutations in arylsulfatase B lead to myocardial accumulation of chondroitin sulfate (CS) glycosaminoglycans, manifesting as myriad cardiac symptoms. Here, we studied changes in myocardial CS in nonmucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling. METHODS: Healthy and diseased human and rat left ventricles were subjected to histological and immunostaining methods to analyze glycosaminoglycan distribution. Glycosaminoglycans were extracted and analyzed for quantitative and compositional changes with Alcian blue assay and liquid chromatography-mass spectrometry. Expression changes in 20 CS-related genes were studied in 3 primary human cardiac cell types and THP-1-derived macrophages under each of 9 in vitro stimulatory conditions. In 2 rat models of pathological remodeling induced by transverse aortic constriction or isoprenaline infusion, recombinant human arylsulfatase B (rhASB), clinically used as enzyme replacement therapy in mucopolysaccharidosis VI, was administered intravenously for 7 or 5 weeks, respectively. Cardiac function, myocardial fibrosis, and inflammation were assessed by echocardiography and histology. CS-interacting molecules were assessed with surface plasmon resonance, and a mechanism of action was verified in vitro. RESULTS: Failing human hearts displayed significant perivascular and interstitial CS accumulation, particularly in regions of intense fibrosis. Relative composition of CS disaccharides remained unchanged. Transforming growth factor-ß induced CS upregulation in cardiac fibroblasts. CS accumulation was also observed in both the pressure-overload and the isoprenaline models of pathological remodeling in rats. Early treatment with rhASB in the transverse aortic constriction model and delayed treatment in the isoprenaline model proved rhASB to be effective at preventing cardiac deterioration and augmenting functional recovery. Functional improvement was accompanied by reduced myocardial inflammation and overall fibrosis. Tumor necrosis factor-α was identified as a direct binding partner of CS glycosaminoglycan chains, and rhASB reduced tumor necrosis factor-α-induced inflammatory gene activation in vitro in endothelial cells and macrophages. CONCLUSIONS: CS glycosaminoglycans accumulate during cardiac pathological remodeling and mediate myocardial inflammation and fibrosis. rhASB targets CS effectively as a novel therapeutic approach for the treatment of heart failure.

Helicobacter pylori CagA promotes the malignant transformation of gastric mucosal epithelial cells through the dysregulation of the miR-155/KLF4 signaling pathway.

The Helicobacter pylori (H. pylori) cytotoxin-associated gene A (CagA) and Krüppel-like transcription factor (KLF4) were both closely associated with the development and progression of gastric cancer (GC). However, the nature of the interactions between CagA and KLF4 in GC development has not been elucidated. Therefore, we focused on the CagA-mediated promotion of the malignant transformation of gastric epithelial cells. Herein, we first examined the expression of KLF4 in both human cancer and paracarcinoma tissues with or without H. pylori infection and found that KLF4 expression was significantly decreased in H. pylori-positive GC cells compared with the H. pylori-negative GC cells. Further functional studies revealed that the increased expression of CagA could suppress KLF4 expression and promote the malignant transformation of normal epithelial cells. Subsequently, we found that CagA could upregulate miR-155 and further restrict the expression of downstream KLF4. More importantly, the overexpression of miR-155 in GES-1 promoted epithelial-mesenchymal transition and eventually facilitated tumor growth in vivo. Overall, the identification of the CagA/miR-155/KLF4 signaling pathway provided a new insight into the development and treatment of GC.

Genome-wide analysis of zinc- and iron-regulated transporter-like protein family members in apple and functional validation of ZIP10.

Deficiency of zinc (Zn) and iron (Fe) is common in apple grown in orchards, which affects fruit yield and quality. However, the mechanisms of absorption and transport of Zn and Fe in apples are still unclear. In the present study, we aimed to identify MdZIP genes and explore the mechanism of response of MdZIPs to Zn and Fe deficiencies. Eighteen Zn- and Fe-regulated transporter-like protein (ZIP) family members were identified in apple (Malus domestica L.) and named according to their chromosomal location. Phylogenetic analysis divided MdZIPs into four groups, and the most closely related MdZIPs in the phylogenetic tree showed similar gene structures and protein motifs. Expression pattern analysis indicated that ZIP genes in apple were differentially expressed among tissues and developmental stages under Zn and Fe deficiency. The overexpression of MdZIP10 increased the content of Zn and Fe in Arabidopsis thaliana L. and MdZIP10 played crucial roles in the uptake and transport of Zn and Fe. MdZIP10 was able to rescue growth of Zn2+ and Fe2+ uptake defective yeast mutants under Zn2+ and Fe2+ deficient conditions, respectively. Symptoms of Zn and Fe deficiency were alleviated in the MdZIP10 transgenic plants. The expression of genes related to Fe and Zn uptake and transport was induced in the MdZIP10 transgenic plants, thereby stimulating endogenous Fe and Zn uptake and transport mechanisms. The present study lays the foundation for future functional analysis of ZIP genes in apple.