Involvement of C6-volatiles in quality formation of herbal medicine: A case study in Astragalus membranaceus var. mongholicus

In this study, the effects of exogenous C6-volatiles on Astragalus membranaceus var. mongholicus growth and secondary metabolism were explored. Five-week old seedlings of A. membranaceus var. mongholicus were exposed to different concentrations of soil-borne hexanal (10, 50, 100 μM) twice/week for 4 weeks. Non-treated plants serve as control. Growth, bioactive compounds and gene expression were measured by conventional and “omic” approaches. The results demonstrated: (1) all doses of hexanal significantly decreased chlorophyll a/b contents; (2) 10 and 100 μM hexanal significantly decreased the shoot length while 50 μM hexanal kept the value at the same level as it was in the control; (3) 50 μM hexanal effectively enhanced the contents of bioactive compounds in roots and the others had no obvious effect; (4) 50 μM hexanal induced more dysregulated metabolites in leaves than in roots, especially those associated with lipid metabolism; (5) expression of unigenes annotaed as “plant-pathogen interaction”, “secondary metabolism” and “lipid metabolism” were largely induced as well as those classified into multiple growth and defense signaling pathways. Taken together, C6-volatiles can serve as potential elicitors for quality formation of herbal medicines. The online version of this article (doi: 10.5073/JABFQ.2017.090.027) contains supplementary files

Study on effect of extrusion of the former tube based on DEFORM-3D

In order to obtain the optimum forming process of the Former tube, two forming schemes were made based on the actual production and processing experience and theory. The two forming schemes were simulated by DEFORM-3D. The optimal forming scheme was determined and the influence of different friction factors and different mould hardness on mould wear and forming load were analyzed; The research results of this paper can provide theoretical guidance for the production and processing of the former tube parts, which can improve the machining quality and precision of the parts, reduce the cost of the test module, and obtain a better shaping effect

Comparisons of three polyethyleneimine-derived nanoparticles as a gene therapy delivery system for renal cell carcinoma

<p>Abstract</p> <p>Background</p> <p>Polyethyleneimine (PEI), which can interact with negatively charged DNA through electrostatic interaction to form nanocomplexes, has been widely attempted to use as a gene delivery system. However, PEI has some defects that are not fit for keeping on gene expression. Therefore, some modifications against PEI properties have been done to improve their application value in gene delivery. In this study, three modified PEI derivatives, including poly(ε-caprolactone)-pluronic-poly(ε-caprolactone) grafted PEI (PCFC-g-PEI), folic acid-PCFC-isophorone diidocyanate-PEI (FA-PEAs) and heparin-PEI (HPEI), were evaluated in terms of their cytotoxicity and transfection efficiency <it>in vitro </it>and <it>in vivo </it>in order to ascertain their potential application in gene therapy.</p> <p>Methods</p> <p>MTT assay and a marker GFP gene, encoding green fluorescent protein, were used to evaluate cell toxicity and transfection activity of the three modified PEI <it>in vitro</it>. Renal cell carcinoma (RCC) models were established in BALB/c nude mice inoculated with OS-RC-2 cells to detect the gene therapy effects using the three PEI-derived nanoparticles as gene delivery vehicles. The expression status of a target gene Von Hippel-Lindau (VHL) in treated tumor tissues was analyzed by semiquantitative RT-PCR and immunohistochemistry.</p> <p>Results</p> <p>Each of three modified PEI-derived biomaterials had an increased transfection efficiency and a lower cytotoxicity compared with its precursor PEI with 25-kD or 2-kD molecule weight <it>in vitro</it>. And the mean tumor volume was obviously decreased 30% by using FA-PEAs to transfer VHL plasmids to treat mice RCC models. The VHL gene expression was greatly improved in the VHL-treated group. While there was no obvious tumor inhibition treated by PCFC-g-PEI:VHL and HPEI:VHL complexes.</p> <p>Conclusions</p> <p>The three modified PEI-derived biomaterials, including PCFC-g-PEI, FA-PEAs and HPEI, had an increased transfection efficiency <it>in vitro </it>and obviously lower toxicities compared with their precursor PEI molecules. The FA-PEAs probably provide a potential gene delivery system to treat RCC even other cancers in future.</p

Efficacy and safety of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer: a systematic review and meta-analysis

BackgroundVarious trials have demonstrated the clinical benefits of lenvatinib plus pembrolizumab in patients with advanced or recurrent endometrial cancer, regardless of mismatch repair (MMR) status or histologic subtype. The majority of the previously published trials had small sample sizes. Here, we aimed to assess the reported efficacy and safety profile of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer.MethodsWe utilized the Cochrane Library, PubMed, Web of Science and Embase databases to identify clinical trials evaluating the efficacy and safety of lenvatinib plus pembrolizumab in patients with advanced and recurrent endometrial cancer. The outcomes analyzed were progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR) and the incidence of adverse events (AEs). Subgroup analysis was conducted on the basis of MMR status (deficient, dMMR or proficient, pMMR).ResultsFour trials (582 patients) were included. The pooled ORR was 32.7% [95% confidence interval (CI): 28.9–36.5]. Subgroup analysis revealed an ORR of 48.1% (95% CI: 26.1–70.2) for dMMR group and 33.1% (95% CI: 25.7–40.6) for pMMR group. The pooled DCR was 74.9% (95% CI: 71.3–78.4%). Subgroup analysis revealed a DCR of 81.0% (95% CI: 64.5–97.6) for the dMMR group and 76.3% (95% CI: 66.3–86.3) for the pMMR group. Follow-up was reported in all included studies. The median range time of PFS and OS was 5.3 months-258 days and 17.2 months-not reached, respectively. Regarding safety, the overall pooled proportions of any-grade AE and AEs ≥ grade 3 were 95.8% (95% CI: 89.5–100.0) and 80.2% (95% CI: 59.9–100.0), respectively.ConclusionLenvatinib plus pembrolizumab showed a relevant clinical benefit and significant toxicity in patients with advanced and recurrent endometrial cancer. Further studies encompassing long-term outcomes are warranted.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=522160/, identifier CRD42024522160

Prion infection impairs cholesterol metabolism in neuronal cells

Conversion of prion protein (PrPC) into a pathological isoform (PrPSc) during prion infection occurs in lipid rafts and is dependent on cholesterol. Here, we show that prion infection increases the abundance of cholesterol transporter, ATP-binding cassette transporter type A1 (ATP-binding cassette transporter type A1), but reduces cholesterol efflux from neuronal cells leading to the accumulation of cellular cholesterol. Increased abundance of ABCA1 in prion disease was confirmed in prion-infected mice. Mechanistically, conversion of PrPC to the pathological isoform led to PrPSc accumulation in rafts, displacement of ABCA1 from rafts and the cell surface, and enhanced internalization of ABCA1. These effects were abolished with reversal of prion infection or by loading cells with cholesterol. Stimulation of ABCA1 expression with liver X receptor agonist or overexpression of heterologous ABCA1 reduced the conversion of prion protein into the pathological form upon infection. These findings demonstrate a reciprocal connection between prion infection and cellular cholesterol metabolism, which plays an important role in the pathogenesis of prion infection in neuronal cells

Human airway organoids as 3D in vitro models for a toxicity assessment of emerging inhaled pollutants: Tire wear particles

Three-dimensional (3D) structured organoids have become increasingly promising and effective in vitro models, and there is an urgent need for reliable models to assess health effects of inhaled pollutants on the human airway. In our study, we conducted a toxicity assessment of human airway organoids (hAOs) for tire wear particles (TWPs) as an emerging inhaled pollutant. We induced primary human bronchial epithelial cells (HBECs) to generated human airway organoids, which recapitulated the key features of human airway epithelial cells including basal cells, ciliated cells, goblet cells, and club cells. TWPs generated from the wearing of tire treads were considered a major source of emerging inhaled road traffic-derived non-exhaust particles, but their health effect on the lungs is poorly understood. We used human airway organoids to assess the toxicology of tire wear particles on the human airway. In an exposure study, the inhibitory effect of TWPs on the growth of human airway organoids was observed. TWPs induced significant cell apoptosis and oxidative stress in a dose-dependent manner. From the qPCR analysis, TWPs significantly up-regulated the expression pf genes involved in the inflammation response. Additionally, the exposure of TWPs reduced SCGB1A1 gene expression associated with the function of the club cell and KRT5 gene expression related to the function of basal cells. In conclusion, this was first study using human airway organoids for a toxicological assessment of TWPs, and our findings revealed that human airway organoids provide an evaluation model of inhaled pollutants potentially affecting the lungs

IL-23 inhibitor enhances the effects of PTEN DNA-loaded lipid nanoparticles for metastatic CRPC therapy

Introduction: Metastatic castration-resistant prostate cancer (mCRPC) patients face challenges due to limited treatment options. About 50% of patients with mCRPC have a functional loss of phosphatase and tensin homology deleted on chromosome 10 (PTEN), leading to tumor progression, metastasis, and immune suppression. Moreover, elevated IL-23 produced by myeloid-derived suppressor cells (MDSCs) is found in CRPC patients, driving tumor progression. Therefore, a combination strategy based on PTEN restoration and IL-23 inhibition may block CRPC progression and metastasis.Methods: The antitumor effect of restoring PTEN expression combined with the IL-23 inhibitor Apilimod was studied in a mouse model of bone metastasis CRPC and mouse prostate cancer RM-1 cells. To verify the targeting ability of PTEN DNA coated with lipid nanoparticles (LNP@PTEN) in vitro and in vivo. In addition, RT-qPCR and flow cytometry were used to investigate the related mechanisms of the antitumor effect of LNP@PTEN combined with Apilimod.Results: LNPs exhibited significant tumor-targeting and tumor accumulation capabilities both in vitro and in vivo, enhancing PTEN expression and therapeutic efficacy. Additionally, the combination of LNP@PTEN with the IL-23 inhibitor Apilimod demonstrated enhanced inhibition of tumor growth, invasion, and metastasis (particularly secondary organ metastasis) compared to other groups, and extended the survival of mice to 41 days, providing a degree of bone protection. These effects may be attributed to the PTEN function restoration combined with IL-23 inhibition, which help reverse immune suppression in the tumor microenvironment by reducing MDSCs recruitment and increasing the CD8+/CD4+ T cell ratio.Discussion: In summary, these findings highlight the potential of LNPs for delivering gene therapeutic agents. And the combination of LNP@PTEN with Apilimod could achieve anti-tumor effects and improve tumor microenvironment. This combinational strategy opens new avenues for the treatment of mCRPC

Comparative Genomic Analysis of Latilactobacillus curvatus and L. sakei

In this study, the genomes of 19 Latilactobacillus curvatus and 40 L. sakei strains were comparatively analyzed. Average nucleic acid identity (ANI) and genome-wide colinearity indicated that the genomes of L. curvatus and L. sakei had weak nucleotide sequence homology, allowing them to be used as indicators to distinguish the two species. Pangenomes for these species were constructed, whose core gene functions were annotated. The results showed that the core genomes of L. curvatus and L. sakei were mainly involved in their basic metabolism. Analysis of individual genomes of the strains revealed that 1) both L. curvatus and L. sakei contained a wide range of genes encoding glycoside hydrolases, which are abundant genetic resources for catabolizing and metabolizing dietary fiber such as polysaccharides, lactose utilization, and lignocellulose; 2) antibiotic resistance genes were annotated in the genomes of three strains, which originate from horizontal gene transfer; 3) the unique arginine deiminase pathway of L. sakei, the serine dehydratase and guanine deaminase pathways of L. curvatus, and the glutamate decarboxylase pathway of several strains were identified, revealing that the acid tolerance mechanisms of these two species are different; and 4) genes encoding cold stress proteins were discovered, which endow the two species with good cold processing properties. Moreover, the genomes of some L. sakei strains contained gene clusters related to the biosynthesis of lactocin S and condensin. In conclusion, this study established taxonomic criteria for the two species and information on individual differences between their strains, which will provide a basis for the study of the physiological, biochemical, molecular genetic mechanisms of L. curvatus and L. sakei and their industrial applications