Interleukin 6-triggered ataxia-telangiectasia mutated kinase activation facilitates epithelial-to-mesenchymal transition in lung cancer by upregulating vimentin expression.

Matrix metalloproteinases (MMPs) and the epithelial-mesenchymal transition (EMT) contribute to metastasis. As shown in our previous studies, interleukin-6 (IL-6) induces ATM phosphorylation to increase MMP expression and metastasis in lung cancer. However, the exact roles of ATM activation in the IL-6-induced epithelial-mesenchymal transition and lung cancer metastasis are currently unclear. Here, ATM phosphorylation exerts its pro-metastatic effect via vimentin-mediated epithelial-mesenchymal transition, which was supported by the evidence described below. Firstly, IL-6 treatment increases vimentin expression via the ATM-NF-κB pathway. Second, ATM inactivation not only abolishes IL-6-induced increases in vimentin expression but also inhibits IL-6-induced nest formation in a xenograft lung metastasis model. Moreover, close positive correlations were observed between ATM phosphorylation and vimentin upregulation, IL-6 levels and metastasis in lung cancer specimens. Hence, ATM modulates vimentin expression to facilitate IL-6-induced epithelial-mesenchymal transition and metastasis in lung cancer, indicating that ATM and vimentin might be potential therapeutic targets for inflammation-associated lung cancer metastasis.

Preparation of novel cisplatin-conjugated hollow gold nanospheres for targeting cervical cancer.

Cervical cancer is a deadly gynecological malignancy in need of innovative treatment strategies. Emerging preclinical data has suggested the benefits of nanocarriers over the traditional chemotherapy for cancer treatment. In particular, gold nanoparticles are gaining popularity due to gold's inert nature, limited side effects, good cytocompatibility, and flexibility in preparation/modification. We conjugated polyethylene glycol (PEG) with hollow gold nanospheres (HGNs) and loaded the pegylated HGNs with an anticancer drug, cisplatin to target cervical cancer. HGNs were irradiated with noninfrared laser to increase the penetration of drug into tumor tissue and improve the delivery of cisplatin. We investigated the comparative characterization studies of prepared cisplatin loaded pegylated HGNs (cis PEG-HGNs), free cisplatin, cisplatin loaded HGNs (cis-HGNs), cis PEG-HGNs without laser, and cis PEG-HGNs with laser and its effects over cervical cancer cells. Transmission electron microscopy photomicrographs confirmed the integrity of prepared HGNs. While no significant difference was observed between encapsulation efficiency and drug loading of cis-HGNs (84.6%) and cis PEG-HGNs (86.7%), the encapsulation efficiency increased almost twice in HGNs, compared with control gold nanoparticles (GNs) because of the hollow cavity in HGNs. In-vitro cytotoxicity was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using HeLa cells. With irradiation, HGNs induced much elevated cytotoxicity. Not only HGNs were internalized by HeLa cells, they were retained in the cellular compartment. We also tested formulations in vivo and observed that the irradiated cis-HGNs and cis PEG-HGNs were most effective in regressing tumors in mice.

Let-7g inhibits synthesis of estradiol by downregulating activity of aromatase in JEG3 cells.

BACKGROUND: Increased production of estrogen in human placenta during pregnancy closely associates with parturition. Aromatase, encoded by CYP19A1 gene, is an enzyme critical for biosynthesis of estrogen. Despite numerous efforts in the past few decades ascribed to characterizing the mechanisms of transcriptional control of aromatase, the posttranscriptional control of CYP19A1 remains poorly understood. OBJECTIVE: In this study, we sought to investigate the role of microRNA, let-7g, in posttranscriptional regulation of aromatase in human trophoblast choriocarcinoma cell line, JEG3. METHODS AND RESULTS: We show that the expression of let-7g was downregulated in JEG3 cell line, but upregulated in primary term trophoblast; conversely, aromatase was upregulated in JEG3 but downregulated in primary trophoblast. We further show that let-7g antagomirs and mimics increased and decreased aromatase expression, respectively; and let-7g directly targeted 3'-untranslated region of CYP19A1 mRNA by using dual luciferase assay. Using ELISA, we also demonstrate that let-7g antagomirs and mimics robustly increased and decreased production of estradiol, respectively. DISCUSSION: Our results suggest that aromatase expression is regulated at multiple molecular layers in the placenta. These results further suggest that JEG3 cell line is a valuable tool to study additional mechanisms associated with human birth.

[Penis growth and development in children and adolescents: a study based on GAMLSS].

OBJECTIVE: To investigate penis development in children and adolescents aged 0-16 years, and to plot the percentile curve for penis development in different age groups. METHODS: A total of 3 024 normal male neonates, children, and adolescents aged 0-16 years in Chongqing, China were selected by simple random sampling and stratified cluster sampling. The length and diameter of the penis were measured for all subjects. A descriptive statistical analysis was used to investigate the data characteristics of the penis, and the GAMLSS fitting model was used to plot the percentile curves of P3, P10, P25, P50, P75, P90, and P97 and obtain percentile reference values. RESULTS: The length and diameter of the penis grew rapidly before the age of 1 year, grew relatively slowly from 1 to 11 years old, and entered a rapid growth period from 11 years old. The length of the penis was positively correlated with its diameter (r=0.961, P<0.01). The percentile reference values of penis length and diameter were obtained and the percentile curve was plotted. CONCLUSIONS: The growth and development of penis length is consistent with that of penis diameter in male children and adolescents in Chongqing, and 0-1 year and 11-16 years are rapid growth periods of penis length and diameter. The percentile curve of penis length and diameter in children and adolescents aged 0-16 years in Chongqing which has been established will provide a reference for further studies on sexual development in children and adolescents.

[Analysis of Pfcrt Gene Polymorphism in Imported Falciparum Malaria Cases in Henan Province in 2015].

Objective: To analyze Plasmodium falciparum chloroquine resistant transporter (Pfcrt) gene polymorphism in imported falciparum malaria cases in Henan Province in 2015. Methods: Blood samples were collected from 132 cases of imported falciparum malaria in Henan Province in 2015. DNA was extracted from the samples, and the Pfcrt was amplified by nested PCR using specific primers. The PCR products were digested by restriction endonuclease enzyme Apol I and sequenced. Pfcrt gene polymorphism and distribution were analyzed. Results: Most of the 132 cases of imported malaria were young male adults returning from the Africa, with the highest percentage in those from West Africa（38.6%, 51/132）, then Central Africa（26.5%, 35/132）, South Africa（25.0%, 33/132）, East Africa（8.3%, 11/132）, and North Africa（1.5%, 2/132）. The nested PCR yielded a 145-bp product for each sample, and 66.7%（88/132） of the products were completely digested by Apol I, resulting in two fragments of 114 bp and 31 bp; 32.6%（43/132） could not been digested and only a single fragment of 145 bp was shown; and 0.8%（1/132） were incompletely digested, yielding three fragments of 145 bp, 114 bp and 31 bp. By blasting against chloroquine sensitive strain 3D7, we found mutations of Pfcrt at sites correspondig to residues 74, 75 and 76 from ATG, AAT and AAA to ATT, GAA and ACA （i.e. M74I, N75E and K76T） in 43 of the 132 blood samples, and mixed type mutations into ATG/T, A/GAA/T and AA/CA at sites correspondig to residues 74, 75 and 76（CVM/I, N/E/D/K, T/K） in one blood sample. The other 88 blood samples showed a wild type with no mutation (CVMNK). Mutations occurred mainly in cases from West Africa（41.2%, 21/51）, then East Africa（36.4%, 4/11）, South Africa（30.3%, 10/33）, and Central Africa（22.9%, 8/27）（χ2=4.07, P＞0.05）. The 2 cases from the North Africa both had wild type Pfcrt; the one with mixed type mutation was from West Africa. Conclusion: Three haplotypes of Pfcrt have been found, including wild type (CVMNK), mutation type (CVIET) and mixed type (CVM/I, N/E/D/K, K/T) in the imported malaria cases. The wild type occupies the highest proportion （66.7%）, while the mutation type possesses a high proportion of 41.2% in cases from West Africa.

[Diagnostic analysis for 52 cases of gastrointestinal neuroendocrine tumor].

OBJECTIVE: To investigate the clinical features, diagnosis, treatments and prognosis for gastrointestinal neuroendocrine tumors (GI-NETs).
 METHODS: Clincal data of 52 patients, who were diagnosed as GI-NETs between January 2004 and October 2014, were reviewed. The patients were divided into a local excision group (n=21) and a transabdominal excision group (n=30), and the major clinical features, treatment modalities and outcomes were analyzed.
 RESULTS: The clinical features of GI-NETs were nonspecific, and most of the clinical manifestation were local invasiveness. CT scan was lack of specific findings. GI-NETs greater than 1 cm often showed local incrassation, upheaval and soft tissue shadow. In the case of lager GI-NETs, necrosis and moderate enhancement could be seen. Positive ratio for expression of chromogranin A (CgA) and synaptophysin (Syn) in the 52 cases of specimen were 63.5% and 88.5%, respectively. Except 1 patient, whose surgery was canceled because of poor health, other 51 patients were treated with surgery through different approaches. Among them, 30 cases were transabdominal resection (57.7%) and 21 were local resection (40.4%). Chemotherapy and/or radiotherapy was only applied for 7 patients. After a follow-up of 40 (3-132) months, 7 patients died, the rest were alive. The median survival in the local resection group and the transabdominal resection group was 43.0 and 39.5 months, respectively (P>0.05).
 CONCLUSION: Under the condition of fully understanding the biological characteristics of GI-NETs, early diagnosis and timely personalized treatment is hopeful to reach the relative good prognosis and survival.

Insights into salt tolerance from the genome of Thellungiella salsuginea.

Thellungiella salsuginea, a close relative of Arabidopsis, represents an extremophile model for abiotic stress tolerance studies. We present the draft sequence of the T. salsuginea genome, assembled based on ~134-fold coverage to seven chromosomes with a coding capacity of at least 28,457 genes. This genome provides resources and evidence about the nature of defense mechanisms constituting the genetic basis underlying plant abiotic stress tolerance. Comparative genomics and experimental analyses identified genes related to cation transport, abscisic acid signaling, and wax production prominent in T. salsuginea as possible contributors to its success in stressful environments.

Interleukin 6 augments lung cancer chemotherapeutic resistance via ataxia-telangiectasia mutated/NF-kappaB pathway activation.

Although it is known that ataxia-telangiectasia mutated (ATM) and interleukin 6 (IL-6) contribute to multiple drug resistance (MDR) in tumor chemotherapy, the exact role of ATM activation in MDR resulting from increased IL-6 expression is still unclear. In the present study, we demonstrate that the activation of the ATM-NF-kappaB pathway, resulting from increased IL-6 expression, plays a central role in augmented chemoresistance in lung cancer cell lines. This result was supported by the increased expressions of Bcl-2, Mcl-1, Bcl-xl, and the upregulation of MDR-associated protein ABCG2. The higher level of IL-6 reveals not only higher ATM/NF-kappaB activity but also increased expressions of ABCG2, Bcl-2, Mcl-1 and Bcl-xl. Most importantly, lung cancer cells themselves upregulated IL-6 secretion by activating the p38/NF-kappaB pathway through treatment with cisplatin and camptothecin. Taken together, these findings demonstrate that chemotherapeutic agents increase IL-6 expression, hence activating the ATM/NF-kappaB pathway, augmenting anti-apoptotic protein expression and contributing to MDR. This indicates that both IL-6 and ATM are potential targets for the treatment of chemotherapeutic resistance in lung cancer.

The role and mechanism of action of activin A in neurite outgrowth of chicken embryonic dorsal root ganglia.

Activin A, a member of the transforming growth factor ß (TGFß) superfamily, plays an essential role in neuron survival as a neurotrophic and neuroprotective factor in the central nervous system. However, the effects and mechanisms of action of activin A on the neurite outgrowth of dorsal root ganglia (DRG) remain unclear. In the present study, we found that activin A is expressed in DRG collected from chicken embryos on embryonic day 8 (E8). Moreover, activin A induced neurite outgrowth of the primary cultured DRG and maintained the survival of monolayer-cultured DRG neurons throughout the observation period of ten days. Follistatin (FS), an activin-binding protein, significantly inhibited activin A-induced neurite outgrowth of DRG, but failed to influence the effect of nerve growth factor (NGF) on DRG neurite outgrowth. Furthermore, the results showed that activin A significantly upregulated mRNA expression of activin receptor type IIA (ActRIIA) and calcitonin gene-related peptide (CGRP) in DRG, and stimulated serotonin (5-HT) production from DRG, indicating that activin A might induce DRG neurite outgrowth by promoting CGRP expression and stimulating 5-HT release. These data suggest that activin A plays an important role in the development of DRG in an autocrine or paracrine manner.

Ontogenesis of coelomocytes in sea cucumber (Apostichopus japonicus) studied with probes of monoclonal antibody.

Monoclonal antibodies (MAbs) specifically against coelomocytes of Apostichopus japonicus were employed to study the ontogenesis of coelomocytes by indirect immunofluorescence assay technique (IIFAT). Different developmental stages were identified by histochemical staining method. Stages including blastula, gastrula, auricularia (small-auricular larvae, mid-auricular larvae and big-auricular larvae), doliolaria, pentactula and juvenile were examined. The positive reactions with both MAb1C2 against all the types of coelomocytes and MAb3F6 specific to spherulocytes, were observed firstly at the blastula stage of the embryos. The positive reaction with MAb1E2 against lymphoid cells was observed from the big-auricular larvae, which indicated that lymphoid cells may not be progenitor cells or stem cells for A. japonicus. An increase of fluorescence intensity for each cell may imply a possible enhancement of the innate defensive mechanism as the embryogenesis progress.

Nicotine up-regulated 4-1BBL expression by activating Mek-PI3K pathway augments the efficacy of bone marrow-derived dendritic cell vaccination.

PURPOSE: To explore the role of 4-1BBL in nicotine-treated immature dendritic cells (imDCs) mediated anti-tumor effects. METHODS: Bone marrow-derived imDCs were stimulated with nicotine and 4-1BBL expression was determinated by flow cytometry, Western blot and RT-PCR respectively. Then, the roles of 4-1BBL in nicotine-augmented DCs-dependent T cell proliferation, CTL priming and anti-tumor effects were investigated by BrdU cell proliferation assay, enzyme-linked immunospot assay and in vivo preventive effect on tumor development, respectively. Finally, using relative kinase inhibitors, the mechanism of 4-1BBL up-regulation by nicotine stimulation and the roles of Mek-PI3K signal pathways in nicotine-augmented DCs-dependent T cell proliferation were explored by Western blot and BrdU cell proliferation assay, respectively. RESULTS: Firstly, nicotine could up-regulate 4-1BBL expression in both protein and mRNA levels. Secondly, the effects of nicotine-augmented DCs-dependent T-cell proliferation, CTL priming and anti-tumor effects could be significantly abolished by blocking CD80, CD86 and 4-1BBL activity, respectively. Thirdly, the combined blockages of CD80/CD86, CD80/4-1BBL, CD86/4-1BBL or CD80/CD86/4-1BBL signals could decrease 53.2 %, 29.6 %, 27.9 % and 54.5 % nicotine-enhanced T cell proliferation, respectively. Importantly, nicotine-induced 4-1BBL up-regulation could be decreased by the usage of Mek-PI3K pathway kinase inhibitors. The pre-treatment of Mek-p38-PI3K kinase inhibitors could obviously abolish nicotine-augmented DCs-dependent T cell proliferation. CONCLUSIONS: CD80/CD86 and 4-1BBL are critical for nicotine augmented DCs-mediated anti-tumor effects. 4-1BBL and CD80/CD86 could be considered as potential candidates for preventive and therapeutic tumor vaccination.

Comparison of cells free in coelomic and water-vascular system of sea cucumber, Apostichopus japonicus.

The sea cucumber, Apostichopus japonicus possesses a variety of cells populating in both the coelomic (cells in the coelomic are called coelomocytes) and water-vascular system. In this study, we compared cells in these two systems of A. japonicus on total cell number, cell types and surface antigens through monoclonal antibodies against coelomocytes. The results demonstrated that the cell types observed in coelomic also could be found in water-vascular system, but the total cell number and percentages of each type were different. The total number of coelomocytes was 2-3 times of that in water-vascular system. Lymphoid cells were numerically dominant in coelomic system, while spherulocytes with pseudopods in water-vascular system. Results of indirect immunofluorescence assay technique showed that both coelomocytes and cells in water-vascular system could be recognized by the corresponding MAbs, and the distribution of its positive signals was not different. In conclusion, cell types and surface antigens in coelomic and water-vascular system were same, but the total cell number and percentages of each type were different. And further researches are needed on whether there are differences in functions of the different composition.

Value of Chuanjin Qinggan decoction in improving the depressive state of patients with herpes zoster combined with depression.

BACKGROUND: Western medicine is beneficial for the recovery of neurological function in patients with depression, but some patients experience side effects such as headaches, dizziness, nausea, gastrointestinal symptoms, insomnia, and cardiac dysfunction. In recent years, integrative medicine has achieved positive results in the treatment of various diseases. AIM: To study Chuanjin Qinggan decoction combined with selective serotonin reuptake inhibitors (SSRIs) in patients with herpes zoster complicated by depression. METHODS: Patients with herpes zoster complicated by depression who were treated at the Yantai Hospital of Traditional Chinese Medicine from January 2021 to December 2022 were retrospectively selected as research participants. Among them, 43 patients with herpes zoster complicated by depression who received SSRI treatment between January and December 2021 were assigned to the Western medicine group, while those who received combined treatment of traditional Chinese and Western medicine between January and December 2022 were assigned to the combined group. Both groups were treated for eight weeks. The degree of pain, effect of herpes zoster treatment, degree of improvement in depressive symptoms, serum neurotransmitter levels, sleep quality, and occurrence of adverse reactions were compared between the two groups. RESULTS: We found that after eight weeks of drug treatment, the two treatment schemes achieved differing efficacy. In further comparison, we found that, compared with patients treated with SSRIs alone, patients treated with Chuanjin Qinggan decoction combined with SSRIs showed more significant improvement in depression and a greater increase in dopamine and 5-hydroxytryptamine levels after treatment (P < 0.05). Patients treated with Chuanjin Qinggan decoction combined with SSRIs also experienced lower pain, better treatment efficacy for herpes zoster, better sleep quality, and a lower incidence of adverse reactions compared to those treated with SSRIs alone (P < 0.05). All minor adverse reactions occurring during treatment were resolved after symptomatic treatment. CONCLUSION: The treatment scheme of Chuanjin Qinggan decoction combined with SSRIs can improve the psychological state of patients with herpes zoster complicated by depression and alleviate adverse reactions.

Transcriptome analysis reveals key transcription factors and pathways of polian vesicle associated with cell proliferation in Vibrio splendidus-challenged Apostichopus japonicus.

Polian vesicle is thought to produce coelomocytes and contribute to the sea cucumber's immune system. Our previous work has indicated that polian vesicle was responsible for cell proliferation at 72 h post pathogenic challenge. However, the transcription factors related to the activation of effector factors and the molecular process behind this remained unknown. In this study, to reveal the early functions of polian vesicle in response to the microbe, a comparative transcriptome sequencing of polian vesicle in V. splendidus-challenged Apostichopus japonicus, including normal group (PV 0 h), pathogen challenging for 6 h (PV 6 h) and 12 h (PV 12 h) was performed. Compared PV 0 h to PV 6 h, PV 0 h to PV 12 h, and PV 6 h to PV 12 h, we found 69, 211, and 175 differentially expressed genes (DEGs), respectively. KEGG enrichment analysis revealed the DEGs, including several transcription factors such as fos, FOS-FOX, ATF2, egr1, KLF2, and Notch3 between PV 6 h and PV 12 h were consistently enriched in MAPK, Apelin and Notch3 signaling pathways related to cell proliferation compared with that in PV 0 h. Important DEGs involved in cell growth were chosen, and their expression patterns were almost the same as the transcriptome profile analysis by qPCR. Protein interaction network analysis indicated that two DEGs of fos and egr1 were probably significant as key candidate genes controlling cell proliferation and differentiation in polian vesicle after pathogenic infection in A. japonicus. Overall, our analysis demonstrates that polian vesicles may play an essential role in regulating proliferation via transcription factors-mediated signaling pathway in A. japonicus and provide new insights into hematopoietic modulation of polian vesicles in response to pathogen infection.

The efficacy and safety of oxycodone in treating the uterine contraction pain after negative pressure aspiration: A randomized, compared, multicenter clinical study.

CONCLUSION: Oxycodone hydrochloride injection could be safely and effectively applied to negative pressure aspiration, and a 0.08 mg/kg dose could significantly reduce postoperative uterine contraction pain of patients with dysmenorrhea.

Optimization and characterization of dry powder of fanhuncaoin for inhalation based on selection of excipients.

In this study, dry powder formulations for inhalation of fanhuncaoin, a newly discovered antiinflammatorily active compound isolated from Chinese herb, were designed to optimize the composition and further explore the relationship between the composition, the physical properties and the aerosolization performance. Dry powders were prepared by spray-drying using leucine, chitosan, chitosan oligosaccharide and dipalmitoyl phosphatidylcholine (DPPC) as excipients. Following spray-drying, resultant powders were characterized using scanning electron microscopy, tapped density analysis, laser diffractometry, thermogravimetric analysis and differential scanning calorimetry. The aerosol behaviour of the powders was studied in a Twin Stage Impinger at an airflow rate of 60 l/min using a HandiHaler® inhaler device. Results revealed that the nature and the relative proportion of the excipients greatly influenced the physical characteristics of the powders and their aerodynamic behavior. Among the combinations tested, the composition ratio of fanhuncaoin/leucine/chitosan/chitosan oligosaccharide/DPPC of 10/45/33.75/11.25/0.4 (w/w/w/w/w) prepared in a total solid mass of 1% (w/v) formulation was found to be particularly optimal and exhibited a tapped density of 0.44 g/cm³, an aerodynamic diameter of 2.24 µm and an respirable fraction of 51.29%. In conclusion, optimization of the aerosolization properties of inhalation dry powders could be achieved by appropriately selecting the composition of the particles.

Glutaminyl Cyclase, Diseases, and Development of Glutaminyl Cyclase Inhibitors.

Pyroglutamate (pE) modification, catalyzed mainly by glutaminyl cyclase (QC), is prevalent throughout nature and is particularly important in mammals including humans for the maturation of hormones, peptides, and proteins. In humans, the upregulation of QC is involved in multiple diseases and conditions including Alzheimer's disease, Huntington's disease, melanomas, thyroid carcinomas, accelerated atherosclerosis, septic arthritics, etc. This upregulation catalyzes the generation of modified mediators such as pE-amyloid beta (Aß) and pE-chemokine ligand 2 (CCL2) peptides. Not surprisingly, QC has emerged as a reasonable target for the development of therapeutics to combat these diseases and conditions. In this manuscript the deleterious effects of upregulated QC resulting in disease manifestation are reviewed, along with progress on the development of QC inhibitors.

Extracellular Vesicles from Human Urine-Derived Stem Cells Ameliorate Particulate Polyethylene-Induced Osteolysis.

PURPOSE: Wear debris particle-induced periprosthetic osteolysis is a severe complication of total joint replacement that results in aseptic loosening and subsequent arthroplasty failure. No effective therapeutic agents or drugs have been approved to prevent or treat osteolysis; thus, revision surgery is often needed. Extracellular vesicles (EVs) are vital nanosized regulators of intercellular communication that can be directly applied to promote tissue repair and regeneration. In this study, we assessed the therapeutic potential of EVs from human urine-derived stem cells (USCs) (USC-EVs) in preventing ultrahigh-molecular-weight polyethylene (UHMWPE) particle-induced osteolysis. METHODS: USCs were characterized by measuring induced multipotent differentiation and flow cytometry. USC-EVs were isolated and characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS) and Western blotting. RAW264.7 cells and bone marrow mesenchymal stem cells (BMSCs) were cultured with USC-EVs to verify osteoclast differentiation and osteoblast formation, respectively, in vitro. The effects of USC-EVs were investigated on a UHMWPE particle-induced murine calvarial osteolysis model by assessing bone mass, the inflammatory reaction, and osteoblast and osteoclast formation. RESULTS: USCs differentiated into osteogenic, adipogenic and chondrogenic cells in vitro and were positive for CD44, CD73, CD29 and CD90 but negative for CD34 and CD45. USC-EVs exhibited a cup-like morphology with a double-layered membrane structure and were positive for CD63 and TSG101 and negative for calnexin. In vitro, USC-EVs promoted the osteogenic differentiation of BMSCs and reduced proinflammatory factor production and osteoclastic activity in RAW264.7 cells. In vivo, local injection of USC-EVs around the central sites of the calvaria decreased inflammatory cytokine generation and osteolysis compared with the control groups and significantly increased bone formation. CONCLUSION: Based on our findings, USC-EVs prevent UHMWPE particle-induced osteolysis by decreasing inflammation, suppressing bone resorption and promoting bone formation.

Sensing and imaging of exosomal CD26 secreted from cancer cells and 3D colorectal tumor model using a novel near-infrared fluorogenic probe.

Cancer-derived exosomes or their specific components hold great promise for early diagnosis and precise staging of cancers. This work aimed to construct a novel enzyme-activatable fluorescent substrate for real-time detection and in situ imaging of a key exosomal surface protein CD26 in various biological systems, as well as to reveal the relevance of exosomal CD26 to the tumorigenesis. For these purposes, a group of Gly-Pro amides deriving from several near-infrared fluorophores were designed on the basis of the unique prolyl-cleaving dipeptidease activity of CD26, while molecular docking simulations were applied to assess the possibility of the designed amides as CD26 specific substrates. Following virtual screening and experimental validation, it was observed that GP-ACM displayed the best combination of high sensitivity and excellent specificity to CD26. The sensing and imaging ability of GP-ACM towards CD26 were examined in a range of biological systems, such as living cells, in situ tissues, and the exosomes secreted from cancer cells. Under physiological conditions, GP-ACM can be readily hydrolyzed by CD26 to release the fluorescent product ACM. The fluorescent product emits strong near-infrared fluorescence signals around 660 nm, which can be easily captured by the devices equipped with a fluorescence detector. GP-ACM prolyl-cleaving reaction shows excellent specificity and rapid response towards CD26, while its fluorescent product ACM displays good chemical stability and outstanding photostability. With the help of GP-ACM, CD26 in living cells, tissues and the tumor-secreted exosomes can be real-time monitored and in-situ imaged, while further investigations reveal that the exosomal CD26 activities are abnormally elevated with the progression of colon tumor. Collectively, the present study offers a practical optical assay for real-time monitoring CD26 activities in multiple complex biological systems including the exosomes secreted by tumor cells. The simplicity and effectiveness of this assay hold great potential for facilitating fundamental researches and clinical diagnosis of exosomal CD26 associated diseases.

[Analysis and Prediction of Health Risk from Heavy Metals in Drinking Water Sources Based on Time Series Model].

Health risk analysis can predict and control the risks posed by heavy metals, especially in drinking water, which is a highly sensitive environmental receptors. In order to evaluate heavy metal pollution in drinking water, the monthly average concentrations of As, Cd, Cu, Hg, Ni, and Zn were used to assess the health risk between January 2015 and December 2018 in a drinking water source. Furthermore, Spearman rank correlation coefficient and the ARIMA model were used to analyze temporal variations. The results showed that the monthly average concentrations of heavy metals exceeded the class Ⅲ values as specified by Chinese environmental quality standard for surface water(GB 3838-2002), especially Hg with a minimum monthly average four times more than that set by the standard limits. Overall, the order of carcinogenic risk of As and Cd was decreased; the non-carcinogenic risk of Zn, Cu, Ni, Pb, and Hg was increased. Further, the comprehensive non-carcinogenic risk for adults was lower than 1 throughout the study period except February 2015, when the comprehensive non-carcinogenic risk for children was lower than or close to 1 after October 2017, and the comprehensive carcinogenic risk for children was more than 10-4. Meanwhile, the children's health risks are higher than that for adults, with the main health risk characteristic factors of As, Cd, and Hg. The Spearman rank correlation coefficient were -0.714069, -0.773122, and -0.62234, indicating the significant downward trend from 2015 to 2018. However, the children's comprehensive carcinogenic risk, whose average value was 0.000234 much more than 10-4, had significant upward trend in 2018 with Spearman rank correlation coefficient 0.902098. The ARIMA(3,1,3) model was able to predict the comprehensive carcinogenic risk for children from heavy metals in drinking water, and the result indicated the children comprehensive carcinogenic risk should be monitored to ensure levels between 0.000200 and 0.000302. The study has positive significance for risk warning and environmental management compared to the analysis and prediction of health risk from heavy metals in drinking water sources based on time series models.