DNA N6-Methyladenosine modification role in transmitted variations from genomic DNA to RNA in Herrania umbratica.

BACKGROUND: DNA methylation is an important epigenetic modification. Recently the developed single-molecule real-time (SMRT) sequencing technology provided an efficient way to detect DNA N6-methyladenine (6mA) modification that played an important role in epigenetic and positively regulated gene expression. In addition, the gene expression was also regulated by genetic variation. However, the relationship between DNA 6mA modification and variation is still unknown. RESULTS: We collected the SMRT long-reads DNA, Illumina short reads DNA and RNA datasets from the young leaves of Herrania umbratica, and used them to detect 35,654 6mA modification sites, 829,894 DNA variations and 60,672 RNA variations respectively, among which, there are 303 DNA variations and 19 RNA variations with 6mA modification, and 57,468 transmitted genetic variations from DNA to RNA. The results illustrated that the genes with 6mA modification were significant disadvantage to mutate than those genes without modification (p-value< 4.9e-08). And result from the linear regression model showed the 6mA densities of genes were associated with the transmitted variations type 0/1 to 1/1 (p-value < 0.001). CONCLUSIONS: The variations of DNA and RNA in genes with 6mA modification were significant less than those in unmodified genes. Furthermore, the variations in 6mA modified genes were easily transmitted from DNA to RNA, especially the transmitted variation from DNA heterozygote to RNA homozygote.

Baicalein attenuates monocrotaline-induced pulmonary arterial hypertension by inhibiting vascular remodeling in rats.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder characterized by elevated pulmonary arterial pressure (PAP) and right ventricular hypertrophy (RVH) driven by progressive vascular remodeling. Reversing adverse vascular remodeling is an important concept in the treatment of PAH. Endothelial injury, inflammation, and oxidative stress are three main contributors to pulmonary vascular remodeling. Baicalein is a natural flavonoid that has been shown to possess anti-proliferative, anti-inflammatory, anti-oxidative, and cardioprotective properties. We hypothesized that baicalein may prevent the progression of PAH and preserve the right heart function by inhibiting pulmonary arterial remodeling. METHODS: Male Sprague-Dawley rats were distributed randomly into 4 groups: control, monocrotaline (MCT)-exposed, and MCT-exposed plus baicalein treated rats (50 and 100 mg/kg/day for 2 weeks). Hemodynamic changes, RVH, and lung morphological features were examined on day 28. Apoptosis was determined by TUNEL staining, and the mRNA levels of tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and IL-6 were detected by qRT-PCR. The changes in oxidative indicators, including malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured using corresponding commercial kits. The levels of Bax, Bcl-2, and cleaved caspase-3, and the activation of mitogen-activated protein kinase (MAPK) and NF-κB were assessed by western blotting. RESULTS: MCT induced an increase in hemodynamic parameters and RVH, which were attenuated by baicalein treatment. Baicalein also blocked MCT-induced pulmonary arterial remodeling. The levels of apoptotic (Bax/Bcl-2 ratio and cleaved caspase-3) and inflammatory (IL-6, TNF-α, and IL-1ß) biomarkers in lung tissue were lower in baicalein-treated groups. Baicalein also decreased MDA level, and increased SOD and GSH-Px activity in rat pulmonary tissue. Furthermore, baicalein inhibited MCT-induced activation of the MAPK and NF-κB pathways. CONCLUSION: Baicalein ameliorates MCT-induced PAH by inhibiting pulmonary arterial remodeling at least partially via the MAPK and NF-κB pathways in rats.

Population Pharmacokinetics of Tigecycline in Critically Ill Patients with Severe Infections.

We sought to describe the population pharmacokinetics of tigecycline in critically ill patients and to determine optimized dosing regimens of tigecycline for different bacterial infections. This prospective study included 10 critically ill patients given a standard dose of tigecycline. Blood samples were collected during one dosing interval and were analyzed using validated chromatography. Population pharmacokinetics and Monte Carlo dosing simulations were undertaken using Pmetrics. Three target exposures, expressed as ratios of the 24-h area under the curve to MICs (AUC0-24/MIC), were evaluated (≥17.9 for skin infections, ≥6.96 for intra-abdominal infections, ≥4.5 for hospital-acquired pneumonia). The median age, total body weight, and body mass index (BMI) were 67 years, 69.1 kg, and 24.7 kg/m2, respectively. A two-compartment linear model best described the time course of tigecycline concentrations. The parameter estimates (expressed as means ± standard deviations [SD]) from the final model were as follows: clearance (CL), 7.50 ± 1.11 liters/h; volume in the central compartment, 72.50 ± 21.18 liters; rate constant for tigecycline distribution from the central to the peripheral compartment, 0.31 ± 0.16 h-1; and rate constant for tigecycline distribution from the peripheral to the central compartment, 0.29 ± 0.30 h-1 A larger BMI was associated with increased CL of tigecycline. Licensed doses were found to be sufficient for Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and methicillin-resistant Staphylococcus aureus for an AUC0-24/MIC target of 4.5 or 6.96. For a therapeutic target of 17.9, an increased tigecycline dose is required, especially for patients with higher BMI. The dosing requirements of tigecycline differ with the indication, with pathogen susceptibility, and potentially with patient BMI.

Improvement of side-effects and treatment on the experimental colitis in mice of a resin microcapsule-loading hydrocortisone sodium succinate.

CONTEXT: Extensive or long-time use of corticosteroids often causes many toxic side-effects. The ion exchange resins and the coating material, Eudragit, can be used in combination to form a new oral delivery system to deliver corticosteroids. OBJECTIVES: The resin microcapsule (DRM) composed by Amberlite 717 and Eudragit S100 was used to target hydrocortisone (HC) to the colon in order to improve its treatment effect on ulcerative colitis (UC) and reduce its toxic side-effects. METHODS: Hydrocortisone sodium succinate (HSS) was sequentially encapsulated in Amberlite 717 and Eudragit S100 to prepare the HSS-loaded resin microcapsule (HSS-DRM). The scanning electron microscopy (SEM) was employed to investigate the morphology and structure of HSS-DRM. The in vitro release and in vivo studies of pharmacokinetics and intestinal drug residues in rat were used to study the colon-targeting of HSS-DRM. The mouse induced by 2,4,6-trinitrobenzenesulfonic acid was used to study the treatment of HSS-DRM on experimental colitis. RESULTS: SEM study showed good morphology and structure of HSS-DRM. In the in vitro release study, > 80% of HSS was released in the colon environment (pH 7.4). The in vivo studies showed good colon-targeting of HSS-DRM (Tmax = 0.97 h, Cmax = 118.28 µg/mL of HSS; Tmax = 2.16 h, Cmax = 64.47 µg/mL of HSS-DRM). Moreover, the HSS-DRM could reduce adverse reactions induced by HSS and had good therapeutic effects on the experimental colitis. CONCLUSIONS: The resin microcapsule system has good colon-targeting and can be used in the development of colon-targeting preparations.

Anti-inflammatory, analgesic and antioxidant activities of 3,4-oxo-isopropylidene-shikimic acid.

Context 3,4-Oxo-isopropylidene-shikimic acid (ISA) is an analog of shikimic acid (SA). SA is extracted from the dry fruit of Illicium verum Hook. f. (Magnoliaceae), which has been used for treating stomachaches, skin inflammation and rheumatic pain. Objective To investigate the anti-inflammatory, analgesic and antioxidant activities of ISA. Materials and methods Analgesic and anti-inflammatory activities of ISA were evaluated using writhing, hot plate, xylene-induced ear oedema, carrageenan-induced paw oedema and cotton pellets-induced granuloma test, meanwhile the prostaglandin E2 (PGE2) and malondialdehyde (MDA) levels were assessed in the oedema paw tissue. ISA (60, 120 and 240 mg/kg in mice model and 50, 120 and 200 mg/kg in rat model) was administered orally, 30 min before induction of inflammation/pain. Additionally, ISA was administered for 12 d in rats from the day of cotton pellet implantation. The active oxygen species scavenging potencies of ISA (10(-3)-10(-5) M) were evaluated by the electron spin resonance spin-trapping technique. Results ISA caused a reduction of inflammation induced by xylene (18.1-31.4%), carrageenan (7.8-51.0%) and cotton pellets (11.4-24.0%). Furthermore, ISA decreased the production of PGE2 and MDA in the rat paw tissue by 1.0-15.6% and 6.3-27.6%, respectively. ISA also reduced pain induced by acetic acid (15.6-48.9%) and hot plate (10.5-28.5%). Finally, ISA exhibited moderate antioxidant activity by scavenging the superoxide radical and hydroxyl radical with IC50 values of 0.214 and 0.450 µg/mL, respectively. Discussion and conclusion Our findings confirmed the anti-inflammatory, analgesic and antioxidant activities of ISA.

Linezolid versus vancomycin for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a systematic review employing meta-analysis.

PURPOSE: The optimal therapy involving linezolid or vancomycin for suspected methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia (NP) remains controversial. This study compared the efficacy and safety of linezolid and vancomycin therapies in patients with NP. METHODS: A systematic review of randomized controlled trials with meta-analyses performed by searching PubMed, EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials. We screened for relevant randomized controlled studies in which patients with NP were enrolled and linezolid and vancomycin therapies were compared. RESULTS: Nine trials involving 2618 pneumonia patients were reviewed. Linezolid was not found to be superior to vancomycin for clinical cure when categories of pathogen were not considered and in a subgroup of NP patients with MRSA infection [relative risk (RR)=1.16, 95 % confidence interval (CI)=0.95-1.43, P=0.15]. Compared with vancomycin, linezolid has no difference in the overall microbiological eradication rate (RR=1.12, 95 % CI=0.96-1.30, P=0.15) and specific MRSA eradication rate (RR=1.16, 95 % CI=0.93-1.45, P=0.19) in NP patients. In addition, nephrotoxicity was more frequent with vancomycin (RR=0.50, 95 % CI=0.31-0.81, P=0.005), but no differences between the treatments were found for all-cause mortality, thrombocytopenia, gastrointestinal effects, and drug discontinuation due to adverse events. CONCLUSION: These results suggest that linezolid is not superior to vancomycin with respect to both clinical and microbiological cure rates in patients with MRSA NP.

Factors on trough teicoplanin levels, associations between levels, efficacy and safety in patients with gram-positive infections.

OBJECTIVE: The objective of this study was to identify the factors influencing trough teicoplanin concentrations (C(min)), to investigate the relationship between teicoplanin C(min) with efficacy and safety, and to determine a target therapeutic concentration. METHODS: An analysis was performed on 95 serum concentrations from 50 patients with gram-positive infections who received teicoplanin treatment. Teicoplanin serum concentrations were measured by high-performance liquid chromatography. Univariate and multivariable analysis were performed to investigate the effect of independent variables on teicoplanin C(min). A logistic regression analysis was used to determine the relationship between teicoplanin C(min) and efficacy and safety. RESULTS: Teicoplanin therapy was effective in 74.0% (37/50) of patients, and 10.0% (5/50) of patients exhibited signs of adverse events. Using multivariable linear regression, two covariates were found to be a significant effect on teicoplanin C(min): dosage (mg/kg), and creatinine clearance rate (CL(cr). There was no covariate that has a significant impact on the safety of teicoplanin and only teicoplanin C(min) has a significant impact on the efficacy of treatment in the logistics regression. The logistics regression analysis showed that teicoplanin C(min) of 10 mg/L was associated with a 79.4% probability of success response. CONCLUSIONS: This study highlighted that teicoplanin C(min) was strongly influenced by the values of dosage (mg/kg) and CL(cr) and the teicoplanin C(min) range of 10 -€“ 20 mg/L was identified as the therapeutic target with optimum clinical efficacy and safety.

Identification of factors influencing the pharmacokinetics of voriconazole and the optimization of dosage regimens based on Monte Carlo simulation in patients with invasive fungal infections.

OBJECTIVES: The objective of this study was to estimate the population pharmacokinetics of voriconazole, to identify the factors influencing voriconazole pharmacokinetics and to identify optimal dosage regimens for attaining target pharmacokinetic/pharmacodynamic indices against Aspergillus and Candida infections in patients with invasive fungal infections (IFIs). METHODS: To prospectively quantify the relationships between the pharmacokinetic parameters of voriconazole and covariates, a population pharmacokinetic analysis was conducted on pooled data from 406 samples taken from 151 patients with IFIs. Voriconazole plasma concentrations were measured by HPLC. The following covariates were tested: demographic factors, laboratory data, concomitant medications and CYP2C19 genotype. Monte Carlo simulation was used to evaluate the effectiveness of the currently recommended dosage regimen and to design an optimized pharmacodynamic dosage strategy for voriconazole. RESULTS: The data were appropriately fit by a one-compartment model with first-order absorption and elimination. The voriconazole clearance (CL) was 6.95 L/h, the volume of distribution (V) was 200 L and the oral bioavailability (F) was 89.5%. CL was significantly associated with age, the serum concentration of alkaline phosphatase and the CYP2C19 genotype. Based on the results of the Monte Carlo stimulation, we concluded that Aspergillus infections could be treated effectively with 200 mg of voriconazole administered intravenously or orally twice daily and that Candida infections could be treated with 300 mg administered orally twice daily or with 200 mg administered intravenously twice daily. CONCLUSIONS: This study showed that optimal voriconazole dosage regimens could be determined successfully with prospective population pharmacokinetic analyses and Monte Carlo simulations.

Quantitative analysis and pharmacokinetics study of tigecycline in human serum using a validated sensitive liquid chromatography with tandem mass spectrometry method.

Tigecycline, a novel intravenously administered glycylcycline antibiotic, currently plays a key role in the management of complicated multiorganism infections. However, current liquid chromatography with tandem mass spectrometry methods briefly describe parameters and the only reported internal standard was sometimes difficult to obtain. In our study, an updated liquid chromatography with tandem mass spectrometry method for the quantitative analysis of tigecycline in human serum was developed. Sample preparation involved precipitation with 20% trichloroacetic acid. Chromatographic separation of tigecycline and tetracycline (internal standard) was achieved on a Hypersil GOLD C18 column using gradient elution. The selected reaction monitoring transitions were performed at m/z 586.1→513.2 for tigecycline and m/z 445.1→410.2 for tetracycline. The assay was linear over the concentration range of 5-2000 ng/mL. The intra- and interday precisions at three concentration levels (10, 100, and 1600 ng/mL) were <15% and their accuracies were within the range of 95.1-106.1%. The mean recovery ranged from 94.3 to 105.6% and the matrix effect from 92.1 to 97.6%. Tigecycline was stable under all tested conditions. This validated method was successfully applied to a pharmacokinetic study in critically ill patients. The data demonstrated that our method allows quantification of tigecycline in serum in a quick and reliable manner for widespread application.

Influence of the gastrointestinal microflora and efflux transporters on the absorption of scutellarin and scutellarein.

Scutellarin (SG) and its aglycone, Scutellarein (S), are flavonoids of therapeutic cardiocerebrovascular disease. SG was hydrolyzed by bacterial enzyme into S which was absorbed in the intestine. The aim of this study was to determine the effects of the microflora in the intestinal lumen and the efflux transporter of intestinal epithelial cells on the absorption process of SG and S. After oral administration of antibiotics in Sprague-Dawley rats, the reduced bacterial enzyme formation significantly hinders the absorption of SG, whereas scarcely that of S. The absorption study in situ single-pass intestinal perfusion revealed that S could be absorbed throughout the intestine of rats. The effective intestinal permeability of S in the jejunum was much lower than in the other sections of the GI tract. The efflux transporter promoted SG secretion into lumen from enterocytes, which hindered the absorption of both SG and S into the bloodstream. The efflux transporter protein inhibitor (verapamil, probenecid and reserpine) remarkably enhanced the absorption of S and the bioconversion of S into SG in both the rat intestine and Caco-2-monolayer models.

Construction and evaluation of a nanosystem that combines acidification promoted chemodynamic therapy and intracellular drug release monitoring.

Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer that seriously affects women's physical and mental health. Chemodynamic therapy (CDT) induces cell death by specifically generating Fenton/Fenton-like reactions within tumor cells. However, the weak acidity of the tumor microenvironment (TME) greatly weakens the effectiveness of CDT. This work constructed a kind of P-CAIDF/PT nanoparticles (NPs), composed of two Pluronic F127 (PF127) based polymers: one was PF127-CAI (P-CAI), composed by connecting PF127 with the carbonic anhydrase IX (CA IX) inhibitor (CAI); the other was PF127-SS-TPE (PT), composed of PF127 and the aggregation-induced emission molecule, tetraphenylethylene (TPE), via the linkage of disulfide bonds. The two polymers were employed to construct the doxorubicin (DOX) and ferrocene (Fc) co-loaded P-CAIDF/PT NPs through the film dispersion method. After being administrated via i.v., P-CAIDF/PT could be accumulated in the TME by the enhanced permeability and retention (EPR) effect and engulfed by tumor cells. P-CAI induced intracellular acidification by inhibiting the overexpressed CA IX, thus promoting CDT by enhancing the Fc-mediated Fenton reaction. The acidification-enhanced CDT combined with the DOX-mediated chemotherapy could improve the therapeutic effect on TNBC. Moreover, P-CAIDF/PT also monitored the intracellular drug release processes through the fluorescence resonance energy transfer (FRET) effect depending on the inherent DOX/TPE pair. In conclusion, the P-CAIDF/PT nanosystem can achieve the combination therapy of acidification-enhanced CDT and chemotherapy as well as therapy monitoring, thus providing new ideas for the design and development of TNBC therapeutic agents.

Correction: Bioreducible and acid-labile polydiethylenetriamines with sequential degradability for efficient transgelin-2 siRNA delivery.

Correction for 'Bioreducible and acid-labile polydiethylenetriamines with sequential degradability for efficient transgelin-2 siRNA delivery' by Pengchong Wang et al., J. Mater. Chem. B, 2019, 7, 6994-7005, https://doi.org/10.1039/C9TB01183H.

Pan-genome and phylogenomic analyses highlight Hevea species delineation and rubber trait evolution.

The para rubber tree (Hevea brasiliensis) is the world's sole commercial source of natural rubber, a vital industrial raw material. However, the narrow genetic diversity of this crop poses challenges for rubber breeding. Here, we generate high-quality de novo genome assemblies for three H. brasiliensis cultivars, two H. brasiliensis wild accessions, and three other Hevea species (H. nitida, H. pauciflora, and H. benthamiana). Through analyzing genomes of 94 Hevea accessions, we identify five distinct lineages that do not align with their previous species delineations. We discover multiple accessions with hybrid origins between these lineages, indicating incomplete reproductive isolation between them. Only two out of four wild lineages have been introduced to commercial rubber cultivars. Furthermore, we reveal that the rubber production traits emerged following the development of a large REF/SRPP gene cluster and its functional specialization in rubber-producing laticifers within this genus. These findings would enhance rubber breeding and benefit research communities.

Anti-Inflammatory and Anti-Oxidant Impacts of Lentinan Combined with Probiotics in Ulcerative Colitis.

Multi-methods have been developed to control ulcerative colitis. This research targeted to probe that lentinan combined with probiotics suppresses inflammation and oxidative stress responses in a dextran sulfate sodium (DSS)-induced colitis model. A mouse model of colitis was induced through oral administration with 2.5% DSS and treated with lentinan and probiotics independently or in combination. Then, bodyweight and Disease Activity Index (DAI) of mice were determined. Histopathology of colon tissue was analyzed, and apoptosis, inflammation and oxidative stress in the colon tissue of mice were observed. An HT-29 cell model of colitis was established by DSS stimulation and cultured with lentinan and/or probiotics to examine cell proliferation and apoptosis. The data discovered that after DSS induction of colitis, mice developed weight loss, increased DAI score, and shortened the length of colon. Also, severe histopathology of the colon, and increased apoptosis, inflammation and oxidative stress were recognizable. Lentinan could alleviate DSS-induced colitis, and the highest dose was the most significant. Probiotics could also relieve UC in mice, and mixed probiotics had a better therapeutic effect than single probiotics. Lentinan combined with probiotics could further alleviate DSS-induced colitis damage. In addition, lentinan combined with probiotics impaired apoptosis and enhanced proliferation of DSS-treated HT-29 cells. In a word, lentinan combined with probiotics reduces the inflammatory response and oxidative stress of UC.

Restoration of dysregulated intestinal barrier and inflammatory regulation through synergistically ameliorating hypoxia and scavenging reactive oxygen species using ceria nanozymes in ulcerative colitis.

BACKGROUND: Reactive oxygen species (ROS) overproduction and excessive hypoxia play pivotal roles in the initiation and progression of ulcerative colitis (UC). Synergistic ROS scavenging and generating O2 could be a promising strategy for UC treatment. METHODS: Ceria nanozymes (PEG-CNPs) are fabricated using a modified reverse micelle method. We investigate hypoxia attenuating and ROS scavenging of PEG-CNPs in intestinal epithelial cells and RAW 264.7 macrophages and their effects on pro-inflammatory macrophages activation. Subsequently, we investigate the biodistribution, pharmacokinetic properties and long-term toxicity of PEG-CNPs in mice. PEG-CNPs are administered intravenously to mice with 2,4,6-trinitrobenzenesulfonic acid-induced colitis to test their colonic tissue targeting and assess their anti-inflammatory activity and mucosal healing properties in UC. RESULTS: PEG-CNPs exhibit multi-enzymatic activity that can scavenge ROS and generate O2, promote intestinal epithelial cell healing and inhibit pro-inflammatory macrophage activation, and have good biocompatibility. After intravenous administration of PEG-CNPs to colitis mice, they can enrich at the site of colonic inflammation, and reduce hypoxia-induced factor-1α expression in intestinal epithelial cells by scavenging ROS to generate O2, thus further promoting disrupted intestinal mucosal barrier restoration. Meanwhile, PEG-CNPs can effectively scavenge ROS in impaired colon tissues and relieve colonic macrophage hypoxia to suppress the pro-inflammatory macrophages activation, thereby preventing UC occurrence and development. CONCLUSION: This study has provided a paradigm to utilize metallic nanozymes, and suggests that further materials engineering investigations could yield a facile method based on the pathological characteristics of UC for clinically managing UC.

Metal-Phenolic Networks for Chronic Wounds Therapy.

Chronic wounds are recalcitrant complications of a variety of diseases, with pathologic features including bacterial infection, persistent inflammation, and proliferation of reactive oxygen species (ROS) levels in the wound microenvironment. Currently, the use of antimicrobial drugs, debridement, hyperbaric oxygen therapy, and other methods in clinical for chronic wound treatment is prone to problems such as bacterial resistance, wound expansion, and even exacerbation. In recent years, researchers have proposed many novel materials for the treatment of chronic wounds targeting the disease characteristics, among which metal-phenolic networks (MPNs) are supramolecular network structures that utilize multivalent metal ions and natural polyphenols complexed through ligand bonds. They have a flexible and versatile combination of structural forms and a variety of formations (nanoparticles, coatings, hydrogels, etc.) that can be constructed. Functionally, MPNs combine the chemocatalytic and bactericidal properties of metal ions as well as the anti-inflammatory and antioxidant properties of polyphenol compounds. Together with the excellent properties of rapid synthesis and negligible cytotoxicity, MPNs have attracted researchers' great attention in biomedical fields such as anti-tumor, anti-bacterial, and anti-inflammatory. This paper will focus on the composition of MPNs, the mechanisms of MPNs for the treatment of chronic wounds, and the application of MPNs in novel chronic wound therapies.

Application of a Dual-Probe Coloading Nanodetection System in the Process Monitoring and Efficacy Assessment of Photodynamic Therapy: An In Vitro Study.

The oxygen-consuming property of photodynamic therapy (PDT) affects its effects and aggravates tumor hypoxia, thus upregulating the vascular endothelial growth factor (VEGF) to exacerbate tumor metastasis and lead to treatment failure. Therefore, it is necessary to monitor the dynamic changes in the factors related to PDT and tumor development trends in real time, thus helping to improve PDT efficiency. This study fabricated a fluorescent probe, TPE-2HPro, and a fluorescein-labeled aptamer probe, FAM-AptamerVEGF, to detect hydrogen peroxide (H2O2) and VEGF through the photoinduced electron-transfer effect and the specific affinity of the aptamer to VEGF, respectively. The two probes were loaded into the inner pores and absorbed on the surface of polydopamine coating-wrapped mesoporous silica nanoparticles (MSN@PDA) to construct the dual-probe-loaded system, MSNTH@PDAApt, which was kept stable in fetal bovine serum (FBS) solution and achieved pH-responsive release behavior, thus helping to increase the accumulation of the two probes in tumor cells. The dichloroacetic acid-mediated in vitro antitumor tests showed that the changing trends of H2O2 and VEGF levels were consistent with the results of related mechanism studies and could be monitored by MSNTH@PDAApt. The in vitro chlorin e6 (Ce6)-mediated PDT treatment demonstrated that when the illumination condition was 650 nm, 50 mW/cm2 for 10 min, cells were more inclined to metastasis and invasion rather than death due to a substantial increase in VEGF expression at the low Ce6 concentrations. With the increase of the Ce6 concentration, the growth of the H2O2 level gradually exceeded that of VEGF, and the reactive oxygen species (ROS)-mediated cell death dominated when the Ce6 concentration was about 2 times its IC50 values. Besides, hypoxia also affected the H2O2 and VEGF changes. These results demonstrated that MSNTH@PDAApt could precisely monitor and assess the tumor development trends during PDT treatment, thus helping improve the treatment effect.

Genome-wide analysis of the SWEET genes in Taraxacum kok-saghyz Rodin: An insight into two latex-abundant isoforms.

Taraxacum kok-saghyz Rodin (Tk) is a promising alternative rubber-producing grass. However, low biomass and rubber-producing capability limit its commercial application. As a carbon source transporter in plants, sugar will eventually be exported transporters (SWEETs) have been reported to play pivotal roles in diverse physiological events in the context of carbon assimilate transport and utilization. Theoretically, SWEETs would participate in Tk growth, development and response to environmental cues with relation to the accumulation of rubber and biomass, both of which rely on the input of carbon assimilates. Here, we identified 22 TkSWEETs through homology searching of the Tk genomes and bioinformatics analyses. RNA-seq and qRT-PCR analysis revealed these TkSWEETs to have overlapping yet distinct tissue expression patterns. Two TkSWEET isofroms, TkSWEET1 and TkSWEET12 expressed substantially in the latex, the cytoplasm of rubber-producing laticifers as well as the rubber source. As revealed by the transient expression analysis using Tk mesophyll protoplasts, both TkSWEET1 and TkSWEET12 were located in the plasma membrane. Heterologous expressions of the two TkSWEETs in a yeast mutant revealed that only TkSWEET1 exhibited apparent sugar transport activities, with a preference for monosaccharides. Interestingly, TkSWEET12, the latex-predominant TkSWEET isoform, seemed to have evolved from a tandem duplication event that results in a cluster of six TkSWEET genes with the TkSWEET12 therein, suggesting its specialized roles in the laticifers.

Hyaluronic acid modified oral drug delivery system with mucoadhesiveness and macrophage-targeting for colitis treatment.

Based on the biocompatibility and macrophage targeting of natural polysaccharides, combined with the physiological and pathological characteristics of the gastrointestinal tract and colonic mucosa of ulcerative colitis (UC), we prepare dexamethasone (Dex)-loaded oral colon-targeted nano-in-micro drug delivery systems coated with multilayers of chitosan (CS), hyaluronic acid (HA), and finally Eudragit S100 (ECHCD MPs) using a layer-by-layer coating technique for UC treatment through regulating the M1/M2 polarization of intestinal macrophages. HA/CS/Dex nanoparticles (HCD NPs) are ingested by macrophages via CD44 receptor-mediated endocytosis to regulate M1-to-M2 macrophage polarization and exert anti-inflammatory effects. Moreover, ECHCD MPs show better colon-targeting properties than Dex-loaded chitosan nanoparticles (CD NPs) and HCD NPs which is demonstrated by stronger mucoadhesion to inflamed colon tissues. After oral administration, ECHCD MPs exert significant anti-UC effects. Therefore, ECHCD MPs are proven to be as promising oral colon-targeting drug delivery systems for Dex and have potential application in UC treatment.

Hyaluronic acid-based M1 macrophage targeting and environmental responsive drug releasing nanoparticle for enhanced treatment of rheumatoid arthritis.

Herein, hyaluronic acid (HA) and ß-cyclodextrin (ß-CD) is used to form targeted drug delivery platform HCPC/DEX NPs with previously prepared carbon dots (CDs) as cross-linker, dexamethasone (DEX) is loaded for rheumatoid arthritis (RA) treatment. The drug loading capacity of ß-CD and M1 macrophage targeting of HA were utilized for efficient delivery of DEX to the inflammatory joints. Because of the environmental responsive degradation of HA, DEX can be released in 24 h and inhibit the inflammatory response in M1 macrophages. The drug loading of NPs is 4.79 %. Cellular uptake evaluation confirmed that NPs can specifically target to M1 macrophages via HA ligands, the uptake of M1 macrophages is 3.7 times that of normal macrophages. In vivo experiments revealed that NPs can accumulate in RA joints to alleviate inflammation and accelerate cartilage healing, the accumulation can be observed in 24 h. The cartilage thickness increased to 0.45 mm after HCPC/DEX NPs treatment, indicating its good RA therapeutic effect. Importantly, this study was the first to utilize the potential acid and reactive oxygen species responsiveness of HA to release drug and prepare M1 macrophage targeting nanodrug for RA treatment, which provides a safe and effective RA therapeutic strategy.