Acute toxicity study of tilmicosin-loaded hydrogenated castor oil-solid lipid nanoparticles

<p>Abstract</p> <p>Background</p> <p>Our previous studies demonstrated that tilmicosin-loaded hydrogenated castor oil solid lipid nanoparticles (Til-HCO-SLN) are a promising formulation for enhanced pharmacological activity and therapeutic efficacy in veterinary use. The purpose of this work was to evaluate the acute toxicity of Til-HCO-SLN.</p> <p>Methods</p> <p>Two nanoparticle doses were used for the study in ICR mice. The low dose (766 mg/kg.bw) with tilmicosin 7.5 times of the clinic dosage and below the median lethal dose (LD₅₀) was subcutaneously administered twice on the first and 7th day. The single high dose (5 g/kg.bw) was the practical upper limit in an acute toxicity study and was administered subcutaneously on the first day. Blank HCO-SLN, native tilmicosin, and saline solution were included as controls. After medication, animals were monitored over 14 days, and then necropsied. Signs of toxicity were evaluated via mortality, symptoms of treatment effect, gross and microscopic pathology, and hematologic and biochemical parameters.</p> <p>Results</p> <p>After administration of native tilmicosin, all mice died within 2 h in the high dose group, in the low dose group 3 died after the first and 2 died after the second injections. The surviving mice in the tilmicosin low dose group showed hypoactivity, accelerated breath, gloomy spirit and lethargy. In contrast, all mice in Til-HCO-SLN and blank HCO-SLN groups survived at both low and high doses. The high nanoparticle dose induced transient clinical symptoms of treatment effect such as transient reversible action retardation, anorexy and gloomy spirit, increased spleen and liver coefficients and decreased heart coefficients, microscopic pathological changes of liver, spleen and heart, and minor changes in hematologic and biochemical parameters, but no adverse effects were observed in the nanoparticle low dose group.</p> <p>Conclusions</p> <p>The results revealed that the LD₅₀of Til-HCO-SLN and blank HCO-SLN exceeded 5 g/kg.bw and thus the nanoparticles are considered low toxic according to the toxicity categories of chemicals. Moreover, HCO-SLN significantly decreased the toxicity of tilmicosin. Normal clinic dosage of Til-HCO-SLN is safe as evaluated by acute toxicity.</p

Testicular Characteristics and the Block to Spermatogenesis in Mature Hinny

Most hinnies (female donkey×male horse) and mules (female horse×male donkey) are sterile with few reports of equine fertile hybrids. The main cause of this sterility is thought to be a meiotic block to spermatogenesis and oogenesis. This study compared the developmental features of the testes and a histological analyses of spermatogenesis in a male hinny with those of a normal, fertile stallion and Jack donkey. Hinny testes showed a thicker tunica albuginea, fewer blood vessels and more connective tissue in the testis parenchyma than those of the stallion and Jack donkey. Although the mean number of seminiferous tubules was significantly higher in stallion and hinny than Jack donkey (p<0.01), the mean proportion of seminiferous tubules was lower in the hinny (p<0.01) which resulted in a smaller diameter of seminiferous tubules. The mean number of spermatogonia and spermatocytes per unit area were significantly lower in hinny testis (p<0.01) and no spermatids or mature spermatozoa cells were found during immunofluorescent analyses. These results indicated that defects in seminiferous tubule development and structure occur in the testis of hinnies. Furthermore, most spermatogonia and spermatocytes cease development in synapsis during mid-meiosis of spermatocytes, which results in a block to spermatogenesis that prevents the formation of spermatids and matured spermatozoa during meiosis in male hinnies

Experimental and analytical study on heating and road performance of asphalt mixture with silicon carbide and ferroferric oxide composite structure layer

Microwave heating is currently considered to be the most promising clean energy technology for asphalt pavement deicing. In order to improve the heating efficiency of pavement surface, a 10 mm silicon carbide (SiC) and ferroferric oxide (Fe3O4) composite structure layer (CSL) was designed on the pavement surface. The surface heating efficiency and road performance of asphalt mixture with CSL were investigated by laboratory experiments, and the distribution of electromagnetic and temperature fields were analyzed by numerical simulations. The experimental results show that the surface temperature of asphalt mixture with CSL was 1.64 and 1.36 times higher than that of the ordinary asphalt mixture and the asphalt mixture with SiC and Fe3O4 composite material, and it remained stable before and after repeated heating and water bath, with a difference of only 1 ℃∼1.7 ℃. The asphalt mixture with CSL had good road performance. The Marshall stability, residual stability and interlayer shear strength could remain above 10 kN, 92% and 4 MPa after repeated heating. The numerical simulation results show that the asphalt mixture mixed with microwave absorbing materials produced a larger electromagnetic field intensity. The heat of asphalt mixture with CSL was mainly concentrated on the road surface because the absorbing material was concentrated on the road surface. In contrast, because there was no difference in microwave absorption capacity throughout the asphalt mixture with SiC and Fe3O4 composite material, the heat distribution was mainly influenced by the electromagnetic field intensity. In general, asphalt mixture with CSL has higher surface heating efficiency and road performance

Metabolic codependencies in the tumor microenvironment and gastric cancer: Difficulties and opportunities

Oncogenesis and the development of tumors affect metabolism throughout the body. Metabolic reprogramming (also known as metabolic remodeling) is a feature of malignant tumors that is driven by oncogenic changes in the cancer cells themselves as well as by cytokines in the tumor microenvironment. These include endothelial cells, matrix fibroblasts, immune cells, and malignant tumor cells. The heterogeneity of mutant clones is affected by the actions of other cells in the tumor and by metabolites and cytokines in the microenvironment. Metabolism can also influence immune cell phenotype and function. Metabolic reprogramming of cancer cells is the result of a convergence of both internal and external signals. The basal metabolic state is maintained by internal signaling, while external signaling fine-tunes the metabolic process based on metabolite availability and cellular needs. This paper reviews the metabolic characteristics of gastric cancer, focusing on the intrinsic and extrinsic mechanisms that drive cancer metabolism in the tumor microenvironment, and interactions between tumor cell metabolic changes and microenvironment metabolic changes. This information will be helpful for the individualized metabolic treatment of gastric cancers

Hypoxia promotes gastric cancer malignancy partly through the HIF-1α dependent transcriptional activation of the long non-coding RNA GAPLINC

Hypoxia-inducible factor (HIF) activates the transcription of genes involved in cancer progression. Recently, HIF was reported to regulate the transcription of non-coding RNAs. Here, we show that the transcription of a long non-coding RNA (lncRNA), Gastric Adenocarcinoma Associated, Positive CD44 Regulator, Long Intergenic Non-Coding RNA (GAPLINC), is directly activated by HIF-1α in gastric cancer (GC). GAPLINC was overexpressed in GC tissues and promoted tumor migration and invasive behavior. GAPLINC overexpression was associated with poor prognosis in GC patients. Luciferase reporter assays and chromatin immunoprecipitation assays confirmed that HIF-1α binds to the promoter region of GAPLINC and activates its transcription. GAPLINC knockdown inhibited hypoxia-induced tumor proliferation in vivo. Taken together, our results identified a novel role for HIF transcriptional pathways in GC tumorigenesis mediated by the regulation of the lncRNA GAPLINC, and suggest GAPLINC as a novel therapeutic target for reversing chemoradioresistance and prolonging survival

Proteomic analysis of the hepatopancreas of Exopalaemon carinicauda in response to Metschnikowia bicuspidate infection

The ridge-tail white prawn, Exopalaemon carinicauda, is an important economic shrimp in the mariculture of China, especially in Jiangsu Province. The “zombie disease” of ridge-tail prawn is a new epidemic that is a highly transmissible and pathogenic fungal disease caused by Metschnikowia bicuspidate infection. To understand the response mechanism of E. carinicauda after M. bicuspidate infection, the hepatopancreas of shrimp injected with M. bicuspidate MQ2101 and normal saline solution were used for proteomics analysis. A total of 5078 proteins were identified, of which 1708 proteins were identified as differentially expressed proteins (DEPs, 1311 upregulated and 397 downregulated) using a 1.2-fold change in expression as a physiologically significant benchmark. These DEPs were mainly involved in cellular processes, single-organism processes, and metabolic processes in the GO enrichment analysis and metabolism, translation, signal transduction, cell growth and death, and immune system pathways in the KEGG enrichment analysis. The DEPs related to immunity and metabolism were significantly changed, such as CTSB, CPs, DSP1, GDP, and ADH3, and these proteins might be potential determinants of E. carinicauda responses to M. bicuspidata infection. qRTPCR was used to detect changes in the expression of nine DEP-related genes at the transcriptional level to validate the proteomics analysis results, and the results of the transcription tendencies in qRTPCR were consistent with proteomics analysis. The results of this study might provide an important theoretical basis for the response mechanism of ridge-tail white prawns to M. bicuspidate infection and scientific prevention and control of this fungus in ridge-tail white prawn aquaculture. Availability of data and materials: The data that support the results of this present study are available from the corresponding author upon reasonable request

Morphological Development of Sub-Grain Cellular/Bands Microstructures in Selective Laser Melting

In this paper, single-layer and bulk 316 L selective laser melting (SLM) experiments were conducted, fine submicron-scale geometric symmetrical cellular (hexagonal, pentagonal and square), elongated cellular and bands solidification morphologies were found in the laser-melt top surface. Meanwhile, morphological developed sub-grain patterns with quasi-hexagonal cellular, elongated cellular and bands structures (size ~1 &#956;m) coexisting inside one single macro-solidified grain were also identified. This demonstrated the transitions from quasi-hexagonal-cells to elongated cells/bands, and transitions reverse, occurred in the whole bulk under some circumstances during SLM. Based on the experimental realities, these morphologies are formed by the local convection and B&#233;nard instabilities in front of the solid/liquid interface (so-called mushy zones) affected by intricate temperature and surface tension gradients. Quasi-hexagonal cellular convective fields are then superimposed on macro-grain solidification to form the sub-grain patterns and micro-segregations. This explanation seems reasonable and is unifying as it can be expanded to other eutectic alloys with face center cubic (FCC) prevenient phase prepared by SLM, e.g., the Al-Si and Co-Cr-Mo systems

Preparation of size tunable, glutathione-responsive hyaluronic acid-quantum dot nanohybrids using microemulsion method

In this paper, a new method for preparing hyaluronic acid-quantum dot (HA-QD) nanohybrids, which are highly monodispersed, colloidally stable, glutathione (GSH)-responsive and size tunable from 80-500 nm, is reported. Due to the fact that HA is a naturally exist polymer and many types of cancer cells are overexpressed with HA receptors on their surfaces, HA has become one of the promising materials to prepare nanocarriers for theranostics applications. Our design is based on the disulfide chemical structure of cystamine dihydrochloride which has been served as the crosslinker. HA-QDs were synthesized in the nano-cavities created by the microemulsion system. The prepared HA-QDs are GSH-responsive. In the presence of GSH, the disulfide bonds can be cleaved and it leads to the degradation of HA-QDs into smaller fragments. Our in vitro studies show that the HA-QDs are highly specific to the pancreatic and cervix cancer cells and no toxicity was detected in the cell proliferation (MTS) assays, revealing the great potentials to use HA-based nanohybrids for cancer imaging and therapy

Silver-Mediated Direct C–H Cyanation of Terminal Alkynes with <i>N</i>‑Isocyanoiminotriphenylphosphorane

A direct cyanation of terminal alkynes for the synthesis of propionitrile derivatives, with the aid of silver salt using water additive, has been achieved. The cyano source used is <i>N</i>-isocyanoiminotriphenylphosphorane, which is nontoxic, safe, and easy to handle. This protocol is characterized by its operational simplicity, high efficiency with excellent yields, broad substrate scope, and greater functional group tolerance

Radical Enamination of Vinyl Azides: Direct Synthesis of <i>N</i>‑Unprotected Enamines

An electron-withdrawing-group-generable radical-induced enamination of vinyl azides is reported, which results in a variety of β-functionalized <i>N</i>-unprotected enamines in a stereoselective manner. A plausible mechanism involving an unusual 1,3-H transfer of in situ generated iminyl radical intermediate was proposed on the basis of experimental results and DFT calculations