Incorporating environmental capacity considerations to prioritize control factors for the management of heavy metals in soil.

Heavy metals (HMs) pollution threatens food security and human health. While previous studies have evaluated source-oriented health risk assessments, a comprehensive integration of environmental capacity risk assessments with pollution source analysis to prioritize control factors for soil contamination is still lacking. Herein, we collected 837 surface soil samples from agricultural land in the Nansha District of China in 2019. We developed an improved integrated assessment model to analyze the pollution sources, health risks, and environmental capacities of As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn. The model graded pollution source impact on environmental capacity risk to prioritize control measures for soil HMs. All HMs except Pb exceeded background values and were sourced primarily from natural, transportation, and industrial activities (31.26%). Approximately 98.92% (children), 97.87% (adult females), and 97.41% (adult males) of carcinogenic values exceeded the acceptable threshold of 1E-6. HM pollution was classified as medium capacity (3.41 kg/hm2) with mild risk (PI = 0.52). Mixed sources of natural backgrounds, transportation, and industrial sources were identified as priority sources, and As a priority element. These findings will help prioritize control factors for soil HMs and direct resources to the most critical pollutants and sources of contamination, particularly when resources are limited.

Investigation of Molecular Interactions Mechanism of Pembrolizumab and PD-1.

Human programmed cell death protein 1 (PD-1) is a checkpoint protein involved in the regulation of immune response. Antibodies are widely used as inhibitors that block the immune checkpoint, preventing strong immune responses. Pembrolizumab is an FDA-approved IgG4 antibody with PD-1 inhibitory ability for the treatment of melanoma. In this study, we investigated the effect of Pembrolizumab on the conformational changes in PD-1 using extensive molecular modeling and simulation approaches. Our study revealed that during the 200 ns simulation, the average values of the solvent accessible surface area, the radius of gyration, and internal hydrogen bonds of PD-1 were 64.46 nm2, 1.38 nm and 78, respectively, while these values of PD-1 in the PD-1/Pembrolizumab complex were 67.29 nm2, 1.39 nm and 76, respectively. The RMSD value of PD-1 gradually increased until 80 ns and maintained its stable conformation at 0.32 nm after 80 ns, while this value of PD-1 in the PD-1/Pembrolizumab complex maintained an increasing trend during 200 ns. The interaction between PD-1 and Pembrolizumab led to a flexible but stable structure of PD-1. PD-1 rotated around the rotation axis of the C'D loop and gradually approached Pembrolizumab. The number of hydrogen bonds involved in the interactions on the C and C' strands increased from 4 at 100 ns to 7 at 200 ns. The strong affinity of Pembrolizumab for the C'D and FG loops of PD-1 disrupted the interactions between PD-1 and PD-L1. Inhibition of the interaction between PD-1 and PD-L1 increased the T cell activity, and is effective in controlling and curing cancer. Further experimental work can be performed to support this finding.

Comparative transcriptome analysis of Chinese grass shrimp (Palaemonetes sinensis) hepatopancreas under ectoparasitic isopod (Tachaea chinensis) infection.

Tachaea chinensis, a parasitic isopod, negatively affects the production of several commercially important shrimp species. To better understand the interaction between shrimp immunity and isopod infection, we performed a transcriptome analysis of the hepatopancreas of Palaemonetes sinensis challenged with T. chinensis. After assembly and annotation, 75,980 high-quality unigenes were obtained using RNA-seq data. Differential gene expression analysis revealed 896 significantly differently expressed genes (DEGs) after infection, with 452 and 444 upregulated and downregulated genes, respectively. Specifically, expression levels of genes involved in detoxification, such as the interferon regulatory factor, venom carboxylesterase-6, serine proteinase inhibitor, and cytochrome P450, were upregulated. Furthermore, expression levels of genes corresponding to retinol dehydrogenase, triosephosphate isomerase, variant ionotropic glutamate receptor, and phosphoenolpyruvate carboxykinase were significantly upregulated after isopod parasitization, indicating that the shrimp's visual system was influenced by isopod parasitization. Moreover, quantitative real-time PCR of 10 DEGs helped validate the RNA-seq findings. These results provide a valuable basis for future studies on the elucidation of immune responses of P. sinensis to T. chinensis infection.

Thiophene Derivatives as Anticancer Agents and Their Delivery to Tumor Cells Using Albumin Nanoparticles.

A series of thiophene derivatives (TPs) were synthesized and evaluated for cytotoxicity in HepG2 and SMMC-7721 cell lines by MTT assay. TP 5 was identified as a potential anticancer agent based on its ability to inhibit tumor cell growth. Drawbacks of TPs, including poor solubility and high toxicity, were overcome through delivery using self-assembling HSA nanoparticles (NPs). The optimum conditions for TP 5-NPs synthesis obtained by adjusting the temperature and concentration of TP 5. The NPs had an encapsulation efficiency of 99.59% and drug-loading capacity of 3.70%. TP 5 was slowly released from TP 5-NPs in vitro over 120 h. HepG2 and SMMC-7721 cell lines were employed to study cytotoxicity of TP 5-NPs, which exhibited high potency. ROS levels were elevated and mitochondrial membrane potentials reversed when the two cell lines were treated with TP 5-NPs for 12 h. Cellular uptake of fluorescence-labeled TP 5-NPs in vitro was analyzed by flow cytometry and laser confocal scanning microscopy. Fluorescence intensity increased over time, suggesting that TP 5-NPs were efficiently taken up by tumor cells. In conclusion, TP 5-NPs showed great promise as an anticancer therapeutic agent.

Shigella flexneri T3SS effector IpaH4.5 modulates the host inflammatory response via interaction with NF-κB p65 protein.

Shigella species possess a type III secretion system (T3SS), which is required for human infection and that delivers effector proteins into target host cells. Here, we show that the effector, IpaH4.5 dampens the pro-inflammatory cytokine response. In both the Sereny test and a murine lung infection model, the Shigella ΔipaH4.5 mutant strain caused more severe inflammatory responses and significantly induced higher pro-inflammatory cytokine levels (MIP-2 and TNF-α) in the lung homogenates of wild type-infected mice. Moreover, there was a threefold decrease in bacterial colonization of the mutant compared with the WT and ΔipaH4.5/ipaH4.5-rescued strains. Yeast two-hybrid screening showed that IpaH4.5 specifically interacts with the p65 subunit of NF-κB. Ten truncated versions of IpaH4.5 and p65 spanning different regions were constructed and expressed to further map the IpaH binding sites with p65. The results revealed thatthe p65 region spanning amino acids 1-190 of p65 interacted with the IpaH4.5/1-293 N-terminal region. In vitro, IpaH4.5 displayed ubiquitin ligase activity towards ubiquitin and p65. Furthermore, the transcriptional activity of NF-κB was shown to be inhibited by IpaH4.5 utilizing a dual-luciferase reporter gene detection system containing NF-κB promoter response elements. Thus, we conclude that the IpaH4.5 protein is an E3 ubiquitin ligase capable of directly regulating the host inflammatory response by inhibiting the NF-κB signalling pathway.

Innovative insights into organic nitrogen degradation through protein family domains analysis in chicken and pig manure composting using metagenomic sequencing.

The nitrogen loss in composting is primarily driven by the transformation of organic nitrogen, yet the mechanisms underlying the degradation process remain incompletely understood. This study employed protein family domains (Pfams) analysis based on metagenomic sequencing to investigate the functional characteristics, key microorganisms, and environmental parameters influencing organic nitrogen degradation in chicken manure and pig manure composting. 154 Pfams associated with ammonification function were identified. Predominant Pfams: proteolytic peptidase, followed by chitin/cell wall degraders, least involved in nucleic acid degradation. Ammonifying microbial diversity was basically consistent among compost types, particularly in the thermophilic stage with the peak of abundance of dominant ammonifying microorganisms. Viruses played an important role in ammonification process, especially Uroviricota. 26 key ammonifying genera were identified by the microbial network. pH dominated the metabolic activity of ammonifying microorganisms in various manure compost types, primarily consisting of protein-degrading bacteria with stable community structures.

Extracellular Vesicles: A New Star for Gene Drug Delivery.

Recently, gene therapy has become a subject of considerable research and has been widely evaluated in various disease models. Though it is considered as a stand-alone agent for COVID-19 vaccination, gene therapy is still suffering from the following drawbacks during its translation from the bench to the bedside: the high sensitivity of exogenous nucleic acids to enzymatic degradation; the severe side effects induced either by exogenous nucleic acids or components in the formulation; and the difficulty to cross the barriers before reaching the therapeutic target. Therefore, for the successful application of gene therapy, a safe and reliable transport vector is urgently needed. Extracellular vesicles (EVs) are the ideal candidate for the delivery of gene drugs owing to their low immunogenicity, good biocompatibility and low toxicity. To better understand the properties of EVs and their advantages as gene drug delivery vehicles, this review covers from the origin of EVs to the methods of EVs generation, as well as the common methods of isolation and purification in research, with their pros and cons discussed. Meanwhile, the engineering of EVs for gene drugs is also highlighted. In addition, this paper also presents the progress in the EVs-mediated delivery of microRNAs, small interfering RNAs, messenger RNAs, plasmids, and antisense oligonucleotides. We believe this review will provide a theoretical basis for the development of gene drugs.

Reversine inhibits proliferation and induces apoptosis of human osteosarcoma cells through targeting MEK1.

Reversine, or 2-(4-morpholinoanilino)-6-cyclohexylaminopurine, is a 2,6-disubstituted purine derivative. This small molecule shows anti-tumor potential by playing a central role in the inhibition of several kinases related to cell cycle regulation and cytokinesis. In this study, systematic review demonstrated the feasibility and pharmacological mechanism of anti-tumor effect of reversine. Firstly, we grafted MNNG/HOS, U-2 OS, MG-63 osteosarcoma cell aggregates onto chicken embryonic chorioallantoic membrane (CAM) to examine the tumor volume of these grafts after reversine treatment. Following culture, reversine inhibited the growth of osteosarcoma cell aggregates on CAM significantly. In vitro experiment, reversine suppressed osteosarcoma cell viability, colony formation, proliferation, and induced apoptosis and cell cycle arrest at G0-G1 phase. Scratch wound assay demonstrated that reversine restrained cell migration. Reversine increased the protein expression of E-cadherin. The mRNA expression of Rac1, RhoA, CDC42, PTK2, PXN, N-cadherin, Vimentin in MNNG/HOS, U-2 OS and MG-63 cells were suppressed and PTEN increased after reversine treatment. Network pharmacology prediction, molecular docking and systematic review revealed MEK1 can be used as an effective target for reversine to inhibit osteosarcoma. Western blot results show the regulation of MEK1 and ERK1/2 by reversine was not consistent in different osteosarcoma cell lines, but we found that reversine significantly inhibited the protein expression of MEK1 in MNNG/HOS, U-2 OS and MG-63. All these suggested that reversine can exert its anti-tumor effect by targeting the expression of MEK1.

Microbial hydrogen sinks in the sand-bentonite backfill material for the deep geological disposal of radioactive waste.

The activity of subsurface microorganisms can be harnessed for engineering projects. For instance, the Swiss radioactive waste repository design can take advantage of indigenous microorganisms to tackle the issue of a hydrogen gas (H2) phase pressure build-up. After repository closure, it is expected that anoxic steel corrosion of waste canisters will lead to an H2 accumulation. This occurrence should be avoided to preclude damage to the structural integrity of the host rock. In the Swiss design, the repository access galleries will be back-filled, and the choice of this material provides an opportunity to select conditions for the microbially-mediated removal of excess gas. Here, we investigate the microbial sinks for H2. Four reactors containing an 80/20 (w/w) mixture of quartz sand and Wyoming bentonite were supplied with natural sulfate-rich Opalinus Clay rock porewater and with pure H2 gas for up to 108 days. Within 14 days, a decrease in the sulfate concentration was observed, indicating the activity of the sulfate-reducing bacteria detected in the reactor, e.g., from Desulfocurvibacter genus. Additionally, starting at day 28, methane was detected in the gas phase, suggesting the activity of methanogens present in the solid phase, such as the Methanosarcina genus. This work evidences the development, under in-situ relevant conditions, of a backfill microbiome capable of consuming H2 and demonstrates its potential to contribute positively to the long-term safety of a radioactive waste repository.

Baicalin administration could rescue high glucose-induced craniofacial skeleton malformation by regulating neural crest development.

Hyperglycemia in pregnancy can increase the risk of congenital disorders, but little is known about craniofacial skeleton malformation and its corresponding medication. Our study first used meta-analysis to review the previous findings. Second, baicalin, an antioxidant, was chosen to counteract high glucose-induced craniofacial skeleton malformation. Its effectiveness was then tested by exposing chicken embryos to a combination of high glucose (HG, 50 mM) and 6 µM baicalin. Third, whole-mount immunofluorescence staining and in situ hybridization revealed that baicalin administration could reverse HG-inhibited neural crest cells (NCC) delamination and migration through upregulating the expression of Pax7 and Foxd3, and mitigate the disordered epithelial-mesenchymal transition (EMT) process by regulating corresponding adhesion molecules and transcription factors (i.e., E-cadherin, N-cadherin, Cadherin 6B, Slug and Msx1). Finally, through bioinformatic analysis and cellular thermal shift assay, we identified the AKR1B1 gene as a potential target. In summary, these findings suggest that baicalin could be used as a therapeutic agent for high glucose-induced craniofacial skeleton malformation.

Abnormal fecal microbiota community and functions in patients with hepatitis B liver cirrhosis as revealed by a metagenomic approach.

BACKGROUND: Assessment and characterization of human colon microbiota is now a major research area in human diseases, including in patients with hepatitis B liver cirrhosis (HBLC). METHODS: We recruited 120 patients with HBLC and 120 healthy controls. The fecal microbial community and functions in the two groups were analyzed using high-throughput Solexa sequencing of the complete metagenomic DNA and bioinformatics methods. RESULTS: Community and metabolism-wide changes of the fecal microbiota in 20 HBLC patients and 20 healthy controls were observed and compared. A negative correlation was observed between the Child-Turcotte-Pugh scores and Bacteroidetes (P < 0.01), whereas a positive correlation was observed between the scores and Enterobacteriaceae and Veillonella (P < 0.01). Analysis of the additional 200 fecal microbiota samples demonstrated that these intestinal microbial markers might be useful for distinguishing liver cirrhosis microbiota samples from normal ones. The functional diversity was significantly reduced in the fecal microbiota of cirrhotic patients compared with in the controls. At the module or pathway levels, the fecal microbiota of the HBLC patients showed enrichment in the metabolism of glutathione, gluconeogenesis, branched-chain amino acid, nitrogen, and lipid (P < 0.05), whereas there was a decrease in the level of aromatic amino acid, bile acid and cell cycle related metabolism (P < 0.05). CONCLUSIONS: Extensive differences in the microbiota community and metabolic potential were detected in the fecal microbiota of cirrhotic patients. The intestinal microbial community may act as an independent organ to regulate the body's metabolic balance, which may affect the prognosis for HBLC patients.

iPCa-Net: A CNN-based framework for predicting incidental prostate cancer using multiparametric MRI.

Incidental prostate cancer (iPCa) is an early stage of clinically significant prostate cancer (csPCa) and is typically asymptomatic, making it difficult to detect in clinical practice. The objective of this study is to predict iPCa by analyzing prostatic MRIs using deep convolutional neural network (CNN). While CNN-based models in medical image analysis have made significant advancements, the iPCa prediction task presents two challenging problems: subtler differences in MRIs that are imperceptible to human eyes and a lower incidence rate, resulting in a more pronounced sample imbalance compared to routine cancer prediction. To address these two challenges, we propose a new CNN-based framework called iPCa-Net, which is designed to jointly optimize two tasks: prostate transition zone segmentation and iPCa prediction. To evaluate the performance of our model, we construct a prostatic MRI dataset comprising 9536 prostate MRI slices from 448 patients diagnosed with benign prostatic hyperplasia (BPH) at our institution. In our study, the incidence rate of iPCa is 5.13% (23 out of 448) . We compare our model with eight state-of-the-art methods for segmentation task and nine established methods for prediction task respectively using our dataset, and experimental results demonstrate the superior performance of our model. Specifically, in the prostate transition zone segmentation task, our iPCa-Net outperforms the top-performing method by 1.23% with respect to mIoU. In the iPCa prediction task, our iPCa-Net surpasses the top-performing method by 2.06% with respect to F1 score. In conclusion, our iPCa-Net demonstrates superior performance in the early identification of iPCa patients compared to state-of-the-art methods. This advancement holds great significance for appropriate disease management and is highly beneficial for patients.

Assessment of groundwater hydrochemistry, water quality, and health risk in Hainan Island, China.

Groundwater is an important source of water for human sustenance. The determination of groundwater quality at island sites is an urgent priority in China, but there are lacking systematic reports relating to them. Here, 63 groups of groundwater samples were collected and analyzed of Hainan Island. The groundwater in the study area is weakly alkaline, mainly comprising hard and soft freshwater. The predominant anions and cations are HCO3-, and Ca2+ and Na+, respectively, and the main water chemistry types are HCO3-Cl-Na and HCO3-Cl-Na-Ca. The chemical evolution of groundwater is mainly affected by water-rock interactions, cation exchange, and human activity. The groundwater is mostly of high quality and, in most areas, is suitable for drinking and irrigation. Contrastingly, the water quality in the west of the island is relatively poor. The spatial distribution of the risk coefficient (HQ) is consistent with the spatial variation in the NO3- concentrations in the groundwater. Notably, there are unacceptable health risks for different groups of people, with infants having the greatest level of impact, followed by children, teenagers, and adults. This study provides a valuable reference for the development and utilization of groundwater resources, as well as the improvement of aquatic ecological conditions on Hainan Island and other island areas worldwide.

A multidimensional chromatography/high-resolution mass spectrometry approach for the in-depth metabolites characterization of two Astragalus species.

To address the chemical complexity is indispensable in a number of research fields. Herb metabolome is typically composed by more than one class of structure analogs produced via different biosynthetic pathways. Multidimensional chromatography (MDC), due to the greatly enhanced separation space, offers the potential solution to comprehensive characterization of herbal metabolites. Here, we presented a strategy, by integrating MDC and quadrupole time-of-flight mass spectrometry (QTOF-MS), to accomplish the in-depth herbal metabolites characterization. Using the metabolome of two Astragalus species (A. membranaceus var. mongholicus,AMM; A. membranaceus, AM) as the case, an off-line three-dimensional liquid chromatography (3D-LC) system was established: hydrophilic interaction chromatography using an XAmide column as the first dimension (1D) for fractionating the total extract, on-line reversed-phase × reversed-phase liquid chromatography separately configuring a CSH Fluoro-Phenyl column and a Cosmocore C18 column as the second dimension (2D) and the third dimension (3D) of chromatography to enable the explicit separation of three well fractionated samples. Moreover, the negative-mode collision-induced dissociation by QTOF-MS under the optimized condition could provide diversified fragments that were useful for the structural elucidation of AMM and AM. An in-house library (composed by 247 known compounds) and comparison with 43 reference standards were utilized to assist more reliable characterization. We could characterize 513 compounds from two Astragalus species (344 from AMM and 323 from AM), including 236 flavonoids, 150 triterpenoids, 18 organic acids, and 109 others. Conclusively, the established MDC approach gained excellent performance favoring the analogs-oriented in-depth characterization of herbal metabolites, but received uncompromising analytical efficiency.

Priority control factors for heavy metal groundwater contamination in peninsula regions based on source-oriented health risk assessment.

Peninsula regions in China face serious environmental issues, such as heavy metal (HM) groundwater contamination. However, attempts to investigate the pollution sources and health risks of HM contamination in such regions require considerable resources and costs. Moreover, the priority control factors for groundwater HMs remain unclear. In this study, absolute principal component score/multiple linear regression (APCS/MLR) was used to quantify the groundwater pollution sources of typical peninsular areas in China, and a health risk assessment (HRA) was performed to assess the health risks caused by different sources. The results showed that the concentrations of Mn and Fe were higher than those of other HMs, and HM pollution was high in shallow groundwater. The dominant source of HMs in groundwater was agricultural activities (31.12 %), followed by natural sources (26.33 %), industrial activities (22.47 %), and atmospheric deposition (20.09 %). The non-carcinogenic risks to residents were acceptable, whereas the carcinogenic risks were high. Agricultural sources, atmospheric deposition sources, and Cr and As were identified as the priority control factors for HM groundwater contamination. This study has implications for improving the control of groundwater HM contamination in peninsula regions and ensuring sustainable groundwater development.

The acute effects of cannabis with and without cannabidiol in adults and adolescents: A randomised, double-blind, placebo-controlled, crossover experiment.

BACKGROUND AND AIMS: Long-term harms of cannabis may be exacerbated in adolescence, but little is known about the acute effects of cannabis in adolescents. We aimed to (i) compare the acute effects of cannabis in adolescent and adult cannabis users and (ii) determine if cannabidiol (CBD) acutely modulates the effects of delta-9-tetrahydocannabinol (THC). DESIGN: Randomised, double-blind, placebo-controlled, crossover experiment. The experiment was registered on ClinicalTrials.gov (NCT04851392). SETTING: Laboratory in London, United Kingdom. PARTICIPANTS: Twenty-four adolescents (12 women, 16- to 17-year-olds) and 24 adults (12 women, 26- to 29-year-olds) who used cannabis 0.5-3 days/week and were matched on cannabis use frequency (mean = 1.5 days/week). INTERVENTION: We administered three weight-adjusted vaporised cannabis flower preparations: 'THC' (8 mg THC for 75 kg person); 'THC + CBD' (8 mg THC and 24 mg CBD for 75 kg person); and 'PLA' (matched placebo). MEASUREMENTS: Primary outcomes were (i) subjective 'feel drug effect'; (ii) verbal episodic memory (delayed prose recall); and (iii) psychotomimetic effect (Psychotomimetic States Inventory). FINDINGS: Compared with 'PLA', 'THC' and 'THC + CBD' significantly (P < 0.001) increased 'feel drug effect' (mean difference [MD] = 6.3, 95% CI = 5.3-7.2; MD = 6.8, 95% CI = 6.0-7.7), impaired verbal episodic memory (MD = -2.7, 95% CI = -4.1 to -1.4; MD = -2.9, 95% CI = -4.1 to -1.7) and increased psychotomimetic effects (MD = 7.8, 95% CI = 2.8-12.7; MD = 10.8, 95% CI = 6.2-15.4). There was no evidence that adolescents differed from adults in their responses to cannabis (interaction P ≥ 0.4). Bayesian analyses supported equivalent effects of cannabis in adolescents and adults (Bayes factor [BF01 ] >3). There was no evidence that CBD significantly modulated the acute effects of THC. CONCLUSIONS: Adolescent cannabis users are neither more resilient nor more vulnerable than adult cannabis users to the acute psychotomimetic, verbal memory-impairing or subjective effects of cannabis. Furthermore, in adolescents and adults, vaporised cannabidiol does not mitigate the acute harms caused by delta-9-tetrahydocannabinol.

Proteomic analysis of clinical isolate of Stenotrophomonas maltophilia with blaNDM-1, blaL1 and blaL2 ß-lactamase genes under imipenem treatment.

The co-occurrence of L1 and AmpR-L2 with bla(NDM-1) gene with an upstream 250-bp promoter was detected in a clinical isolate of Stenotrophomonas maltophilia DCPS-01, which was resistant to all ß-lactams and sensitive only to colistin and fluoroquinolones. To investigate expression of resistance genes and the molecular mechanisms of bacteria resistance to carbapenems, proteomic profiles of the isolate was passaged with and without the drug by using 2D-PAGE. The results showed that 33 genes exhibiting a ≥3-fold change were identified as candidates that may help S. maltophilia survive drug selection. Strikingly, L1 was expressed more highly in cells grown with imipenem, and the abundant NDM-1 further increased, while very little L2 was detected even following induction. Specific activities for ß-lactamase revealed that L2 remained at constitutive low levels (10.6 U/mg), while L1 and NDM-1 showed clear activity (69.8 U/mg). Our data support that imipenem could specifically and reversibly induce L1 and NDM-1, which together played key roles in drug resistance in DCPS-01. Although NDM-1 mediated resistance to carbapenems has been found in very few cases, to our knowledge, this is the first proteomics research of S. maltophilia with NDM-1, giving very broad-spectrum antibiotic resistance profiles.

LuxS-dependent AI-2 regulates versatile functions in Enterococcus faecalis V583.

Bacteria utilize a quorum sensing (QS) system to coordinate gene expression by monitoring the concentration of molecules known as autoinducers (AI). In the present study, we confirmed the presence of a LuxS/AI-2 dependent QS system in vancomycin-resistant Enterococcus faecalis V583. Then, the cellular targets controlled by AI-2 were identified by comparative proteomics analysis in order to elucidate the possible role of AI-2 in E. faecalis. Results demonstrated 15 proteins that are differentially expressed upon the addition of AI-2, including proteins involved in metabolism, translation, energy production and/or conversion, and cell wall biogenesis. Glyceraldehyde-3-phosphate dehydrogenase and malate dehydrogenase associated with carbohydrate metabolism and energy production were up-regulated upon inducing by AI-2. In addition, externally added AI-2 could down-regulate acetyl-coenzyme A carboxylase and ornithine carbamoyltransferase, two key enzyme involved in metabolism. All these data suggest that AI-2 signaling may play a role in the regulation of a number of important metabolic properties of E. faecali. We further investigated the role of AI-2 in biofilm formation by E. faecalis, showing the addition of AI-2 to E. faecalis V583 cultures resulted in increased biofilm formation. Our results provide important clues to the role of a LuxS/AI-2 dependent QS system in vancomycin-resistant E. faecalis.

Small extracellular vesicles encapsulating lefty1 mRNA inhibit hepatic fibrosis.

Liver fibrosis is the deposition of extracellular matrix (ECM) in the liver caused by persistent chronic injury, which can lead to more serious diseases such as cirrhosis or cancer. Blocking the effect of transforming growth factor ß1 (TGF-ß1), one of the most important cytokines in liver fibrosis, may be one of the effective ways to inhibit liver fibrosis. As a kind of natural nano-scale vesicles, small extracellular vesicles (sEvs) have displayed excellent delivery vehicle properties. Herein, we prepared hepatic stellate cell (HSC)-derived sEvs loading left-right determination factor 1 (lefty1) mRNA (sEvLs) and we wanted to verify whether they can inhibit fibrosis by blocking the TGF-ß1 signaling pathway. The results showed that sEvLs had effective cell uptake and reduced activation of HSCs. Rats that were injected with CCl4 by intraperitoneal injection for 6 weeks exhibited obvious symptoms of liver fibrosis and were treated with systemically administered sEvLs and free sEvs for 4 weeks. Rats injected with olive oil alone served as sham controls. Administration of sEvLs significantly reduced the area of fibrosis compared with free sEvs. We demonstrated that sEvLs inhibited HSCs activation and ECM production, and promote ECM degradation by downregulating α-smooth muscle actin (α-SMA), collagen I, tissue inhibitor of metalloproteinase (TIMP) -1 and upregulating matrix metalloprotease (MMP) -1. In summary, as an endogenous delivery vehicle, sEvs could deliver mRNA to attenuate hepatic fibrosis by blocking the TGF-ß/Smad signaling pathway.

Exosomes as smart drug delivery vehicles for cancer immunotherapy.

Exosomes (Exos) as drug delivery vehicles have been widely used for cancer immunotherapy owing to their good biocompatibility, low toxicity, and low immunogenicity. Some Exos-based cancer immunotherapy strategies such as tuning of immunosuppressive tumor microenvironment, immune checkpoint blockades, and cancer vaccines have also been investigated in recent years, which all showed excellent therapeutic effects for malignant tumor. Furthermore, some Exos-based drug delivery systems (DDSs) for cancer immunotherapy have also undergone clinic trails, indicating that Exos are a promising drug delivery carrier. In this review, in order to promote the development of Exos-based DDSs in cancer immunotherapy, the biogenesis and composition of Exos, and Exos as drug delivery vehicles for cancer immunotherapy are summarized. Meanwhile, their clinical translation and challenges are also discussed. We hope this review will provide a good guidance for Exos as drug delivery vehicles for cancer immunotherapy.