[Infection of human normal lung epithelial cells by Hantaan virus (HTNV) and its impact on innate immunity and metabolism].

Objective To confirm that Hantaan virus (HTNV) can infect BEAS-2B human normal lung epithelial cells and examine the host immune response and metabolic changes induced by HTNV infection by transcriptomic analysis. Methods Western blotting, quantitative real-time PCR and immunofluorescence assay were used to assess the viral load in BEAS-2B cells, and RNA sequencing was employed for transcriptomic analysis. Results Following the infection of BEAS-2B cells with HTNV, there was an increase in the expression of HTNV nucleocapsid protein (NP) and small segment (S) over time. A transcriptomic analysis of these infected cells at 48-hour mark identified 328 genes that were differentially expressed. GO and KEGG enrichment analysis revealed that these differences were primarily associated with interferon response and innate immune pattern recognition receptor pathways. Protein-protein interaction network analysis identified several genes related to innate immune responses, including four genes encoding disintegrin and metalloproteinase with thrombospondin motifs. Metabolic pathway analysis showed three genes related to terpenoid backbone biosynthesis, two genes related to glycolysis/gluconeogenesis and two genes related to steroid hormone biosynthesis. Subcellular localization analysis indicated that many of the differentially expressed genes were located in mitochondria. Conclusion HTNV is capable of effectively infecting BEAS-2B cells, making them a suitable in vitro model for studying HTNV infection in human lung epithelial. By utilizing bioinformatics methods to screen for differentially expressed genes and metabolic pathways associated with HTNV infection, researchers can establish a theoretical foundation for investigating the molecular mechanisms underling HTNV infection.

T-cell immunoglobulin and mucin 1 (TIM-1) mediates infection of Hantaan virus in Jurkat T cells.

Hantaan virus (HTNV) is a major public health concern due to its ability to cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia. Symptoms of HFRS include fever, hemorrhage, immune dysfunction and renal impairment, and severe cases can be fatal. T cell-mediated adaptive immune responses play a pivotal role in countering HTNV infection. However, our understanding of HTNV and T cell interactions in the disease progression is limited. In this study, we found that human CD4+ T cells can be directly infected with HTNV, thereby facilitating viral replication and production. Additionally, T-cell immunoglobulin and mucin 1 (TIM-1) participated in the process of HTNV infection of Jurkat T cells, and further observed that HTNV enters Jurkat T cells via the clathrin-dependent endocytosis pathway. These findings not only affirm the susceptibility of human CD4+ T lymphocytes to HTNV but also shed light on the viral tropism. Our research elucidates a mode of the interaction between the virus infection process and the immune system. Critically, this study provides new insights into the pathogenesis of HTNV and the implications for antiviral research.

NLRX1: a key regulator in mitochondrial respiration and colorectal cancer progression.

Colorectal cancer (CRC) is a prevalent and aggressive malignancy with high mortality rates and significant risks to human well-being. Population-wide screening for tumor suppressor genes and oncogenes shows promise for reducing the incidence and fatality of CRC. Recent studies have suggested that NLRX1, an innate immunity suppressor, may play a role in regulating chronic inflammation and tumorigenesis. However, further investigation is needed to understand the specific role of NLRX1 in CRC. To evaluate the impact of NLRX1 on migration, invasion, and metastasis, two human colon cancer cell lines were studied in vitro. Additionally, a knockout mouse tumor-bearing model was used to validate the inhibitory effect of NLRX1 on tumor emergence and progression. The Seahorse XF96 technology was employed to assess mitochondrial function and glycolysis in colorectal cancer cells overexpressing NLRX1. Moreover, public databases were consulted to analyze gene and protein expression levels of NLRX1. Finally, the results were validated using a series of CRC patient samples. Our findings demonstrate that downregulation of NLRX1 enhances proliferation, colony formation, and tumor-forming capacity in HCT116 and LoVo cells. Conversely, overexpression of NLRX1 negatively impacts basal respiration and mitochondrial ATP-linked respiration in both cell lines, resulting in a notable decrease in maximal respiration during the standard mitochondrial stress test. Furthermore, analysis of data from the TCGA database reveals a significant reduction in NLRX1 expression in colon and rectal cancer tissues compared to normal tissues. This result was validated using clinical samples, where immunohistochemistry staining and western blotting demonstrated a notable reduction in NLRX1 protein levels in CRC compared to adjacent normal tissues. The decreased expression of NLRX1 may serve as a significant prognostic indicator and diagnostic biomarker for CRC patients.

A tetraploid-dominated cytochimera developed from a natural bud mutant of the nonapomictic mandarin variety 'Orah'.

Nonapomictic citrus tetraploids are desirable in citrus breeding for the production of triploid, seedless varieties, and polyploid rootstocks. However, only a few lines have been reported, and they were all generated using chemical methods. A 2x + 4 × cytochimera of the nonapomictic citrus variety 'Orah' mandarin, which developed from a bud mutant, was found due to its morphology differing from that of diploid plants and characterised via ploidy analysis combining flow cytometry and chromosome observation. The chimaera was stable, and there were 1.86-1.90 times as tetraploid cells as diploid cells. Anatomical structure observation revealed that the 'Orah' chimaera may be a periclinal chimaera with diploid cells in the L1 layer and tetraploid cells in the L2 and L3 layers. The chimaera showed some typical traits of polyploid plants, including thicker shoots, wider and thicker leaves, larger flowers and fruits, and fewer but larger seeds in fruits than in diploid plants. Almost all the seeds of the chimaera were monoembryonic. Most of the self-pollinated progenies of the chimaera were identified as tetraploids, and some triploid, pentaploid, and hexaploid plants were found. As a female, the chimaera produced allotriploids when crossed with Australian finger lime. In addition, 6 plants developed from polyembryonic seeds of the chimaera were identified as sexual tetraploid progenies with low-level recombinant genomes. Therefore, the 'Orah' 2x + 4 × chimaera can be used as a female parent to produce hybrid triploid and tetraploid citrus plants with high efficiency. Identification of the chimaera demonstrated that tetraploid citrus plants, especially nonapomictic varieties, can be generated from shoot bud mutants. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01456-x.

The Structure, Functions and Potential Medicinal Effects of Chlorophylls Derived from Microalgae.

Microalgae are considered to be natural producers of bioactive pigments, with the production of pigments from microalgae being a sustainable and economical strategy that promises to alleviate growing demand. Chlorophyll, as the main pigment of photosynthesis, has been widely studied, but its medicinal applications as an antioxidant, antibacterial, and antitumor reagent are still poorly understood. Chlorophyll is the most important pigment in plants and algae, which not only provides food for organisms throughout the biosphere, but also plays an important role in a variety of human and man-made applications. The biological activity of chlorophyll is closely related to its chemical structure; its specific structure offers the possibility for its medicinal applications. This paper reviews the structural and functional roles of microalgal chlorophylls, commonly used extraction methods, and recent advances in medicine, to provide a theoretical basis for the standardization and commercial production and application of chlorophylls.

Cellulose Nanofiber-Based Triboelectric Nanogenerators for Efficient Air Filtration in Harsh Environments.

Advanced portable healthcare devices with high efficiencies, small pressure drops, and high-temperature resistance are urgently desired in harsh environments with high temperatures, high humidities, and high levels of atmospheric pollution. Triboelectric nanogenerators (TENGs), which serve as energy converters in a revolutionary self-powered sensor device, present a sustainable solution for meeting these requirements. In this work, we developed a porous negative triboelectric material by synthesizing ZIF-8 on the surface of a cellulose/graphene oxide aerogel, grafting it with trimethoxy(1H,1H,2H,2H-heptadecafluorodecyl)silane, and adding a negative corona treatment, and it was combined with a positive triboelectric material to create a cellulose nanofiber-based TENG self-powered filter. The devices achieved a balance between a small pressure drop (53 Pa) and high filtration efficiency (98.97%, 99.65%, and 99.93% for PM0.3, PM0.5, and PM1, respectively), demonstrating robust filtration properties at high temperatures and high humidities. Our work provides a new approach for developing self-powered wearable healthcare devices with excellent air filtration properties.

Nanotechnologies meeting natural sources: Engineered lipoproteins for precise brain disease theranostics.

Biological nanotechnologies have provided considerable opportunities in the management of malignancies with delicate design and negligible toxicity, from preventive and diagnostic to therapeutic fields. Lipoproteins, because of their inherent blood-brain barrier permeability and lesion-homing capability, have been identified as promising strategies for high-performance theranostics of brain diseases. However, the application of natural lipoproteins remains limited owing to insufficient accumulation and complex purification processes, which can be critical for individual therapeutics and clinical translation. To address these issues, lipoprotein-inspired nano drug-delivery systems (nano-DDSs), which have been learned from nature, have been fabricated to achieve synergistic drug delivery involving site-specific accumulation and tractable preparation with versatile physicochemical functions. In this review, the barriers in brain disease treatment, advantages of state-of-the-art lipoprotein-inspired nano-DDSs, and bio-interactions of such nano-DDSs are highlighted. Furthermore, the characteristics and advanced applications of natural lipoproteins and tailor-made lipoprotein-inspired nano-DDSs are summarized. Specifically, the key designs and current applications of lipoprotein-inspired nano-DDSs in the field of brain disease therapy are intensively discussed. Finally, the current challenges and future perspectives in the field of lipoprotein-inspired nano-DDSs combined with other vehicles, such as exosomes, cell membranes, and bacteria, are discussed.

C5a enhances Vδ1 T cells recruitment via the CCL2-CCR2 axis in IgA nephropathy.

BACKGROUND: Mucosal immune-associated γδ T cells have been implicated in IgA nephropathy (IgAN). However, the involvement of Vδ1 T cells, the major γδ T cells subtype, in renal damage and the mechanism underlying their migration from peripheral blood to kidney in IgAN remain unclear. METHODS: Clinical data from IgAN patients and healthy controls (HC) were analyzed. Phenotypes and chemokine receptors of γδ T cell were compared between IgAN patients and HC. Immunohistochemistry and immunofluorescence were performed to assess the infiltration of γδ T cell subsets and the expression of chemokine in renal tissues. In vitro, C5a was used to stimulate the human glomerular mesangial cells (HMCs) and chemotaxis experiment was used to examine Vδ1 T cells migration. Correlation between Vδ1 T cells and related clinical indicators were analyzed. RESULTS: IgAN patients exhibited decreased Vδ1 T cell in blood but increased levels in kidneys compared to HC. Increased CCR2-expressing Vδ1 T cells and serum level of CCL2 were observed in IgAN patients. CCL2 co-localized with CCR2 in HMCs of IgAN. In vitro, C5a enhanced Vδ1 T cells recruitment by HMCs through CCL2-CCR2 axis. Importantly, circulating Vδ1 T cell levels showed a negatively correlated with both the urinary protein creatinine ratio (UACR) and 24-hour urine protein (UP). Moreover, kidney infiltration of Vδ1 cells positively correlated with UACR, UP, mesangial hyperplasia and renal tubule atrophy/interstitial fibrosis in IgAN. CONCLUSIONS: C5a-induced production of CCL2 by HMCs facilitates Vδ1 T cells recruitment via the CCL2-CCR2 axis, contributing to renal damage in IgAN.

Urinary isomorphic red blood cells for the prediction of disease severity and renal outcomes in MPO-ANCA-associated vasculitis: a retrospective cohort study.

BACKGROUND: Hematuria is common in myeloperoxidase anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-MPO). Previous studies have mainly focused on urinary dysmorphic red blood cells and few have reported the clinical significance of isomorphic urinary red blood cells. Therefore, the main aim of this study was to assess the predictive yield  of urinary isomorphic red blood cells for disease severity and renal outcomes in patients with ANCA-MPO associated vasculitis. METHODS: A total of 191 patients with ANCA-MPO associated vasculitis with hematuria were retrospectively selected and were divided into two groups (with isomorphic red blood cells versus dysmorphic red blood cells) according to the percentage of isomorphic red blood cells on urinary sediment analysis. Clinical, biological and pathological data at diagnosis were compared. Patients were followed up for a median of 25 months and progression to end-stage kidney disease and death were regarded as main outcome events. Additionally, univariate and multivariate Cox regression models were used to estimate the risk factors for end-stage kidney disease. RESULTS: Out of 191 patients, 115 (60%) had ≥ 70% and 76 (40%) had < 30% urine isomorphic red blood cells. Compared with patients in the dysmorphic red blood cell group, patients in the isomorphic red blood cell group had a significantly lower estimated glomerular filtration rate (eGFR) [10.41 mL/min (IQR 5.84-17.06) versus 12.53 (6.81-29.26); P = 0.026], higher Birmingham Vasculitis Activity Score [16 (IQR 12-18) versus 14 (10-18); P = 0.005] and more often received plasma exchange [40.0% versus 23.7% (P = 0.019)] at diagnosis. Kidney biopsies revealed a higher proportion of patients with glomerular basement membrane fracture in the isomorphic red blood cell group [46.3% versus 22.9% (P = 0.033)]. Furthermore, patients with predominant urinary isomorphic red blood cells were more likely to progress to end-stage kidney disease [63.5% versus 47.4% (P = 0.028)] and had a higher risk of death [31.3% versus 19.7% (P = 0.077)]. The end-stage kidney disease-free survival was lower in patients in the isomorphic red blood cell group (P = 0.024). However, urine isomorphic red blood cells ≥ 70% could not predict the presence of end-stage kidney disease in multivariate Cox analysis. CONCLUSION: Myeloperoxidase-anti-neutrophil cytoplasmic antibody associated vasculitis patients with predominant urinary isomorphic red blood cells at diagnosis had more severe clinical manifestations and a higher risk of poor renal outcomes. In this respect, urinary isomorphic red blood cells could be viewed as a promising biomarker of ANCA_MPO vasculitis severity and progression.

Estimation of optical properties of turbid media using spatially resolved diffuse reflectance combined with LSTM-attention network.

The accurate estimation of the optical properties of turbid media by using a spatially resolved (SR) technique remains a challenging task due to measurement errors in the acquired spatially resolved diffuse reflectance (SRDR) and challenges in inversion model implementation. In this study, what we believe to be a novel data-driven model based on a long short-term memory network and attention mechanism (LSTM-attention network) combined with SRDR is proposed for the accurate estimation of the optical properties of turbid media. The proposed LSTM-attention network divides the SRDR profile into multiple consecutive and partially overlaps sub-intervals by using the sliding window technique, and uses the divided sub-intervals as the input of the LSTM modules. It then introduces an attention mechanism to evaluate the output of each module automatically and form a score coefficient, finally obtaining an accurate estimation of the optical properties. The proposed LSTM-attention network is trained with Monte Carlo (MC) simulation data to overcome the difficulty in preparing training (reference) samples with known optical properties. Experimental results of the MC simulation data showed that the mean relative error (MRE) with 5.59% for the absorption coefficient [with the mean absolute error (MAE) of 0.04 cm-1, coefficient of determination (R2) of 0.9982, and root mean square error (RMSE) of 0.058 cm-1] and 1.18% for the reduced scattering coefficient (with an MAE of 0.208 cm-1, R2 of 0.9996, and RMSE of 0.237 cm-1), which were significantly better than those of the three comparative models. The SRDR profiles of 36 liquid phantoms, collected using a hyperspectral imaging system that covered a wavelength range of 530-900 nm, were used to test the performance of the proposed model further. The results showed that the LSTM-attention model achieved the best performance (with the MRE of 14.89%, MAE of 0.022 cm-1, R2 of 0.9603, and RMSE of 0.026 cm-1 for the absorption coefficient; and the MRE of 9.76%, MAE of 0.732 cm-1, R2 of 0.9701, and RMSE of 1.470 cm-1for the reduced scattering coefficient). Therefore, SRDR combined with the LSTM-attention model provides an effective method for improving the estimation accuracy of the optical properties of turbid media.

Organizing Pneumonia in A Patient Double-Positive for ANCA and Anti-GBM Antibodies: A Case Report.

Both anti-glomerular basement membrane (GBM) disease and the anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are common causes of pulmonary-renal syndrome. Organizing pneumonia (OP), a special pattern of interstitial lung disease, is extremely rare either in AAV or anti-GBM disease. We report an old woman presented with OP on a background of co-presentation with both ANCA and anti-GBM antibodies.

Mixotrophic culture of bait microalgae for biomass and nutrients accumulation and their synergistic carbon metabolism.

Microalgae cannot meet the bait demand for aquaculture due to light intensity limitation and other disadvantageous conditions. This research selected 6 mixotrophic microalgae, and the optimal strains and organic carbon were screened. The results showed that Thalassiosira pseudonana and Chlorella sp. are suitable for mixotrophic culture. The maximum cell density of Thalassiosira pseudonana was found to be 1.67 times than that of the photoautotrophic group when glycerol was added. The maximum cell density of Chlorella sp. with acetic acid was 1.69 times than that of the photoautotrophic group. When the concentration of acetic acid was 5.0 g·L-1 and the concentration of KNO3 was 0.2 g·L-1, the maximum biomass of Chlorella sp. could reach 3.54 × 107 cells·mL-1; the maximum biomass of Thalassiosira pseudonana was 5.53 × 106 cells·mL-1 with 10.0 g·L-1 glycerol and 0.2 g·L-1 KNO3. Metabolomic analysis further revealed that mixotrophic bait microalgae could promote the accumulation of lipids and amino acids.

Stimulating mechanism of corn oil on biomass and polysaccharide production of Pleurotus tuber-regium mycelium.

Hyperbranched polysaccharides (HBPSs) are the main components in cell wall and exopolysaccharide (EPS) of Pleurotus tuber-regium. To enhance the yield of these macromolecules, corn oil at 4% addition exhibited the best effect for production of mycelial biomass at 20.49 g/L and EPS at 0.59 g/L, which was 2.56 folds and 1.90 folds of the control, respectively. The treated hyphae were much thicker with smooth surface, while its cell wall content (43.81 ± 0.02%) was 1.96 times of the control (22.34 ± 0.01%). Moreover, a large number of lipid droplets could be visualized under the view of confocal laser scanning microscopy (CLSM). RNA-seq analysis revealed that corn oil could enter the cells and result in the up-regulation of genes on cell morphology and membrane permeability, as well as the down-regulation on expression level of polysaccharide hydrolase and genes involved in the MAPK pathway, all of which probably contribute to the increase of polysaccharides production.

Mechanical and biological properties of Ti-(0-25 wt%)Nb alloys for biomedical implants application.

Binary titanium-niobium (Ti-Nb) alloys have recently been attracted due to low Young's moduli and non-toxic properties. This study explores the influence of low Nb content (0-25 wt%) on the comprehensive parameters of tensile stress-strain relationships (ultimate strength (σUTS), yield strength (σ0.2) and elastic modulus (E)), surfaces properties (Vickers microhardness, surface roughness (R a), water contact angle (WCA), X-ray diffraction (XRD) and scanning electron microscopy (SEM)), corrosion resistance (in artificial saliva and lactic acid) and biological properties (cytotoxicity and alkaline phosphatase activity of MC3T3-E1 pre-osteoblasts) of Ti-xNb alloys (x = 5, 10, 15, 20 and 25 wt%), with using commercially pure grade 2 titanium (cp-Ti) as control. XRD results shown that all the Ti-xNb alloys comprised α + ß Ti alloy phases, such that the ß phase increased correspondingly with the increased amount of Nb in the alloy, as well as the reduction of E (69-87 GPa). Except Ti-5Nb, all other Ti-xNb alloys showed a significantly higher hardness, increased σUTS and σ0.2, and decreased WCA compared with cp-Ti. No corrosion was detected on Ti-xNb alloys and cp-Ti in artificial saliva and lactic acid solutions. The cytotoxicity of Ti-xNb alloys was comparable to that of cp-Ti in MC3T3-E1 pre-osteoblasts without interference from differentiation behaviour, but the proliferation rate of the Ti-5Nb alloy was lower than other groups. In overall, binary Ti-(10-25 wt%)Nb alloys are promising candidate for orthopaedic and dental implants due to their improved mechanical properties and comparable biological performance, while Ti-5Nb should be used with caution.

Neutrophil-to-lymphocyte ratio and incident end-stage renal disease in Chinese patients with chronic kidney disease: results from the Chinese Cohort Study of Chronic Kidney Disease (C-STRIDE).

BACKGROUND: Chronic kidney disease (CKD) leads to end-stage renal failure and cardiovascular events. An attribute to these progressions is abnormalities in inflammation, which can be evaluated using the neutrophil-to-lymphocyte ratio (NLR). We aimed to investigate the association of NLR with the progression of end stage of renal disease (ESRD), cardiovascular disease (CVD) and all-cause mortality in Chinese patients with stages 1-4 CKD. METHODS: Patients with stages 1-4 CKD (18-74 years of age) were recruited at 39 centers in 28 cities across 22 provinces in China since 2011. A total of 938 patients with complete NLR and other relevant clinical variables were included in the current analysis. Cox regression analysis was used to estimate the association between NLR and the outcomes including ESRD, CVD events or all-cause mortality. RESULTS: Baseline NLR was related to age, hypertension, serum triglycerides, total serum cholesterol, CVD history, urine albumin to creatinine ratio (ACR), chronic kidney disease-mineral and bone disorder (CKD-MBD), hyperlipidemia rate, diabetes, and estimated glomerular filtration rate (eGFR). The study duration was 4.55 years (IQR 3.52-5.28). Cox regression analysis revealed an association of NLR and the risk of ESRD only in patients with stage 4 CKD. We did not observe any significant associations between abnormal NLR and the risk of either CVD or all-cause mortality in CKD patients in general and CKD patients grouped according to the disease stages in particular. CONCLUSION: Our results suggest that NLR is associated with the risk of ESRD in Chinese patients with stage 4 CKD. NLR can be used in risk assessment for ESRD among patients with advanced CKD; this application is appealing considering NLR being a routine test. Trial registration ClinicalTrials.gov Identifier NCT03041987. Registered January 1, 2012. (retrospectively registered) ( https://www.clinicaltrials.gov/ct2/show/NCT03041987?term=Chinese+Cohort+Study+of+Chronic+Kidney+Disease+%28C-STRIDE%29&rank=1 ).

Wu-Tou Decoction Inhibits Angiogenesis in Experimental Arthritis by Targeting VEGFR2 Signaling Pathway.

Wu-tou decoction (WTD) is a classic traditional Chinese medicine formula and has been extensively used for the treatment of rheumatoid arthritis (RA). Previous reports indicate that WTD possesses anti-inflammatory and antinociceptive activities, and inhibits the development of arthritic joints and disease severity of collagen-induced arthritis (CIA) or adjuvant-induced rats; however, its action on angiogenesis of RA has not been clarified. This study aims to determine the anti-angiogenic activity of WTD in CIA rats and in various angiogenesis models. Our data showed that WTD (0.95, 1.9, and 3.8 g/kg) markedly reduced the immature blood vessels in synovial membrane tissues of inflamed joints from CIA rats. It also inhibited in vivo angiogenesis in chick embryo and VEGF165-induced microvessel sprout formation ex vivo. Meanwhile, WTD suppressed VEGF165-/MH7A-induced migration, invasion, adhesion, and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, WTD significantly reduced the expression of angiogenic activators, including vascular endothelial growth factor (VEGF), VEGFR2, interleukin (IL)-1ß, IL-17, transforming growth factor-ß, platelet-derived growth factor, placenta growth factor, angiopoietin (Ang) I and Ang II in synovium of CIA rats, and/or in HUVECs. More interestingly, WTD blocked the autophosphorylation of VEGF165-induced VEGFR2 and consequently downregulated the signaling pathways of activated AKT, ERK1/2, JNK, and p38 in VEGF165-induced HUVECs. These findings suggest for the first time that WTD possesses the anti-angiogenic effect in RA in vivo, ex vivo, and in vitro by interrupting the targeting of VEGFR2 activation.

CTC clusters induced by heparanase enhance breast cancer metastasis.

Aggregated metastatic cancer cells, referred to as circulating tumor cell (CTC) clusters, are present in the blood of cancer patients and contribute to cancer metastasis. However, the origin of CTC clusters, especially intravascular aggregates, remains unknown. Here, we employ suspension culture methods to mimic CTC cluster formation in the circulation of breast cancer patients. CTC clusters generated using these methods exhibited an increased metastatic potential that was defined by the overexpression of heparanase (HPSE). Heparanase induced FAK- and ICAM-1-dependent cell adhesion, which promoted intravascular cell aggregation. Moreover, knockdown of heparanase or inhibition of its activity with JG6, a heparanase inhibitor, was sufficient to block the formation of cell clusters and suppress breast cancer metastasis. Our data reveal that heparanase-mediated cell adhesion is critical for metastasis mediated by intravascular CTC clusters. We also suggest that targeting the function of heparanase in cancer cell dissemination might limit metastatic progression.

Molecular mechanisms of the analgesic action of Wu-tou Decoction on neuropathic pain in mice revealed using microarray and network analysis.

Wu-tou Decoction (WTD) is a classic herbal formula in traditional Chinese medicine for the treatment of joint diseases, neuropathic pain (NP) and inflammatory pain. In this study we investigated whether WTD produced analgesic action in a mouse spinal nerve ligation (SNL) model and elucidated the underlying molecular mechanisms. Mice were subjected to SNL and orally treated with WTD (3.15, 6.30 or 12.60 g·kg-1·d-1) for 21 d. SNL induced mechanical hyperalgesia and heat hyperalgesia characterized by rapid and persistent pain hypersensitivity. In addition, the expression levels of IL-1ß, TNF-α, CCL2 and CXCL1 in the spinal cord dorsal horn were dramatically increased on the 10th d post-surgery. Oral administration of WTD dose-dependently suppressed both mechanical and heat hyperalgesia as well as the expression levels of inflammatory cytokines in the spinal cord dorsal horn on the 21st d post-surgery. Then whole-genome microarray analyses were conducted to detect the gene expression profiles of spinal cord dorsal horn in SNL mice with or without WTD treatment. After construction of the WTD-SNL-network and topological analysis, a list of candidate target genes of WTD acting on SNL-induced NP was identified and found to be functionally enriched in several glial cell activation-related pathways and neuroinflammatory pathways. Our data have clarified the gene expression patterns in the mouse spinal cord under the NP condition. We also demonstrate the analgesic action of WTD through suppression of glial cell activation and neuroinflammation, which suggest the potential of WTD as a promising candidate for the treatment of NP.

Macrophage migration inhibitory factor promotes tumor aggressiveness of esophageal squamous cell carcinoma via activation of Akt and inactivation of GSK3ß.

The pleiotropic pro-inflammatory cytokine, macrophage migration inhibitory factor (MIF), represents an important link between chronic inflammation and tumorigenesis. Although accumulating evidence demonstrates that MIF overexpression is implicated in the development and progression of multiple cancers, including esophageal squamous cell carcinoma (ESCC), the molecular mechanisms underlying its tumor-promoting roles in ESCC remain unclear. In the present study, we observed that MIF is overexpressed in ESCC and correlated significantly with lymph node metastasis, advanced clinical stage, and poor survival of ESCC. MIF knockdown attenuated the proliferation, migration, and invasion of ESCC cells in vitro and in vivo. Moreover, blockage of MIF expression decreased the activation of the Akt, MEK/ERK, and NF-κB pathways and enhanced sensitivity to apoptosis. Meanwhile, repression of MIF expression resulted in activation of glycogen synthase kinase 3 beta (GSK3ß) and subsequent decrease of active ß-catenin, as well as its downstream targets including cyclin D1, matrix metalloproteinase (MMP)-7, c-myc, and c-Jun. Collectively, our results provided mechanistic insights into the tumor-promoting role of MIF in ESCC, and suggested that MIF represents a potential therapeutic target for treatment of ESCC.