Cynarin ameliorates dextran sulfate sodium-induced acute colitis in mice through the STAT3/NF-κB pathway.

OBJECTIVE: Cynarin is a derivative of hydroxycinnamic acid presented in various medicinal plants, such as Cynara scolymus L. and Onopordum illyricum L. To date, the antioxidant and antihypertensive activities of cynarin have been reported. However, whether cynarin has a therapeutic impact on ulcerative colitis (UC) is unclear. Therefore, the aim of this study was to explore the potential effect of cynarin on dextran sulfate sodium (DSS)-induced acute colitis in vivo and on lipopolysaccharide (LPS)/interferon-γ (IFN-γ)-induced RAW264.7 and J774A.1 cellular inflammation model in vitro. METHODS AND RESULTS: In this study, we investigated that cynarin alleviated clinical symptoms in animal models, including disease activity index (DAI) and histological damage. Furthermore, cynarin can attenuate colon inflammation through decreasing the proportion of neutrophils in peripheral blood, reducing the infiltration of neutrophils, and macrophages in colon tissue, inhibiting the release of pro-inflammatory cytokines and suppressing the expression of STAT3 and p65. In cellular inflammation models, cynarin inhibited the expression of M1 macrophage markers, such as TNF-α, IL-1ß, and iNOS. Besides, cynarin suppressed the expression of STAT3 and p65 as well as the phosphorylation of STAT3, p65. Cynarin inhibited the polarization of RAW264.7 and J774A.1 cells toward M1 and alleviated LPS/IFN-γ-induced cellular inflammation. CONCLUSION: Considering these results, we conclude that cynarin mitigates experimental UC partially through inhibiting the STAT3/NF-кB signaling pathways and macrophage polarization toward M1. Accordingly, cynarin might be a potential and effective therapy for UC.

Elevated expression of CXCL3 in colon cancer promotes malignant behaviors of tumor cells in an ERK-dependent manner.

BACKGROUND: CXC chemokine ligand 3 (CXCL3) is a member of CXC-type chemokine family that is identified as a major regulator in immune and inflammation responses. Recently, numerous evidence indicated that CXCL3 is broadly expressed in various human tumor types, and it is also known to play a critical role in mediating tumor development and progression. However, the expression profile of CXCL3 and the exact molecular mechanism behind the role of CXCL3 in colon adenocarcinoma (COAD) has not been fully elucidated. METHODS: The expression and clinical significance of CXCL3 mRNA and protein in the tissues from COAD patients were estimated using bioinformatics and immunohistochemistry assays. The expression and roles of exogenous administration or overexpression of CXCL3 in HT-29 and SW480 COAD cells were determined using enzyme-linked immunosorbent assay(ELISA), Cell Counting Kit-8 (CCK-8) and Transwell assays. Mechanically, CXCL3-induced malignant behaviors were elucidated using western blotting assay and extracellular signal-regulated protein kinase 1/2 (ERk1/2) inhibitor PD98059. RESULTS: The cancer genome atlas (TCGA)-COAD data analysis revealed that CXCL3 mRNA is highly expressed and has high clinical diagnostic accuracy in COAD. Increased expression of CXCL3 mRNA was associated with patient's clinical stage, race, gender, age, histological subtype, nodal mestastasis and tumor protein 53 (TP53) mutation status. Similarly, immunohistochemistry assay also exhibited that CXCL3 protein in COAD tissues was significantly up-regulated. Gene expression associated assay implied that CXC chemokine ligand 1 (CXCL1) and CXC chemokine ligand 2 (CXCL2) were markedly correlated with CXCL3 in COAD. Protein-protein interaction (PPI) analysis revealed that cyclin B1 (CCNB1), mitotic arrest deficient 2 like 1 (MAD2L1), H2A family member Z (H2AFZ) and CXCL2 may be the important protein molecules involved in CXCL3-related tumor biology. Gene set enrichment analysis (GSEA) analysis revealed that CXCL3 was mainly enriched in the cell cycle, DNA replication, NOD-like receptors, NOTCH and transforming growth factor-ß (TGF-ß) Signal pathways. In vitro, exogenous administration or overexpression of CXCL3 resulted in increased malignant behaviors of HT-29 and SW480 cells, and down-regulation of CXCL3 expression inhibited the malignant behaviors of these tumor cells. In addition, overexpression of CXCL3 affected the expression of genes related to extracellular signal regulated kinase (ERK) pathway, including ERK1/2, p-ERK, B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax) and Cyclin D1. Finally, CXCL3-induced malignant behaviors in HT-29 and SW480 cells were obviously attenuated following treatment with ERK inhibitor PD98059. CONCLUSION: CXCL3 is upregulated in COAD and plays a crucial role in the control of malignant behaviors of tumor cells, which indicated its involvement in the pathogenesis of COAD.

Periosteal Bone Formation Varies with Age in Periostin Null Mice.

Periostin, also known as osteoblast-specific factor 2, is a matricellular protein predominantly expressed at the periosteum of bone. During growth and development, periostin contributes to periosteal expansion by facilitating osteoblast differentiation and mineralization. Later in life, periosteal expansion provides an adaptive strategy to increase tissue strength without requiring substantial increase in bone mass. However, the function of periostin past skeletal maturity and during advanced aging is relatively unknown. The objective of this study was to examine the function of periostin in maintaining bone mass and tissue strength across different ages. In periostin null mice (Postn-/-), periosteal bone formation was significantly reduced in young (3 months) and adult mice (9 months). The lack of bone formation resulted in reduced bone mass and ultimate strength. Conversely, periosteal bone formation increased at advanced ages in 18-month-old Postn-/- mice. The increase in periosteal mineralization at advanced ages coincides with increased expression of vitronectin and osteopontin. Periosteal progenitors from Postn-/- mice displayed an increased capacity to mineralize when cultured on vitronectin, but not type-1 collagen. Altogether, these findings demonstrate the unique role of periostin in regulating periosteal bone formation at different ages and the potential for vitronectin to compensate in the absence of periostin.

The mechanotransduction of MLO-Y4 cells is disrupted by the senescence-associated secretory phenotype of neighboring cells.

Age-related bone loss is attributed to the accumulation of senescent cells and their increasing production of inflammatory cytokines as part of the senescence-associated secretory phenotype (SASP). In otherwise healthy individuals, osteocytes play a key role in maintaining bone mass through their primary function of responding to skeletal loading. Given that osteocytes' response to loading is known to steadily decline with age, we hypothesized that the increasing presence of senescent cells and their SASP inhibit osteocytes' response to loading. To test this hypothesis, we developed two in vitro models of senescent osteocytes and osteoblasts derived from MLO-Y4 and MC3T3 cell lines, respectively. The senescent phenotype was unique to each cell type based on distinct changes in cell cycle inhibitors and SASP profile. The SASP profile of senescent osteocytes was in part dependent on nuclear factor-κB signaling and presents a new potential mechanism to target the SASP in bone. Nonsenescent MLO-Y4 cells cultured with the SASP of each senescent cell type failed to exhibit changes in gene expression as well as ERK phosphorylation and prostaglandin E2 release. The SASP of senescent osteocytes had the largest effect and neutralizing interleukin-6 (IL-6) as part of the SASP restored osteocytes' response to loading. The loss in mechanotransduction due to IL-6 was attributed to a decrease in P2X7 expression and overall sensitivity to purinergic signaling. Altogether, these findings demonstrate that the SASP of senescent cells have a negative effect on the mechanotransduction of osteocytes and that IL-6 is a key SASP component that contributes to the loss in mechanotransduction.

Comprehensive analysis of CXCR family members in lung adenocarcinoma with prognostic values.

BACKGROUND: The expression profiles and molecular mechanisms of CXC chemokine receptors (CXCRs) in Lung adenocarcinoma (LUAD) have been extensively explored. However, the comprehensive prognostic values of CXCR members in LUAD have not yet been clearly identified. METHODS: Multiple available datasets, including Oncomine datasets, the cancer genome atlas (TCGA), HPA platform, GeneMANIA platform, DAVID platform and the tumor immune estimation resource (TIMER) were used to detect the expression of CXCRs in LUAD, as well as elucidate the significance and value of novel CXCRs-associated genes and signaling pathways in LUAD. RESULTS: The mRNA and/or protein expression of CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CXCR6 displayed predominantly decreased in LUAD tissues as compared to normal tissues. On the contrary, compared with the normal tissues, the expression of CXCR7 was significantly increased in LUAD tissues. Subsequently, we constructed a network including CXCR family members and their 20 related genes, and the related GO functions assay showed that CXCRs connected with these genes participated in the process of LUAD through several signal pathways including Chemokine signaling pathway, Cytokine-cytokine receptor interaction and Neuroactive ligand-receptor interaction. TCGA and Timer platform revealed that the mRNA expression of CXCR family members was significantly related to individual cancer stages, cancer subtypes, patient's gender and the immune infiltration level. Finally, survival analysis showed that low mRNA expression levels of CXCR2 (HR = 0.661, and Log-rank P = 1.90e-02), CXCR3 (HR = 0.674, and Log-rank P = 1.00e-02), CXCR4 (HR = 0.65, and Log-rank P = 5.01e-03), CXCR5 (HR = 0.608, and Log-rank P = 4.80e-03) and CXCR6 (HR = 0.622, and Log-rank P = 1.85e-03) were significantly associated with shorter overall survival (OS), whereas high CXCR7 mRNA expression (HR = 1.604, and Log-rank P = 4.27e-03) was extremely related with shorter OS in patients. CONCLUSION: Our findings from public databases provided a unique insight into expression characteristics and prognostic values of CXCR members in LUAD, which would be benefit for the understanding of pathogenesis, diagnosis, prognosis prediction and targeted treatment in LUAD.

CXCL3 overexpression promotes the tumorigenic potential of uterine cervical cancer cells via the MAPK/ERK pathway.

CXCL3 belongs to the CXC-type chemokine family and is known to play a multifaceted role in various human malignancies. While its clinical significance and mechanisms of action in uterine cervical cancer (UCC) remain unclear. This investigation demonstrated that the UCC cell line HeLa expressed CXCL3, and strong expression of CXCL3 was detected in UCC tissues relative to nontumor tissues. In addition, CXCL3 expression was strongly correlated with CXCL5 expression in UCC tissues. In vitro, HeLa cells overexpressing CXCL3, HeLa cells treated with exogenous CXCL3 or treated with conditioned medium from WPMY cells overexpressing CXCL3, exhibited enhanced proliferation and migration activities. In agreement with these findings, CXCL3 overexpression was also associated with the generation of HeLa cell tumor xenografts in athymic nude mice. Subsequent mechanistic studies demonstrated that CXCL3 overexpressing influenced the expression of extracellular signal-regulated kinase (ERK) signaling pathway associated genes, including ERK1/2, Bcl-2, and Bax, whereas the CXCL3-induced proliferation and migration effects were attenuated by exogenous administration of the ERK1/2 blocker PD98059. The data of the current investigation support that CXCL3 appears to hold promise as a potential tumor marker and interference target for UCC.

MARVELD1 interacting with catalase regulates reactive oxygen species metabolism and mediates the sensitivity to chemotherapeutic drugs in epithelial tumors of the reproductive system.

Previous investigations have found that MARVEL domain-containing 1 (MARVELD1) could inhibit tumor cell proliferation and enhance the sensitivity to chemotherapeutic drugs in hepatocellular carcinoma. Hence, it may be a valuable therapeutic target. In the study, we analyzed the responsive changes of MARVELD1 to 25 stress factors and expression of MARVELD1 in epithelial tumors of the reproductive system. We found that MARVELD1 was transferred to the cytoplasm and mitochondria under cell stress. And under cellular stress, the reactive oxygen species (ROS) levels decreased in MARVELD1 expressed cells while increased in the cells of MARVELD1-specific siRNA treatment. Meanwhile, MARVELD1 overexpression significantly promoted the inhibition of tumor cell proliferation under cellular stress via affecting ROS metabolism, not cell cycle. In xenograft tumor tissues with MARVELD1 expression, the tumor growth was inhibited and accompanied by the lower ROS levels. Furthermore, we identified that MARVELD1 could interact with catalase (CAT) to enhance latter activity and maintain stability. And the enhanced sensitivity to chemotherapeutic drugs clearly depended on the ability of MARVELD1 scavenge the ROS in carcinoma cells of the reproductive system. Our findings clearly explain that MARVELD1 may regulate tumor cell proliferation and sensitivity to chemotherapeutic drugs via reducing the exorbitant ROS. The mechanism was that MARVELD1 interacted with CAT to maintain latter stability, and then ensure continuous ROS scavenge.

Association of genetic polymorphisms with COVID-19 infection and outcomes: An updated meta-analysis based on 62 studies.

Background: The relationship between genetic polymorphisms and coronavirus disease 2019 (COVID-19) remains to be inconsistent. This meta-analysis aimed to provide an updated evaluation of the role of genetic polymorphisms in the infection, severity and mortality of COVID-19 based on all available published studies. Methods: A systematic search was performed using six databases: PubMed, Embase, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and Wanfang. Summary odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were used to calculate the genotypic comparison. All statistical analyses were conducted in Stata 12.0. Results: A total of 62 studies with 19600 cases and 28899 controls was included in this meta-analysis. For COVID-19 infection, ACE Ins/Del polymorphism might be related with significantly decreased risk of COVID-19 infection under dominant, homozygote and allelic models. Meanwhile, the IFITM3 rs12252 and TMPRSS2 rs12329760 polymorphisms were significantly associated with the increased risk of COVID-19 infection under one or more models. Regarding COVID-19 severity, ACE2 rs2074192, ACE2 rs2106809, IFITM3 rs12252 and VDR rs1544410 polymorphisms might be related with significantly increased risk of COVID-19 severity in one or more models. Moreover, the analysis of TMPRSS2 rs2070788 indicated that a variant A allele decreased the risk of COVID-19 severity in recessive model. For COVID-19 mortality, the variant C allele of IFITM3 rs12252 polymorphism might be related with significantly increased risk of COVID-19 mortality under all genetic models. Conclusions: This meta-analysis indicated that he infection, severity or mortality of COVID-19 were related to the above genetic polymorphisms, which might provide an important theoretical basis for understanding the clinical feature of COVID-19 disease.

Comprehensive analysis of the clinical and biological significances for chemokine CXCL3 in cholangiocarcinoma.

Cholangiocarcinoma (CHOL) is a race malignant cancer arising from bile duct epithelial cells in clinical practice. C-X-C motif chemokine ligand 3 (CXCL3) is a member of chemokines family, which participates in the pathogenesis of various tumors. However, the association between CXCL3 and CHOL is unclear. This present study was to assess the role of CXCL3 expression in the progress of CHOL. TIMER, GEPIA, UALCAN, GSCA, LinkedOmics, Metascape and STRING databases were performed to evaluate the clinical and biological significances for CXCL3 with CHOL patients including expression, clinicopathological factors, immune cell infiltration, GO enrichment and KEGG pathway analyses, as well as PPI network analysis. The immunohistochemistry analysis of tissue microarray was conducted to detect the protein expression level, subcellular localization, clinicopathological factors and prognosis of CXCL3 in CHOL. The mRNA and protein expression levels of CXCL3 were markedly increased in CHOL tissues. The overexpression of CXCL3 was strongly associated with maximum tumor diameter of patients with CHOL. Additionally, there were negative correlations between the expression of CXCL3 and monocyte as well as Th17. Low infiltration of neutrophil indicated significantly shorter cumulative survival in CHOL patients. And CXCL3 was significantly associated with arm-level deletion of CD8+ T cell. Furthermore, functional network analysis suggested that CXCL3 and its associated genes were mainly enriched for chemotaxis, secretory granule membrane, cytokine activity and IL-17 signaling pathway. CXCL3 might potentially participate in the carcinogenesis of CHOL, which provided a direction for future research on the mechanism of CXCL3 in CHOL.

Etiological surveillance of viral diarrhea from 2017 to 2019 in Zhangzhou city, Fujian province, China.

Background: Viral diarrhea is one of the major causes of morbidity and mortality in children. This study aimed to conduct etiological surveillance of viral diarrhea in Zhangzhou city, Fujian province, China, from 2017 to 2019 to identify the prevalence, distribution, and characteristics of viral pathogens causing gastrointestinal infections in the region. Methods: Stool samples were collected from patients with acute diarrhea in Zhangzhou city, Fujian province, China, from 2017 to 2019. Rotavirus, norovirus, astrovirus, and adenovirus were detected using fluorescence immunochromatography assay. Results: Of the total 5,627 samples that were collected, at least one of the viruses (rotavirus, norovirus, astrovirus and adenovirus) was found to be positive in 1,422 samples. Rotavirus, norovirus, astrovirus, and adenovirus, were detected in 53.73, 16.68, 15.52, and 14.97%, respectively. Mixed infections were determined in 17.65% of the positive samples. The predominant mixed infections observed were a combination of norovirus and astrovirus, followed by rotavirus and norovirus, and rotavirus and astrovirus. The highest positive rate was observed in the 12-23-month group for rotavirus and adenovirus, while a significantly higher positive rate was observed for norovirus and astrovirus in the 6-11-month group. Conclusion: These findings from this etiological surveillance highlight the significant burden of viral diarrhea in Zhangzhou city, with rotavirus being the predominant pathogen. The identification of common mixed infections provides insights into the complex nature of viral diarrhea transmission. Target interventions and public health strategies should be implemented, particularly during the winter and spring seasons, to prevent and control the spread of viral pathogens causing gastrointestinal infections in this region.

Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model.

BACKGROUND & AIMS: Air pollution is a global challenge to public health. Epidemiological studies have linked exposure to ambient particulate matter with aerodynamic diameters<2.5 µm (PM(2.5)) to the development of metabolic diseases. In this study, we investigated the effect of PM(2.5) exposure on liver pathogenesis and the mechanism by which ambient PM(2.5) modulates hepatic pathways and glucose homeostasis. METHODS: Using "Ohio's Air Pollution Exposure System for the Interrogation of Systemic Effects (OASIS)-1", we performed whole-body exposure of mice to concentrated ambient PM(2.5) for 3 or 10 weeks. Histological analyses, metabolic studies, as well as gene expression and molecular signal transduction analyses were performed to determine the effects and mechanisms by which PM(2.5) exposure promotes liver pathogenesis. RESULTS: Mice exposed to PM(2.5) for 10 weeks developed a non-alcoholic steatohepatitis (NASH)-like phenotype, characterized by hepatic steatosis, inflammation, and fibrosis. After PM(2.5) exposure, mice displayed impaired hepatic glycogen storage, glucose intolerance, and insulin resistance. Further investigation revealed that exposure to PM(2.5) led to activation of inflammatory response pathways mediated through c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and Toll-like receptor 4 (TLR4), but suppression of the insulin receptor substrate 1 (IRS1)-mediated signaling. Moreover, PM(2.5) exposure repressed expression of the peroxisome proliferator-activated receptor (PPAR)γ and PPARα in the liver. CONCLUSIONS: Our study suggests that PM(2.5) exposure represents a significant "hit" that triggers a NASH-like phenotype and impairs hepatic glucose metabolism. The information from this work has important implications in our understanding of air pollution-associated metabolic disorders.

Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice.

UNLABELLED: cAMP responsive element-binding protein, hepatocyte specific (CREBH), is a liver-specific transcription factor localized in the endoplasmic reticulum (ER) membrane. Our previous work demonstrated that CREBH is activated by ER stress or inflammatory stimuli to induce an acute-phase hepatic inflammation. Here, we demonstrate that CREBH is a key metabolic regulator of hepatic lipogenesis, fatty acid (FA) oxidation, and lipolysis under metabolic stress. Saturated FA, insulin signals, or an atherogenic high-fat diet can induce CREBH activation in the liver. Under the normal chow diet, CrebH knockout mice display a modest decrease in hepatic lipid contents, but an increase in plasma triglycerides (TGs). After having been fed an atherogenic high-fat (AHF) diet, massive accumulation of hepatic lipid metabolites and significant increase in plasma TG levels were observed in the CrebH knockout mice. Along with the hypertriglyceridemia phenotype, the CrebH null mice displayed significantly reduced body-weight gain, diminished abdominal fat, and increased nonalcoholic steatohepatitis activities under the AHF diet. Gene-expression analysis and chromatin-immunoprecipitation assay indicated that CREBH is required to activate the expression of the genes encoding functions involved in de novo lipogenesis, TG and cholesterol biosynthesis, FA elongation and oxidation, lipolysis, and lipid transport. Supporting the role of CREBH in lipogenesis and lipolysis, forced expression of an activated form of CREBH protein in the liver significantly increases accumulation of hepatic lipids, but reduces plasma TG levels in mice. CONCLUSION: All together, our study shows that CREBH plays a key role in maintaining lipid homeostasis by regulating the expression of the genes involved in hepatic lipogenesis, FA oxidation, and lipolysis under metabolic stress. The identification of CREBH as a stress-inducible metabolic regulator has important implications in the understanding and treatment of metabolic disease.

Hydrothermal Synthesis of Molybdenum Disulfide Quantum Dots for Highly Sensitive Detection of Iron Ions in Protein Succinate Oral Solution.

In this paper, a molybdenum disulfide fluorescent probe with an Fe3+ fluorescent system was first synthesized by the hydrothermal method for the detection of iron ion concentration in oral solution of protein succinate. It was characterized by infrared, fluorescence, X-ray photoelectron spectroscopy, scanning electron microscopy, and transmission electron microscopy. The probes were found to have good stability, photobleaching, and storage stability. The effects of dilution, pH, reaction time, and iron ion concentration on the fluorescent system were also investigated. The relative fluorescence intensity [(I0 - I)/I0] showed a good linear relationship with the iron ion concentration in the range of 0-50 µM, with the linear equation [(I0 - I)/I0] = 0.0148[Fe3+] + 0.0833 (r2 = 0.9943, n = 11) and the detection limit of 2.43 µM. The reaction mechanism was also explored, as well as its ion selectivity, reversibility, accuracy, precision, and concentration of Fe ions in the actual sample. It was found that the probe can selectively detect Fe ions with a certain degree of reversibility, accuracy, precision, and ideal recovery, and it can be used for the determination of Fe3+ in proteosuccinic acid oral solution.

Dynamic back analysis of soil deformation during the construction of deep cantilever foundation pits.

Field monitoring of foundation pits alone cannot predict the future deformation of retaining structures. Numerical simulations can predict the deformation of foundation pits and the working state of retaining structures to avoid the risk of foundation pit damage in advance. Accurate inversion of the soil parameters used for simulation and prediction is a key step. The associated multivariable problem is transformed into a single-variable problem by using the interval influence coefficient. Soil layer weightings and excavation step weightings are introduced and exploited to optimize the calculation process, and the soil parameters are calculated through inversion based on the least squares method. Based on actual engineering, the excavation sequence is regarded as a progressive sequence for back analysis, and the parameters of each soil layer are calculated through dynamic calculations with the excavation process in a cycle comprising inversion, prediction, reinversion and reprediction. The soil parameters after inversion are used to predict the maximum value and the depth of the deep horizontal displacement of the retaining structure, which verified the feasibility of the back-analysis method. Compared with the results before inversion, after the final inversion, t the overall error of section 2 is reduced by 67.24%, the overall error of section 3 is reduced by 40.5%, and the overall error of section 4 is reduced by 35%. The prediction curves are all close to the monitoring displacement curves, which plays a good guiding role and ensures the safe construction of the foundation pit. A new effective idea is proposed for the inverse analysis of the composite formation parameters of the deep foundation pit engineering.

Genetic analysis and QTL detection of reproductive period and post-flowering photoperiod responses in soybean.

Reproductive period (RP) is an important trait of soybean [Glycine max (L.) Merr.] It is closely related to yield, quality and tolerances to environmental stresses. To investigate the inheritance and photoperiod response of RP in soybean, the F(1), F(2), and F(2:3) populations derived from nine crosses were developed. The inheritance of RP was analyzed through the joint segregation analysis. It was shown that the RP was controlled by one major gene plus polygenes. 181 recombinant inbred lines (RILs) generated from the cross of Xuyong Hongdou × Baohexuan 3 were further used for QTL mapping of RP under normal conditions across 3 environments, using 127 SSR markers. Four QTLs, designated qRP-c-1, qRP-g-1, qRP-m-1 and qRP-m-2, were mapped on C1, G and M linkage groups, respectively. The QTL qRP-c-1 on the linkage group C1 showed stable effect across environments and explained 25.6, 27.5 and 21.4% of the phenotypic variance in Nanjing 2002, Beijing 2003 and Beijing 2004, respectively. Under photoperiod-controlled conditions, qRP-c-1, and two different QTLs designated qRP-l-1 and qRP-o-1, respectively, were mapped on the linkage groups L and O. qRP-o-1 was detected under SD condition and can explained 10.70% of the phenotypic variance. qRP-c-1 and qRP-l-1 were detected under LD condition and for photoperiod sensitivity. The two major-effect QTLs can explain 19.03 and 19.00% of the phenotypic variance, respectively, under LD condition and 16.25 and 14.12%, respectively, for photoperiod sensitivity. Comparative mapping suggested that the two major-effect QTLs, qRP-c-1 and qRP-l-1, might associate with E8 or GmCRY1a and the maturity gene E3 or GmPhyA3, respectively. These results could facilitate our understanding of the inheritance of RP and provide information on marker-assisted breeding for high yield and wide adaptation in soybean.

Analysis of complete genome sequence of Neorickettsia risticii: causative agent of Potomac horse fever.

Neorickettsia risticii is an obligate intracellular bacterium of the trematodes and mammals. Horses develop Potomac horse fever (PHF) when they ingest aquatic insects containing encysted N. risticii-infected trematodes. The complete genome sequence of N. risticii Illinois consists of a single circular chromosome of 879 977 bp and encodes 38 RNA species and 898 proteins. Although N. risticii has limited ability to synthesize amino acids and lacks many metabolic pathways, it is capable of making major vitamins, cofactors and nucleotides. Comparison with its closely related human pathogen N. sennetsu showed that 758 (88.2%) of protein-coding genes are conserved between N. risticii and N. sennetsu. Four-way comparison of genes among N. risticii and other Anaplasmataceae showed that most genes are either shared among Anaplasmataceae (525 orthologs that generally associated with housekeeping functions), or specific to each genome (>200 genes that are mostly hypothetical proteins). Genes potentially involved in the pathogenesis of N. risticii were identified, including those encoding putative outer membrane proteins, two-component systems and a type IV secretion system (T4SS). The bipolar localization of T4SS pilus protein VirB2 on the bacterial surface was demonstrated for the first time in obligate intracellular bacteria. These data provide insights toward genomic potential of N. risticii and intracellular parasitism, and facilitate our understanding of PHF pathogenesis.

Clinical significance and biological functions of chemokine CXCL3 in head and neck squamous cell carcinoma.

CXCL3 plays extensive roles in tumorigenesis in various types of human cancers through its roles in tumor cell differentiation, invasion, and migration. However, the mechanisms of CXCL3 in head and neck squamous cell carcinoma (HNSCC) remain unclear. In our study, multiple databases were used to explore the expression level, prognostic value, and related mechanisms of CXCL3 in human HNSCC through bioinformatic methods. We also performed further experiments in vivo and in vitro to evaluate the expression of CXCL3 in a human head and neck tissue microarray and the underlying effect mechanisms of CXCL3 on the tumor biology of HNSCC tumor cells. The result showed that the expression level of CXCL3 in patients with HNSCC was significantly higher as compared with that in normal tissues (P<0.05). Kaplan-Meier survival analysis demonstrated that patients with high CXCL3 expression had a lower overall survival rate (P=0.038). CXCL3 was further identified as an independent prognostic factor for HNSCC patients by Cox regression analysis, and GSEA exhibited that several signaling pathways including Apoptosis, Toll-like receptor, Nod-like receptor, Jak-STAT, and MAPK signaling pathways may be involved in the tumorigenesis of HNSCC. CAL27 cells overexpressing or HNSCC cells treated with exogenous CXCL3 exhibited enhanced cell malignant behaviors, whereas down-regulating CXCL3 expression resulted in decreased malignant behaviors in HSC4 cells. In addition, CXCL3 may affect the expression of several genes, including ERK1/2, Bcl-2, Bax, STAT3, and NF-κB. In summary, our bioinformatics and experiment findings effectively suggest the information of CXCL3 expression, roles, and the potential regulatory network in HNSCC.

USP18-deficiency in cervical carcinoma is crucial for the malignant behavior of tumor cells in an ERK signal-dependent manner.

Ubiquitin-specific peptidase (USP)18 belongs to the USP family, and is involved in cleaving and removing ubiquitin or ubiquitin-like molecules from their target molecules. Recently, increasing evidence has suggested that USP18 is constitutively expressed in different types of human tumors, and ectopic expression or downregulation of USP18 expression may contribute to tumorigenesis. However, the role of USP18 in uterine cervical cancer (UCC) remains unclear. Thus, the present study aimed to investigate USP18 expression in a human tissue microarray constructed using UCC and non-cancer cervical tissues, and to determine the potential role and molecular mechanism by which USP18 is implicated in the tumor biology of human UCC HeLa cells. Microarray analysis demonstrated that USP18 protein expression was downregulated in tumor tissues compared with in normal tissues. In addition, in vitro analysis revealed that USP18-knockdown markedly promoted the proliferation, colony formation, migration and aggressiveness of HeLa cells. Mechanistic analysis demonstrated that USP18-knockdown increased the levels of Bcl-2, STAT3 and phosphorylated-ERK in HeLa cells. Notably, USP18 silencing-induced malignant phenotypes were interrupted following exogenous administration of the ERK1/2 inhibitor PD98059. Overall, the results of the present study suggested that USP18 may be a potent inhibitor involved in UCC tumor-associated biological behaviors, which are associated with the ERK signaling pathway.

Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues.

Recent studies have suggested a link between inhaled particulate matter (PM) exposure and increased mortality and morbidity associated with pulmonary and cardiovascular diseases. However, a precise understanding of the biological mechanism underlying PM-associated toxicity and pathogenesis remains elusive. Here, we investigated the impact of PM exposure in intracellular stress signaling pathways with animal models and cultured cells. Inhalation exposure of the mice to environmentally relevant fine particulate matter (aerodynamic diameter < 2.5 µm, PM(2.5)) induces endoplasmic reticulum (ER) stress and activation of unfolded protein response (UPR) in the lung and liver tissues as well as in the mouse macrophage cell line RAW264.7. Ambient PM(2.5) exposure activates double-strand RNA-activated protein kinase-like ER kinase (PERK), leading to phosphorylation of translation initiation factor eIF2α and induction of C/EBP homologous transcription factor CHOP/GADD153. Activation of PERK-mediated UPR pathway relies on the production of reactive oxygen species (ROS) and is critical for PM(2.5)-induced apoptosis. Furthermore, PM(2.5) exposure can activate ER stress sensor IRE1α, but it decreases the activity of IRE1α in splicing the mRNA encoding the UPR trans-activator X-box binding protein 1 (XBP1). Together, our study suggests that PM(2.5) exposure differentially activates the UPR branches, leading to ER stress-induced apoptosis through the PERK-eIF2α-CHOP UPR branch. This work provides novel insights into the cellular and molecular basis by which ambient PM(2.5) exposure elicits its cytotoxic effects that may be related to air pollution-associated pathogenesis.

Osteocytes' expression of the PTH/PTHrP receptor has differing effects on endocortical and periosteal bone formation during adenine-induced CKD.

Osteocytes play a key role in the pathophysiology of chronic kidney disease (CKD). However, the extent to which osteocytes contribute to abnormalities in bone turnover due to excessive levels of parathyroid hormone (PTH) remains poorly understood. The purpose of this study was to determine the extent to which bone formation and tissue strength during the progression of CKD is modified through osteocytes' response to PTH. Conditional knockout mice targeting osteocytes' expression of the PTH/PTH-related protein type 1 receptor (PPR) were subjected to adenine-induced CKD. After 6-weeks of treatment, adenine-induced CKD was found to reduce bone formation at the periosteal and endocortical surfaces of the tibia. The loss in bone mass corresponded with a significant decrease in structural-level mechanical properties. In knockout mice, the loss of PPR expression in osteocytes further exacerbated the loss in bone formation at the endocortical surface, but inhibited bone loss at the periosteal surface. In general, the effects of adenine-induced CKD were not as extensive in female mice. Collectively, these findings demonstrate that osteocytes' response to PTH under adenine-induced CKD has a unique impact on bone turnover that is specific to the periosteal and endocortical surfaces.