Majority of neuroblastoma patients develop metastatic disease at diagnosis and their prognosis is poor with current therapeutic approach. Major challenges are how to tackle the mechanisms responsible ...for tumorigenesis and metastasis. Human mesenchymal stem cells (hMSCs) may be actively involved in the constitution of cancer microenvironment.
An orthotopic neuroblastoma murine model was utilized to mimic the clinical scenario. Human neuroblastoma cell line SK-N-LP was transfected with luciferase gene, which were inoculated with/without hMSCs into the adrenal area of SCID-beige mice. The growth and metastasis of neuroblastoma was observed by using Xenogen IVIS 100 in vivo imaging and evaluating gross tumors ex vivo. The homing of hMSCs towards tumor was analyzed by tracing fluorescence signal tagged on hMSCs using CRI Maestro™ imaging system.
hMSCs mixed with neuroblastoma cells significantly accelerated tumor growth and apparently enhanced metastasis of neuroblastoma in vivo. hMSCs could be recruited by primary tumor and also become part of the tumor microenvironment in the metastatic lesion. The metastatic potential was consistently reduced in lung and tumor when hMSCs were pre-treated with stromal cell derived factor-1 (SDF-1) blocker, AMD3100, suggesting that the SDF-1/CXCR4 axis was one of the prime movers in the metastatic process.
hMSCs accelerated and facilitated tumor formation, growth and metastasis. Furthermore, the homing propensity of hMSCs towards both primary tumor and metastatic loci can also provide new therapeutic insights in utilizing bio-engineered hMSCs as vehicles for targeted anti-cancer therapy.
In terms of photoelectrochemical (PEC) hydrogen evolution, substantial challenge still remains regarding the controllable fabrication of quantum dots (QDs)-sensitized photocathodes with enhanced ...visible-light absorption, efficient charge carrier separation, and directional migration at the electrode interface. In this work, the CdTe/CdSe QDs-sensitized photocathodes were delicately constructed on p-type NiO-coated indium tin oxide (ITO) electrodes by spin-coating approach. The resulting co-sensitized photocathode exhibits a favorable pseudo-Type II energetic band alignment that combines the advantages of strong light absorption of constituent QDs as well as the effective and oriented charge separation and migration. Upon green LED light illumination, the photogenerated electrons could be effectively transferred to a tetra-nickel-substituted polyoxometalate catalyst for hydrogen production while photogenerated holes will be scavenged at the NiO/ITO electrode. Under minimally optimized conditions, the pseudo-Type II CdTe/CdSe-sensitized photocathode yields a photocurrent density of over 100 µA/cm
2
and a Faradaic efficiency of ∼ 100%, which is among one of the most efficient QDs-based photocathode systems coupling with Ni-substituted polyoxometalate catalyst for photoelectrochemical hydrogen generation.
Socially directed gaze following is an important component of social interaction and communication, allowing us to attend mutually with others to objects or people so that we can share their ...experience and also learn from them. This type of joint social attention is impaired in disorders such as autism. Previous research has demonstrated that the neuropeptide oxytocin can facilitate attention toward social cues, although to date no study in humans has investigated its influence on socially directed gaze or on associations of the latter with autistic and empathic traits. In a within‐subject, randomized, placebo‐controlled trial we used eye‐tracking to investigate the effects of intranasal oxytocin (24 IU) on socially directed gaze toward one of two objects in 40 adult male subjects. Subjects viewed videos of an actor and actress directing their gaze toward one of two objects by either moving only their eyes, moving both their eyes and head, or moving their eyes and head and pointing with a finger. Results showed that OXT increased the proportion of time subjects viewed the object the actor or actress were looking/pointing at across all three conditions, although unexpectedly we found no associations with trait autism or empathy under either placebo or OXT treatments. These findings demonstrate that OXT can facilitate socially directed gaze following to promote mutual attention toward objects which may be potentially beneficial therapeutically in disorders with impaired social communication and interaction.
Our ability to share socially important information through joint social attention is of critical importance for normal social communication and interaction and is impaired in disorders such as autism. Here in a placebo controlled randomized trial we used eye‐tracking to show for the first time that intranasal oxytocin administration facilitates gaze‐following behavior in humans. Our findings therefore suggest that oxytocin may have a potential therapeutic role in disorders with impaired joint social attention.
Weaning stress caused marked changes in intestinal structure and function. Transforming growth factor-β1 (TGF-β1) and canonical Smads signaling pathway are suspected to play an important regulatory ...role in post-weaning adaptation of the small intestine. In the present study, the intestinal morphology and permeability, developmental expressions of tight junction proteins and TGF-β1 in the intestine of piglets during the 2 weeks after weaning were assessed. The expressions of TGF-β receptor I/II (TβRI, TβRII), smad2/3, smad4 and smad7 were determined to investigate whether canonical smads signaling pathways were involved in early weaning adaption process. The results showed that a shorter villus and deeper crypt were observed on d 3 and d 7 postweaning and intestinal morphology recovered to preweaning values on d 14 postweaning. Early weaning increased (P<0.05) plasma level of diamine oxidase (DAO) and decreased DAO activities (P<0.05) in intestinal mucosa on d 3 and d 7 post-weaning. Compared with the pre-weaning stage (d 0), tight junction proteins level of occludin and claudin-1 were reduced (P<0.05) on d 3, 7 and 14 post-weaning, and ZO-1 protein was reduced (P<0.05) on d 3 and d 7 post-weaning. An increase (P<0.05) of TGF-β1 in intestinal mucosa was observed on d 3 and d 7 and then level down on d 14 post-weaning. Although there was an increase (P<0.05) of TβR II protein expression in the intestinal mucosa on d3 and d 7, no significant increase of mRNA of TβRI, TβRII, smad2/3, smad4 and smad7 was observed during postweaning. The results indicated that TGF-β1 was associated with the restoration of intestinal morphology and barrier function following weaning stress. The increased intestinal endogenous TGF-β1 didn't activate the canonical Smads signaling pathway.
How to enhance the homing of human mesenchymal stem cells (hMSCs) to the target tissues remains a clinical challenge nowadays. To overcome this barrier, the mechanism responsible for the hMSCs ...migration and engraftment has to be defined. Currently, the exact mechanism involved in migration and adhesion of hMSCs remains unknown. Exchange protein directly activated by cAMP (Epac), a novel protein discovered in cAMP signaling pathway, may have a potential role in regulating cells adhesion and migration by triggering the downstream Rap family signaling cascades. However, the exact role of Epac in cells homing is elusive. Our study evaluated the role of Epac in the homing of hMSCs. We confirmed that hMSCs expressed functional Epac and its activation enhanced the migration and adhesion of hMSCs significantly. The Epac activation was further found to be contributed directly to the chemotactic responses induced by stromal cell derived factor-1 (SDF-1) which is a known chemokine in regulating hMSCs homing. These findings suggested Epac is connected to the SDF-1 signaling cascades. In conclusion, our study revealed that Epac plays a role in hMSCs homing by promoting adhesion and migration. Appropriate manipulation of Epac may enhance the homing of hMSCs and facilitate their future clinical applications.
Lysine-specific demethylase 5B (KDM5B) has been recognized as a potential drug target for cardiovascular diseases. In this work, we first found that the KDM5B level was increased in mouse hearts ...after transverse aortic constriction (TAC) and in Ang II-induced activated cardiac fibroblasts. Structure-based design and further optimizations led to the discovery of highly potent pyrazole-based KDM5B inhibitor TK-129 (IC50 = 0.044 μM). TK-129 reduced Ang II-induced activation of cardiac fibroblasts in vitro, exhibited good PK profile (F = 42.37%), and reduced isoprenaline-induced myocardial remodeling and fibrosis in vivo. Mechanistically, we found that KDM5B up-regulation in cardiac fibroblast activation was associated with the activation of Wnt-related pathway. The protective effects of TK-129 were associated with its KDM5B inhibition and blocking KDM5B-related Wnt pathway activation. Taken together, TK-129 may represent a novel KDM5-targeting lead compound for cardiac remodeling and fibrosis.
An 8‐week feeding trial was conducted to investigate the effects of dietary manganese (Mn) levels on growth performance, Mn bioaccumulation in tissues and antioxidant capacity in juvenile swimming ...crab (Portunus trituberculatus). Six semipurified experimental diets were formulated to contain graded levels of Mn (manganese sulphate monohydrate as Mn source); the analysed Mn concentrations were 9.8, 20.2, 29.7, 38.2, 65.6 and 123.6 mg/kg. The percent weight gain (PWG) and specific growth rate (SGR) were significantly affected by dietary Mn levels; the highest PWG and SGR were found in crabs fed with the diet containing 38.2 mg/kg Mn. Crabs fed with the diet containing 123.6 mg/kg Mn had higher Mn concentration in muscle and carapace than those fed with the other diets. However, the highest Mn concentration in hepatopancreas was recorded in crabs fed with the diet containing 65.6 mg/kg Mn. Moreover, the lowest activities of manganese superoxide dismutase (Mn‐SOD), catalase (CAT) and total antioxidant capacity (T‐AOC) occurred at crabs fed with the dietary 9.8 mg/kg Mn. Crabs fed with the 9.8 mg/kg Mn diet exhibited lower relative expression of genes involved into antioxidant ability such as cytosolic manganese superoxide dismutase (cMnsod), glutathione peroxidase (gpx), peroxiredoxin (prx) and catalase (cat) in hepatopancreas than those fed with the other diets, and the highest expression were recorded in crabs fed with the diet containing 38.2 mg/kg Mn. Based on two slope broken‐line and quadratic regression analysis of PWG against dietary Mn levels, the optimum dietary Mn requirement was estimated to be 48.02 and 53.30 mg/kg for juvenile Portunus trituberculatus. The present study provided further insight into the function of dietary Mn in crustacean.
Daptomycin is a cyclic lipopeptide antibiotic with a significant antibacterial action against antibiotic-resistant Gram-positive bacteria. Despite numerous attempts to enhance daptomycin yield ...throughout the years, the production remains unsatisfactory. This study reports the application of multilevel metabolic engineering strategies in
to reconstruct high-quality daptomycin overproducing strain L2797-VHb, including precursor engineering (i.e., refactoring kynurenine pathway), regulatory pathway reconstruction (i.e., knocking out negative regulatory genes
and
), byproduct engineering (i.e., removing pigment), multicopy biosynthetic gene cluster (BGC), and fermentation process engineering (i.e., enhancing O
supply). The daptomycin titer of L2797-VHb arrived at 113 mg/l with 565% higher comparing the starting strain L2790 (17 mg/l) in shake flasks and was further increased to 786 mg/l in 15 L fermenter. This multilevel metabolic engineering method not only effectively increases daptomycin production, but can also be applied to enhance antibiotic production in other industrial strains.
To discover novel anticancer agents with potent and low toxicity, we designed and synthesized a range of new thiosemicarbazone-indole analogues based on lead compound 4 we reported previously. Most ...compounds displayed moderate to high anticancer activities against five tested tumor cells (PC3, EC109, DU-145, MGC803, MCF-7). Specifically, the represented compound 16f possessed strong antiproliferative potency and high selectivity toward PC3 cells with the IC50 value of 0.054 μM, compared with normal WPMY-1 cells with the IC50 value of 19.470 μM. Preliminary mechanism research indicated that compound 16f could significantly suppress prostate cancer cells (PC3, DU-145) growth and colony formation in a dose-dependent manner. Besides, derivative 16f induced G1/S cycle arrest and apoptosis, which may be related to ROS accumulation due to the activation of MAPK signaling pathway. Furthermore, molecule 16f could effectively inhibit tumor growth through a xenograft model bearing PC3 cells and had no evident toxicity in vivo. Overall, based on the biological activity evaluation, analogue 16f can be viewed as a potential lead compound for further development of novel anti-prostate cancer drug.
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•New thiosemicarbazone-indole derivatives were designed and synthesized based on previous work.•Most compounds were more sensitive to prostate cancer PC3 cells in comparison to other cancer cells.•16f exhibited stronger activity and better safety profile than 3-AP, DPC and lead 4.•16f induced G1/S cycle arrest and apoptosis in prostate cancer cells (PC3, DU-145) via ROS accumulation.
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