Oral cancer cell to endothelial cell communication via exosomal miR-21/RMND5A pathway.

Required for meiotic nuclear division 5 homolog A (RMND5A), a novel ubiquitin E3 Ligase, has been reported to correlate with poor prognosis of several cancers. However, its role in endothelial cells has not been reported. In this study, overexpression of RMND5A in human umbilical vein endothelial cells (HUVECs) was performed via lentiviral infection, followed by MTT, would healing and tube formation assay as well as signaling analysis. Moreover, crosstalk between HUVECs and oral squamous cell carcinoma (OSCC) cells was investigated by indirect co-culture with condition medium or tumor cell derived exosomes. Our results showed that overexpression of RMND5A reduced the proliferation, migration and tube formation ability of HUVECs by inhibiting the activation of ERK and NF-κB pathway. Interestingly, OSCC cells can inhibit RMND5A expression of endothelial cells via exosomal miR-21. In summary, our present study unveils that OSCC cells can activate endothelial cells via exosomal miR-21/RMND5A pathway to promote angiogenesis, which may provide novel therapeutic targets for the treatment of OSCC.

Patterns of Spatial Variation in Rumen Microbiology, Histomorphology, and Fermentation Parameters in Tarim wapiti (Cervus elaphus yarkandensis).

The rumen is divided into multiple rumen sacs based on anatomical structure, and each has its unique physiological environment. Tarim wapiti preserved roughage tolerance after domestication, and adaptation to the desertified environment led to the development of a unique rumen shape and intraruminal environment. In this work, six Tarim wapiti were chosen and tested for fermentation parameters, microbes, and histomorphology in four rumen areas (Dorsal sac, DS; Ventral sac, VS; Caudodorsal blind sac, CDBS; Caudoventral blind sac, CVBS). Tarim wapiti's rumen blind sac had better developed rumen histomorphology, the ventral sac was richer in VFAs, and the dominant bacteria varied most notably in the phylum Firmicutes, which was enriched in the caudoventral blind sac. The ventral sac biomarkers focused on carbohydrate fermentation-associated bacteria, the dorsal sac focused on N recycling, and the caudoventral blind sac identified the only phylum-level bacterium, Firmicutes; we were surprised to find a probiotic bacterium, Bacillus clausii, identified as a biomarker in the ventral sac. This research provides a better understanding of rumen fermentation parameters, microorganisms, and histomorphology in the Tarim wapiti rumen within a unique ecological habitat, laying the groundwork for future regulation targeting the rumen microbiota and subsequent animal production improvement.

M6A Demethylase Inhibits Osteogenesis of Dental Follicle Stem Cells via Regulating miR-7974/FKBP15 Pathway.

N6-methyladenosine (m6A) is the most abundant RNA modification, regulating gene expression in physiological processes. However, its effect on the osteogenic differentiation of dental follicle stem cells (DFSCs) remains unknown. Here, m6A demethylases, the fat mass and obesity-associated protein (FTO), and alkB homolog 5 (ALKBH5) were overexpressed in DFSCs, followed by osteogenesis assay and transcriptome sequencing to explore potential mechanisms. The overexpression of FTO or ALKBH5 inhibited the osteogenesis of DFSCs, evidenced by the fact that RUNX2 independently decreased calcium deposition and by the downregulation of the osteogenic genes OCN and OPN. MiRNA profiling revealed that miR-7974 was the top differentially regulated gene, and the overexpression of m6A demethylases significantly accelerated miR-7974 degradation in DFSCs. The miR-7974 inhibitor decreased the osteogenesis of DFSCs, and its mimic attenuated the inhibitory effects of FTO overexpression. Bioinformatic prediction and RNA sequencing analysis suggested that FK506-binding protein 15 (FKBP15) was the most likely target downstream of miR-7974. The overexpression of FKBP15 significantly inhibited the osteogenesis of DFSCs via the restriction of actin cytoskeleton organization. This study provided a data resource of differentially expressed miRNA and mRNA after the overexpression of m6A demethylases in DFSCs. We unmasked the RUNX2-independent effects of m6A demethylase, miR-7974, and FKBP15 on the osteogenesis of DFSCs. Moreover, the FTO/miR-7974/FKBP15 axis and its effects on actin cytoskeleton organization were identified in DFSCs.

Overexpression of RAB27A in Oral Squamous Cell Carcinoma Promotes Tumor Migration and Invasion via Modulation of EGFR Membrane Stability.

Oral squamous cell carcinoma (OSCC) is the most prevalent subtype of head and neck tumors, highly prone to lymph node metastasis. This study aims to examine the expression pattern of Ras-related protein Rab-27A (RAB27A) and explore its potential implications in OSCC. The expression of RAB27A was assessed through immunohistochemical analysis utilizing tissue microarrays. In vitro experiments were conducted using RAB27A-knockdown cells to investigate its impact on OSCC tumor cells. Additionally, transcriptome sequencing was performed to elucidate potential underlying mechanisms. RAB27A was significantly overexpressed in OSCC, and particularly in metastatic lymph nodes. It was positively correlated with the clinical progression and poor survival prognosis. Silencing RAB27A notably decreased the proliferation, migration, and invasion abilities of OSCC cells in vitro. A Gene Ontology (GO) enrichment analysis indicated a strong association between RAB27A and the epidermal growth factor receptor (EGFR) signaling pathway. Further investigations revealed that RAB27A regulated the palmitoylation of EGFR via zinc finger DHHC-type containing 13 (ZDHHC13). These findings provide insights into OSCC progression and highlight RAB27A as a potential therapeutic target for combating this aggressive cancer.

RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils.

The transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancy (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 was shown to regulate inflammation in multiple cell types. Here we show that RUNX1 is required in granulocyte-monocyte progenitors (GMPs) to epigenetically repress two inflammatory signaling pathways in neutrophils: Toll-like receptor 4 (TLR4) and type I interferon (IFN) signaling. RUNX1 loss in GMPs augments neutrophils' inflammatory response to the TLR4 ligand lipopolysaccharide through increased expression of the TLR4 coreceptor CD14. RUNX1 binds Cd14 and other genes encoding proteins in the TLR4 and type I IFN signaling pathways whose chromatin accessibility increases when RUNX1 is deleted. Transcription factor footprints for the effectors of type I IFN signaling-the signal transducer and activator of transcription (STAT1::STAT2) and interferon regulatory factors (IRFs)-were enriched in chromatin that gained accessibility in both GMPs and neutrophils when RUNX1 was lost. STAT1::STAT2 and IRF motifs were also enriched in the chromatin of retrotransposons that were derepressed in RUNX1-deficient GMPs and neutrophils. We conclude that a major direct effect of RUNX1 loss in GMPs is the derepression of type I IFN and TLR4 signaling, resulting in a state of fixed maladaptive innate immunity.

Is it safe and effective to extract impacted maxillary tooth adjacent to maxillary sinus via submaxillary sinus membrane space approach?-a randomized controlled trial.

OBJECTIVE: To evaluate the clinical outcomes following extraction of impacted maxillary tooth adjacent to maxillary via submaxillary sinus membrane space approach. MATERIALS AND METHODS: Seventy-two patients were enrolled in our study. The positions of the maxillary impacted tooth were confirmed by cone-beam computed tomography (CBCT). Cases were randomly divided into two groups: the "submaxillary sinus membrane space approach" was applied in the new method (NM) group, and the conventional "avoid maxillary sinus membrane exposure" strategy was executed in the traditional method (TM) group. The clinical and follow-up data were recorded. RESULTS: The duration of the procedure in the TM group was significantly longer than those in the NM group (P < 0.05). Four teeth were accidentally displaced into the maxillary sinus with MSM perforation. The MSM perforation rate was slightly higher in the TM group than in the NM group, however, without significant difference between the two groups (8/36 vs. 3/36, P = 0.19). The maxillary sinus membrane perforation was associated with the displacement of tooth into the maxillary sinus (OR = 16.2, P = 0.026). The root tip exposure of the adjacent tooth was significantly higher in the TM group than in the NM group (10/36 vs. 1/36, P = 0.006). The incidence of reduced pulp vitality of the adjacent tooth was significantly higher in the TM group (10/36 vs. 1/36, P = 0.006), and it was associated with the exposure of the root tip intraoperatively (OR = 456.5, P < 0.001). The incidence of external root resorption was significantly lower in the NM group, and there was no significant association with the root exposure intraoperatively (OR = 3.7, P = 0.47). CONCLUSIONS: Submaxillary sinus membrane space approach is a safe and efficient approach in extraction of impacted maxillary tooth. It is an alternative way for cases which are in close proximity to the maxillary sinus. CLINICAL RELEVANCE: A novel method to extract impacted maxillary tooth adjacent to maxillary sinus.

RAB27B controls palmitoylation-dependent NRAS trafficking and signaling in myeloid leukemia.

RAS mutations are among the most prevalent oncogenic drivers in cancers. RAS proteins propagate signals only when associated with cellular membranes as a consequence of lipid modifications that impact their trafficking. Here, we discovered that RAB27B, a RAB family small GTPase, controlled NRAS palmitoylation and trafficking to the plasma membrane, a localization required for activation. Our proteomic studies revealed RAB27B upregulation in CBL- or JAK2-mutated myeloid malignancies, and its expression correlated with poor prognosis in acute myeloid leukemias (AMLs). RAB27B depletion inhibited the growth of CBL-deficient or NRAS-mutant cell lines. Strikingly, Rab27b deficiency in mice abrogated mutant but not WT NRAS-mediated progenitor cell growth, ERK signaling, and NRAS palmitoylation. Further, Rab27b deficiency significantly reduced myelomonocytic leukemia development in vivo. Mechanistically, RAB27B interacted with ZDHHC9, a palmitoyl acyltransferase that modifies NRAS. By regulating palmitoylation, RAB27B controlled c-RAF/MEK/ERK signaling and affected leukemia development. Importantly, RAB27B depletion in primary human AMLs inhibited oncogenic NRAS signaling and leukemic growth. We further revealed a significant correlation between RAB27B expression and sensitivity to MEK inhibitors in AMLs. Thus, our studies presented a link between RAB proteins and fundamental aspects of RAS posttranslational modification and trafficking, highlighting future therapeutic strategies for RAS-driven cancers.

Conformational Changes of Acyl Carrier Protein Switch the Chain Length Preference of Acyl-ACP Thioesterase ChFatB2.

Microbial fatty acids are synthesized by Type II fatty acid synthase and could be tailored by acyl-ACP thioesterase. With the prospects of medium-chain fatty-acid-derivative biofuels, the selectivity of thioesterase has been studied to control the fatty acid product chain length. Here, we report an alternative approach by manipulating the acyl carrier protein portion of acyl-ACP to switch the chain length propensity of the thioesterase. It was demonstrated that ChFatB2 from Cuphea hookeriana preferred C10-ACP to C8-ACP with ACP from E. coli, while converting preference to C8-ACP with ACP from Cuphea lanceolate. Circular dichroism (CD) results indicated that the C8-EcACP encountered a 34.4% α-helix increment compared to C10-EcACP, which resulted in an approximate binding affinity decrease in ChFatB2 compared to C10-EcACP. Similarly, the C10-ClACP2 suffered a 45% decrease in helix content compared to C8-ClACP2, and the conformational changes resulted in an 18% binding affinity decline with ChFatB2 compared with C10-ClACP2. In brief, the study demonstrates that the ACP portion of acyl-ACP contributes to the selectivity of acyl-ACP thioesterase, and the conformational changes of EcACP and ClACP2 switch the chain length preference of ChFatB2 between C8 and C10. The result provides fundamentals for the directed synthesis of medium-chain fatty acids based on regulating the conformational changes of ACPs.

RUNX1 is required in granulocyte-monocyte progenitors to attenuate inflammatory cytokine production by neutrophils.

The transcription factor RUNX1 is mutated in familial platelet disorder with associated myeloid malignancies (FPDMM) and in sporadic myelodysplastic syndrome and leukemia. RUNX1 regulates inflammation in multiple cell types. Here we show that RUNX1 is required in granulocyte-monocyte progenitors (GMPs) to restrict the inflammatory response of neutrophils to toll-like receptor 4 (TLR4) signaling. Loss of RUNX1 in GMPs increased the TLR4 coreceptor CD14 on neutrophils, which contributed to neutrophils’ increased inflammatory cytokine production in response to the TLR4 ligand lipopolysaccharide. RUNX1 loss increased the chromatin accessibility of retrotransposons in GMPs and neutrophils and induced a type I interferon signature characterized by enriched footprints for signal transducer and activator of transcription (STAT1::STAT2) and interferon regulatory factors (IRF) in opened chromatin, and increased expression of interferon-stimulated genes. The overproduction of inflammatory cytokines by neutrophils was reversed by inhibitors of type I IFN signaling. We conclude that RUNX1 restrains the chromatin accessibility of retrotransposons in GMPs and neutrophils, and that loss of RUNX1 increases proinflammatory cytokine production by elevating tonic type I interferon signaling.

The prospective multiple-centre randomized controlled clinical study of high-dose amoxicillin-proton pump inhibitor dual therapy for H. pylori infection in Sichuan areas.

OBJECTIVES: To evaluate the safety and efficacy of high-dose amoxicillin-proton pump inhibitor dual therapy, and to provide a new eradication regimen as a first-line option for patients with H. pylori infection. METHODS: A total of 971 H. pylori positive patients who received initial treatment were recruited from March to August 2020, and randomly divided into treatment group and control group. The treatment group received of 20 mg esomeprazole four times daily and 750 mg amoxicillin four times daily for 14 days. Control group received of 220 mg bismuth potassium citrate twice daily, 20 mg esomeprazole twice daily, 1000 mg amoxicillin twice daily and 250 mg clarithromycin capsule twice daily for 14 days. Four weeks after the end of treatment, the urea breath test was reviewed to detect whether H. pylori was eradicated. RESULTS: There were no statistical differences in age, gender, the total clinical symptom scores before and after initial treatment, the compliance, and the degree of remission of symptoms before and after initial treatment between the two groups. The eradication rates of H. pylori between dual therapy and quadruple therapy were 88.31% and 85.26% (p=.158) by intention-to-treat (ITT) analysis, 88.66% and 85.44% (p=.186) by modified intention-to-treat (mITT) analysis, and 91.63% and 90.60% (p=.116) by PP analysis, respectively. Adverse events in dual therapy group were significantly lower than quadruple therapy group (13.3% vs. 28.2% (p<.01)). CONCLUSIONS: For the initial treatment of H. pylori infection, the high-dose dual therapy regimen has the same efficacy as the bismuth-containing quadruple therapy regimen, good compliance, less adverse reactions and high safety, so it can be recommended as the empirical first-line treatment regimen for the eradication of H. pylori (KY2019173).

Downregulation of microRNA-21 contributes to decreased collagen expression in venous malformations via transforming growth factor-ß/Smad3/microRNA-21 signaling feedback loop.

OBJECTIVE: Venous malformations (VMs) are the most frequent vascular malformations and are characterized by dilated and tortuous veins with a dysregulated vascular extracellular matrix. The purpose of the present study was to investigate the potential involvement of microRNA-21 (miR-21), a multifunctional microRNA tightly associated with extracellular matrix regulation, in the pathogenesis of VMs. METHODS: The expression of miR-21, collagen I, III, and IV, transforming growth factor-ß (TGF-ß), and Smad3 (mothers against decapentaplegic homolog 3) was evaluated in VMs and normal skin tissue using in situ hybridization, immunohistochemistry, Masson trichrome staining, and real-time polymerase chain reaction. Human umbilical vein endothelial cells (HUVECs) were used to explore the underlying mechanisms. RESULTS: miR-21 expression was markedly decreased in the VM specimens compared with normal skin, in parallel with downregulation of collagen I, III, and IV and the TGF-ß/Smad3 pathway in VMs. Moreover, our data demonstrated that miR-21 positively regulated the expression of collagens in HUVECs and showed a positive association with the TGF-ß/Smad3 pathway in the VM tissues. In addition, miR-21 was found to mediate TGF-ß-induced upregulation of collagens in HUVECs. Our data have indicated that miR-21 and the TGF-ß/Smad3 pathway could form a positive feedback loop to synergistically regulate endothelial collagen synthesis. In addition, TGF-ß/Smad3/miR-21 feedback loop signaling was upregulated in bleomycin-treated HUVECs and VM specimens, which was accompanied by increased collagen deposition. CONCLUSIONS: To the best of our knowledge, the present study has, for the first time, revealed downregulation of miR-21 in VMs, which might contribute to decreased collagen expression via the TGF-ß/Smad3/miR-21 signaling feedback loop. These findings provide new information on the pathogenesis of VMs and might facilitate the development of new therapies for VMs.

Depalmitoylation rewires FLT3-ITD signaling and exacerbates leukemia progression.

Internal tandem duplication within FLT3 (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and correlates with a poor prognosis. Whereas the FLT3 receptor tyrosine kinase is activated at the plasma membrane to transduce PI3K/AKT and RAS/MAPK signaling, FLT3-ITD resides in the endoplasmic reticulum and triggers constitutive STAT5 phosphorylation. Mechanisms underlying this aberrant FLT3-ITD subcellular localization or its impact on leukemogenesis remain poorly established. In this study, we discovered that FLT3-ITD is S-palmitoylated by the palmitoyl acyltransferase ZDHHC6. Disruption of palmitoylation redirected FLT3-ITD to the plasma membrane and rewired its downstream signaling by activating AKT and extracellular signal-regulated kinase pathways in addition to STAT5. Consequently, abrogation of palmitoylation increased FLT3-ITD-mediated progression of leukemia in xenotransplant-recipient mouse models. We further demonstrate that FLT3 proteins were palmitoylated in primary human AML cells. ZDHHC6-mediated palmitoylation restrained FLT3-ITD surface expression, signaling, and colonogenic growth of primary FLT3-ITD+ AML. More important, pharmacological inhibition of FLT3-ITD depalmitoylation synergized with the US Food and Drug Administration-approved FLT3 kinase inhibitor gilteritinib in abrogating the growth of primary FLT3-ITD+ AML cells. These findings provide novel insights into lipid-dependent compartmentalization of FLT3-ITD signaling in AML and suggest targeting depalmitoylation as a new therapeutic strategy to treat FLT3-ITD+ leukemias.

HectD1 controls hematopoietic stem cell regeneration by coordinating ribosome assembly and protein synthesis.

Impaired ribosome function is the underlying etiology in a group of bone marrow failure syndromes called ribosomopathies. However, how ribosomes are regulated remains poorly understood, as are approaches to restore hematopoietic stem cell (HSC) function loss because of defective ribosome biogenesis. Here we reveal a role of the E3 ubiquitin ligase HectD1 in regulating HSC function via ribosome assembly and protein translation. Hectd1-deficient HSCs exhibit a striking defect in transplantation ability and ex vivo maintenance concomitant with reduced protein synthesis and growth rate under stress conditions. Mechanistically, HectD1 ubiquitinates and degrades ZNF622, an assembly factor for the ribosomal 60S subunit. Hectd1 loss leads to accumulation of ZNF622 and the anti-association factor eIF6 on 60S, resulting in 60S/40S joining defects. Importantly, Znf622 depletion in Hectd1-deficient HSCs restored ribosomal subunit joining, protein synthesis, and HSC reconstitution capacity. These findings highlight the importance of ubiquitin-coordinated ribosome assembly in HSC regeneration.

The YAP signaling pathway promotes the progression of lymphatic malformations through the activation of lymphatic endothelial cells.

BACKGROUND: To investigate whether the YAP/TAZ (Yes-associated protein/transcriptional coactivator with PDZ binding motif) pathway contributes to the pathogenesis of lymphatic malformations (LMs). METHODS: YAP, TAZ, CTGF (connective tissue growth factor), and Ki-67 were detected in LMs by immunohistochemistry. The colocalization of YAP and Ki-67 was analyzed by double immunofluorescence. Pearson's correlation and cluster analyses were performed to analyze the relationships between these proteins. Human dermal lymphatic endothelial cells (HDLECs) were used for mechanistic investigation. Rat models of LMs were established to investigate the role of the YAP pathway in LM development. RESULTS: Compared with those in normal skin, the expression levels of YAP, TAZ, CTGF, and Ki-67 were significantly upregulated in lymphatic endothelial cells (LECs) of LMs. Interestingly, YAP and CTGF presented much higher expression levels in infected LMs. In experiments in vitro, lipopolysaccharide (LPS) enhanced the expression of YAP in a concentration- and time-dependent manner via the increased phosphorylation of Erk1/2 (extracellular signal-regulated kinase 1/2). Moreover, the proliferation, invasion, and tubule formation of HDLECs increased significantly in accordance with the activation of the YAP signaling pathway. Furthermore, LM rat models validated that LPS facilitated the development of LMs, which was dependent on the activation of YAP. CONCLUSIONS: The data reveal that activation of the YAP signaling pathway in LECs may play a crucial role in the progression of LMs. IMPACT: Compared with that in normal skin, the YAP signaling pathway was activated in LECs of LMs. Inhibiting the YAP signaling pathway attenuated the proliferation, invasion, and tubule formation of HDLECs. Additionally, the activation of the YAP signaling pathway could promote LM development in a rat model. Activation of the YAP signaling pathway in LECs may play a crucial role in the progression of LMs. The YAP signaling pathway was activated in LMs. Inhibition of the YAP signaling pathway could promote regression of the lesions.

Bleomycin: A novel osteogenesis inhibitor of dental follicle cells via a TGF-ß1/SMAD7/RUNX2 pathway.

BACKGROUND AND PURPOSE: Tooth eruption is a complicated process regulated by the dental follicles (DF). Our recent study discovered that tooth eruption was inhibited upon injection of bleomycin into DF. However, the mechanisms were unknown. EXPERIMENTAL APPROACH: Human dental follicle cells (hDFCs) were treated by bleomycin or exogenous TGF-ß1 or transfected by plasmids loading SMAD7 or shRNA targeting SMAD7, followed by osteogenesis induction assay and signalling analysis. Human fresh DF tissues and Wistar rats were used to further confirm bleomycin function. KEY RESULTS: Bleomycin decreased expression of RUNX2 and osteogenic genes in hDFCs, reducing osteogenic capacity. TGF-ß1 expression was up-regulated in bleomycin-treated hDFCs. The effects of exogenous TGF-ß1 were similar to those of bleomycin in hDFCs. Additionally, compared to SMAD2/3, SMAD7 expression increased more in bleomycin- or TGF-ß1-treated hDFCs. Overexpression of SMAD7 likewise significantly decreased RUNX2 expression and osteogenic capacity of hDFCs. Knockdown of SMAD7 markedly attenuated the inhibitory effects of bleomycin and TGF-ß1 on osteogenic capacity and RUNX2 expression of hDFCs. Most importantly, changes in TGF-ß1, SMAD7, and RUNX2 expressions were similar in the DF of rats and humans treated with bleomycin. CONCLUSION AND IMPLICATIONS: SMAD7 was a negative regulator of osteogenic differentiation in DFCs through suppressing RUNX2 expression. Bleomycin or TGF-ß1 inhibited osteogenic differentiation of DFCs via a TGF-ß1/SMAD7/RUNX2 pathway. Our findings might be beneficial for enhancing the osteogenic activity of DFCs or inhibiting the eruption of undesirable teeth.

Nitrogen and sulfur codoped micro-mesoporous carbon sheets derived from natural biomass for synergistic removal of chromium(VI): adsorption behavior and computing mechanism.

We reported the effective removal of chromium(VI) (Cr(VI)) from wastewater with nitrogen and sulfur codoped micro-mesoporous carbon sheets (N,S-MMCSs), which were fabricated by pyrolysis of natural biomass (luffa sponge) followed by chemical activation and hydrothermal treatment. N,S-MMCSs possessed a hierarchical micro-mesoporous sheet-like framework, large specific surface area (1525.45 m2 g-1), high pore volume (1.21 cm3 g-1), and appropriate N (1.81 wt%) and S (1.01 wt%) co-doping. Batch adsorption experiments suggested that Cr(VI) adsorption by the N,S-MMCSs increased with increase the solution acidity, adsorbent dosage, Cr(VI) concentration, temperature, and time. The Cr(VI) adsorption was mainly controlled by the chemisorptions and could be well interpreted by the Langmuir isotherm and pseudo-second-order kinetic models. The maximum adsorption capacities of Cr(VI) were 217.39, 277.78, and 312.50 mg g-1 at 298, 308, and 318 K, respectively. The Cr(VI) adsorption procedure was spontaneous, endothermic, and randomness. The Cr(VI) adsorption mechanism followed the physical adsorption, electrostatic attraction, in situ reduction, and surface chelation. Besides, the density functional theory (DFT) calculation demonstrated that the N and S co-doping could decrease the adsorption energy and enhance the attractive interaction between N,S-MMCSs and Cr(VI) through the synergistic effect, and thus significantly improve the Cr(VI) adsorption property.

Downregulation of lysyl oxidase in venous malformations: Association with vascular destabilization and sclerotherapy.

Venous malformations (VM) are localized defects in vascular morphogenesis manifested by dilated venous channels with reduced perivascular cell coverage. As a vital enzyme for extracellular matrix (ECM) deposition, lysyl oxidase (LOX) plays important roles in vascular development and diseases. However, the expression and significance of LOX are unknown in VM. Herein, 22 VM specimens and eight samples of normal skin tissues were evaluated immunohistochemically for the expression of LOX, α-smooth muscle cell actin (α-SMA) and transforming growth factor-ß (TGF-ß). In vitro studies on human umbilical vein endothelial cells (HUVEC) were employed for determining potential mechanisms. Our results showed that LOX expression was significantly reduced in VM compared with normal skin tissues, in parallel with attenuated perivascular α-SMA+ cell coverage and TGF-ß downregulation in VM. Further correlation analysis indicated that LOX expression was positively correlated with perivascular α-SMA+ cell coverage and TGF-ß expression in VM. Moreover, marked elevation of LOX, TGF-ß and α-SMA was observed in bleomycin-treated VM samples. Furthermore, our in vitro data demonstrated that both recombinant TGF-ß and bleomycin induced obvious increase of LOX expression and activity and a concomitant increase in ECM components in HUVEC, which could be reversed by LOX inhibition. To our best knowledge, this study revealed for the first time the downregulation of LOX in VM and its correlation with vascular destabilization and TGF-ß-induced endothelial ECM deposition. Moreover, our results highlighted that LOX may be implicated in the sclerotherapy of VM and holds promise as a therapeutic target.

Effects of bleomycin on tooth eruption: a novel potential application.

There are many kinds of potentially undesirable teeth. At present, surgical extraction is the most efficient way to eliminate these teeth, but it's very complex and invasive. In this study, we investigated the effects of bleomycin (BLM) on dental follicle and tooth eruption as a potential conservative therapy for undesirable teeth. Our data showed that local injection of 0.2 U/kg BLM had no significant effects on tooth eruption compared to the control group in Wistar rats. With higher dose of BLM (0.5 or 2 U/kg), the eruption of treated teeth was interrupted and their root formation failed until 4 weeks postnatal without significant systemic toxicity. Additionally, those effects were not depending on the toxicity of overdose evidenced by TUNEL assay. In summary, injecting BLM into dental follicle at an early stage could interrupt tooth development and eruption, and may prevent the potentially clinical problems resulting from undesirable teeth instead of surgical removal.

Magnetic Chip Based Extracorporeal Circulation: A New Tool for Circulating Tumor Cell in Vivo Detection.

In vivo detection of circulating tumor cells (CTCs) which inspect all of the circulating blood in body seems to have more advantages on cell capture, especially in earlier cancer diagnosis. Herein, based on in vivo microfluidic chip detection system (IV-chip-system), an extracorporeal circulation was constructed to effectively detect and monitor CTCs in vivo. Combined with microfluidic chip and immunomagnetic nanosphere (IMN), this system not only acts as a window for CTC monitoring but also serves as a collector for further cancer diagnosis and research on CTCs. Compared with the current in vivo detection method, this system can capture and detect CTCs in the bloodstream without any pretreatments, and it also has a higher CTC capture efficiency. It is worth mentioning that this system is stable and biocompatible without any irreversible damage to living animals. Taking use of this system, the mimicked CTC cleanup process in the blood vessel is monitored, which may open new insights in cancer research and early cancer diagnosis.