Hypomethylating agent decitabine sensitizes diffuse large B-cell lymphoma to venetoclax.

Despite recent advances in the therapy of diffuse large B-cell lymphoma (DLBCL), many patients are still not cured. Therefore, new therapeutic strategies are needed. The anti-apoptotic B-cell lymphoma 2 (BCL2) gene is commonly dysregulated in DLBCL due to various mechanisms such as chromosomal translocation t(14;18)(q32;q21) and copy number alterations; however, targeting BCL-2 with the selective inhibitor, venetoclax, led to response in only a minority of patients. Thus, we sought to identify a rational combination partner of venetoclax to improve its activity against DLBCL cells. Utilizing a functional assay, dynamic BH3 profiling, we found that the DNA hypomethylating agent decitabine increased mitochondrial apoptotic priming and BCL-2 dependence in DLBCL cells. RNA-sequencing analysis revealed that decitabine suppressed the pro-survival PI3K-AKT pathway and altered the mitochondria membrane composition in DLBCL cell lines. Additionally, it induced a DNA damage response and increased BAX and BAK activities. The combination of decitabine and venetoclax synergistically suppressed proliferation of DLBCL cells both in vitro and in vivo in a DLBCL cell line-derived xenograft mouse model. Our study suggests that decitabine plus venetoclax is a promising combination to explore clinically in DLBCL.

Steroid hormone ecdysone deficiency stimulates preparation for photoperiodic reproductive diapause.

Diapause, a programmed developmental arrest primarily induced by seasonal environmental changes, is very common in the animal kingdom, and found in vertebrates and invertebrates alike. Diapause provides an adaptive advantage to animals, as it increases the odds of surviving adverse conditions. In insects, individuals perceive photoperiodic cues and modify endocrine signaling to direct reproductive diapause traits, such as ovary arrest and increased fat accumulation. However, it remains unclear as to which endocrine factors are involved in this process and how they regulate the onset of reproductive diapause. Here, we found that the long day-mediated drop in the concentration of the steroid hormone ecdysone is essential for the preparation of photoperiodic reproductive diapause in Colaphellus bowringi, an economically important cabbage beetle. The diapause-inducing long-day condition reduced the expression of ecdysone biosynthetic genes, explaining the drop in the titer of 20-hydroxyecdysone (20E, the active form of ecdysone) in female adults. Application of exogenous 20E induced vitellogenesis and ovarian development but reduced fat accumulation in the diapause-destined females. Knocking down the ecdysone receptor (EcR) in females destined for reproduction blocked reproductive development and induced diapause traits. RNA-seq and hormone measurements indicated that 20E stimulates the production of juvenile hormone (JH), a key endocrine factor in reproductive diapause. To verify this, we depleted three ecdysone biosynthetic enzymes via RNAi, which confirmed that 20E is critical for JH biosynthesis and reproductive diapause. Importantly, impairing Met function, a component of the JH intracellular receptor, partially blocked the 20E-regulated reproductive diapause preparation, indicating that 20E regulates reproductive diapause in both JH-dependent and -independent manners. Finally, we found that 20E deficiency decreased ecdysis-triggering hormone signaling and reduced JH production, thereby inducing diapause. Together, these results suggest that 20E signaling is a pivotal regulator that coordinates reproductive plasticity in response to environmental inputs.

Polyethylene glycol with dual three-dimensional porous carbon nanotube/diamond: a high thermal conductivity of composite PCM.

Polyethylene glycol (PEG) is widely used as a phase change material (PCM) in thermal energy storage systems due to its high latent heat and chemical stability. However, practical application has been hindered by its low thermal conductivity and leakage issues. Therefore, developing shape-stable high thermal conductivity PCM is of great importance. In this study, new shape-stable composite PCM with high thermal conductivity and leak-prevention capabilities were designed. The porous carbon skeleton of diamond foam (DF) and dual-3D carbon nanotube-diamond foam (CDF) were prepared using the microwave plasma chemical vapor deposition method. The composite materials (DF/PEG and CDF/PEG) were produced by vacuum impregnation with PEG and skeletons. The results showed that CDF/PEG had the highest thermal conductivity, measuring 2.30 W·m-1·K-1, which is 707% higher than that of pure PEG. The employing of 3D networks of CNTs, which can improve the phonon mean free path in DF/PEG (1.79 W·m-1·K-1) while reducing phonon dispersion.The phonon vibration of dual-3D CDF plays an important role in heat transfer. PEG was physically absorbed and well-distributed in CDF, alleviating leakage of liquid PEG. The weight loss of CDF/PEG was only 25% at 70 °C for 120 s. Using CDF is an attractive and efficient strategy to increase the heat transfer of PEG and improve heat storage efficiency, alleviate the problem of poor shape-stability.

Diagnostic value of mesenteric CTA combined with D-dimer level and inflammatory factor changes in severity of mesenteric artery embolism.

Objective: To investigate the value of mesenteric CTA combined with D-dimer (DD) level and inflammatory factor changes in evaluating the severity of mesenteric artery embolism. Methods: This is a retrospective study. The imaging data of mesenteric CTA and the levels of plasma DD and inflammatory factors in 120 patients with mesenteric artery embolism confirmed by DSA or surgery in Baoding No.1 Central Hospital were analyzed retrospectively from January 2021 to December 2022. The coincidence rate of CTA alone and CTA combined with DD and inflammatory factors with the results of surgery or DSA was compared and analyzed. The specificity, sensitivity and accuracy of CTA alone and CTA combined with DD and inflammatory factors in diagnosing superior mesenteric artery embolism were compared. The correlations of different severity of mesenteric artery embolism with DD and inflammatory factor levels were compared and analyzed. Results: There was a significant difference in the coincidence rate between CTA diagnosis and CTA combined with DD and inflammatory factors diagnosis (p= 0.01). And the sensitivity and accuracy of the latter were significantly higher than those of the former (sensitivity, p= 0.01; accuracy, p= 0.00). The levels of plasma DD, TNF-a, CRP and IL-6 in the intestinal wall thinning group were significantly higher than those in the thickening group (p= 0.00). The above indexes increased significantly in the decreased intestinal wall enhancement group compared with the increased intestinal wall enhancement group (p= 0.00). DD, TNF-ɑ, CRP and IL-6 levels increased with the increase in stenosis severity. Conclusion: Mesenteric CTA combined with plasma DD and inflammatory factor levels can effectively determine the severity of mesenteric arterial embolism, and provide a scientific basis for early clinical diagnosis and treatment.

Genes from Carboxypeptidase A, glutathione S-transferase, and cytochrome b families were found involved in lead transport in insect Musca domestica.

Lead (Pb) is a typical toxic contamination source all over the world. In this research, larvae of the housefly (Musca domestica) were fed a Pb-contaminated diet at different Pb doses of 0, 20 and 5000 mg/kg. RNA sequencing was used to identify genes that were differentially expressed in relation to lead transport or detoxification. RNA interference (RNAi) was carried on 12 candidate genes. The results showed that three luminal pH regions of mid-gut were at pH values of 6.33, 3.10, and 7.80. With increasing Pb concentration, the pH of the middle mid-gut decreased by one unit. The expression levels of carboxypeptidase A (CPA1), glutathione S-transferase (GST), and cytochrome b (Cyt b) were linked to Pb treatments, particularly high Pb concentration of 5000 mg/kg. RNAi-mediated down expression of CPA1, GST2, and CYTb-c1 resulted in low Pb accumulation in the larvae of 5000 mg/kg Pb group. These proteins played key roles in Pb transport and detoxification in M. domestica larvae.

Comparisons of Stroke Knowledge and Health Behaviors in Patients With Hypertensive Stroke at Different Recurrence Risk Strata: The Comprehensive Reminder System Based on the Health Belief Model Study.

BACKGROUND: Risk factor management via behavioral change contributes substantially to secondary stroke prevention. The health belief model identified self-perceived risk as a significant factor in behavior change. In previous studies, people have tended to incorrectly estimate their risk of stroke. Little is known about the differences in stroke knowledge and health behaviors in patients who have had a stroke with different risks of stroke recurrence in China. OBJECTIVE: The aims of this study were to determine the accuracy of self-perceived risk of stroke recurrence and to compare stroke knowledge and health behaviors in patients with hypertensive stroke at different recurrence risk strata. METHODS: Baseline data from 174 patients in the Comprehensive Reminder System based on the Health Belief Model (CRS-HBM) study were used. Self-perceived risk was assessed via the susceptibility subcategory of the Short-Form Health Belief Model Scale, and actual risk was stratified using the Essen Stroke Risk Score. RESULTS: Only 27.0% of the patients estimated their risks of stroke recurrence accurately. Patients who perceived themselves to be at higher risk had better knowledge of warning signs. Compared with patients who underestimated their risk of stroke recurrence, those who accurately estimated or overestimated their risk less likely to smoke. CONCLUSIONS: Most patients incorrectly estimated their risk of stroke recurrence. Communicating with patients about their future risk of recurrent stroke may help improve their stroke knowledge and health behaviors. Implementation of the Comprehensive Reminder System based on the Health Belief Model focusing on risk education aimed at prevention of stroke recurrence is warranted in China.

Long noncoding Mirt2 reduces apoptosis to alleviate myocardial infarction through regulation of the miR-764/PDK1 axis.

Acute myocardial infarction (AMI) is a common clinical cardiovascular disease, which is the leading cause of death and disability worldwide. Abnormal expression of long noncoding RNAs (lncRNA) is reported to be related to myocardial dysfunctions such as myocardial infarction (MI). In this study, we aimed to investigate the role of lncRNA myocardial infarction-related transcription factors 2 (Mirt2) in AMI and the underlying molecular mechanisms in vivo and in vitro. In vivo AMI model was established by occlusion of the left anterior descending coronary artery. Rats were randomly divided into two groups (five rats per group): the sham group and the AMI group. H9c2 cells were cultured under hypoxia for 4 h and then cultured under normoxia to establish the in vitro hypoxia reoxygenation (H/R) model. Our study shows that the myocardial infarct size and the apoptosis in AMI rats were both significantly increased, indicating that the AMI rat model was successfully established. Additionally, the levels of Mirt2 in AMI rats were increased significantly. Knockdown of Mirt2 by shRNA (shMirt2) had no significant effect on apoptosis and MI in sham rats, but significantly promoted apoptosis and MI in AMI rats. In vitro experiments showed that shMirt2 significantly decreased the level of Mirt2 in H9c2 cells and H9c2 cells treated with H/R. It is worth noting that shMirt2 had no significant effect on H9c2 cells, but significantly increased the levels of oxidative stress markers (malondialdehyde and lactate dehydrogenase), and also increased the number of apoptosis of H/R-treated H9c2 cells. Further mechanistic analysis showed that Mirt2 could protect MI and apoptosis in AMI rats by competitively adsorbing miR-764 and reducing the inhibitory effect of miR-764 on 3-phosphoinositide-dependent kinase 1 (PDK1). More importantly, after overexpression of Mirt2, MI and apoptosis were significantly improved in AMI rats, indicating that Mirt2 showed a protective effect in AMI rats. In summary, these findings suggest that that Mirt2 participated in the regulation of MI through the miR-764/PDK1 axis. Therefore, the current findings provide a theoretical basis for the diagnosis and treatment of clinical MI with changes in Mirt2 levels.

Gene regulation and suppression of type I interferon signaling by STAT3 in diffuse large B cell lymphoma.

STAT3 is constitutively activated in many cancers and regulates gene expression to promote cancer cell survival, proliferation, invasion, and migration. In diffuse large B cell lymphoma (DLBCL), activation of STAT3 and its kinase JAK1 is caused by autocrine production of IL-6 and IL-10 in the activated B cell-like subtype (ABC). However, the gene regulatory mechanisms underlying the pathogenesis of this aggressive lymphoma by STAT3 are not well characterized. Here we performed genome-wide analysis and identified 2,251 STAT3 direct target genes, which involve B cell activation, survival, proliferation, differentiation, and migration. Whole-transcriptome profiling revealed that STAT3 acts as both a transcriptional activator and a suppressor, with a comparable number of up- and down-regulated genes. STAT3 regulates multiple oncogenic signaling pathways, including NF-κB, a cell-cycle checkpoint, PI3K/AKT/mTORC1, and STAT3 itself. In addition, STAT3 negatively regulates the lethal type I IFN signaling pathway by inhibiting expression of IRF7, IRF9, STAT1, and STAT2 Inhibition of STAT3 activity by ruxolitinib synergizes with the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL cells in vitro and in a xenograft mouse model. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate ruxolitinib or a specific JAK1 inhibitor combined with lenalidomide in ABC DLBCL.

Neutrophil to lymphocyte ratio as prognostic and predictive factor in patients with coronavirus disease 2019: A retrospective cross-sectional study.

This retrospective study was designed to explore whether neutrophil to lymphocyte ratio (NLR) is a prognostic factor in patients with coronavirus disease 2019 (COVID-19). A cohort of patients with COVID-19 admitted to the Tongren Hospital of Wuhan University from 11 January 2020 to 3 March 2020 was retrospectively analyzed. Patients with hematologic malignancy were excluded. The NLR was calculated by dividing the neutrophil count by the lymphocyte count. NLR values were measured at the time of admission. The primary outcome was all-cause in-hospital mortality. A multivariate logistic analysis was performed. A total of 1004 patients with COVID-19 were included in this study. The mortality rate was 4.0% (40 cases). The median age of nonsurvivors (68 years) was significantly older than survivors (62 years). Male sex was more predominant in nonsurvival group (27; 67.5%) than in the survival group (466; 48.3%). NLR value of nonsurvival group (median: 49.06; interquartile range [IQR]: 25.71-69.70) was higher than that of survival group (median: 4.11; IQR: 2.44-8.12; P < .001). In multivariate logistic regression analysis, after adjusting for confounding factors, NLR more than 11.75 was significantly correlated with all-cause in-hospital mortality (odds ratio = 44.351; 95% confidence interval = 4.627-425.088). These results suggest that the NLR at hospital admission is associated with in-hospital mortality among patients with COVID-19. Therefore, the NLR appears to be a significant prognostic biomarker of outcomes in critically ill patients with COVID-19. However, further investigation is needed to validate this relationship with data collected prospectively.

Semi-solid extrusion 3D printing ODFs: an individual drug delivery system for small scale pharmacy.

Orodispersible films (ODFs) are promising drug delivery systems for customized medicines as it provide an alternative approach to increase consumer acceptance by advantages of rapid dissolution and administration without water. The aim of this study was to develop a platform to support the realization of tailored treatments suitable for the extemporaneous production of ODFs by semi-solid extrusion (SSE) 3D printing (3DP). Hydroxypropyl methyl cellulose (HPMC) was used as the polymer of ODFs, and levocetirizine hydrochloride was used as the model drug. The optimal formulation was HPMC:API:PS:maltitol:sucralose at a ratio of 64:10:10:15:1. Seventeen percent HPMC solution and optimal formulation were used to prepare film precursors. The impact of dynamic viscosities and fluid mechanics difference on printing applicability was discussed. The ODFs of cube designs with aimed dose of 1.25 mg, 2.5 mg, and 5 mg were printed by SSE 3DP. Good linear relationship between theoretical model volume and drug content (R2 = 0.999) and good dose accuracy indicate that 3DP is a suitable method for preparing individualized ODFs.

[Study on anti-inflammatory active components and mechanism of Corydalis Bungeanae Herba].

Corydalis Bungeanae Herba is often used to treat a variety of inflammatory diseases in traditional Chinese medicine. In order to determine its chemical material basis, the components of Corydalis Bungeanae Herba were isolated by automated purification system. Flavonoids and alkaloids were prepared, and all such components were identified by mass spectrometry. The effects of the components on the production of inflammatory mediators and pharmacological mechanisms in the lipopolysaccharide(LPS)-induced RAW264.7 cell inflammation model were examined. Mouse macrophages(RAW264.7) were first treated with LPS. The relationship between cell viability and LPS concentration was observed. Then, the effects of flavonoids components and alkaloid components with different administration concentrations on cell viability were detected to determine the maximum administration concentration. Secondly, 2.5, 5, 10 and 20 µg·mL~(-1) flavonoids components and alkaloid components were added respectively to observe the effects and mechanism of different concentrations of flavonoids components and alkaloid components on LPS-induced inflammation of RAW264.7 macrophages. Griess reagent assay was used to detect NO content in cell supernatant. The inflammatory cytokines(TNF-α, IL-1ß and IL-6) in cell supernatant were determined by ELISA method. Western blot method was used to detect the intracellular nuclear factor(NF-κB) IκBα phosphorylation(p-IκBα), p65 phosphorylation(p-p65) and protein expression of TLR4, TLR2. The results showed that the alkaloid components inhibited the production of NO, TNF-α, IL-1ß and IL-6 in a dose-dependent mannerin the concentration range of 2.5-20 µg·mL~(-1). In inflammation upstream pathways, the inhibitory effect of the alkaloid components on the TLR2 expression level was weaker than that of TLR4. In inflammation downstream, alkaloid components significantly inhibited phosphorylation of IκBα and p65 in a dose-dependent manner. These data suggested that the alkaloid components were the material basis components of Corydalis Bungeanae Herba, and its anti-inflammatory mechanism might be related to inhibiting the transmission of inflammatory signals in TLRs/NF-κB signaling pathways dominated by TLR4, interfering with the activation of inflammatory genes and inhibiting their over expression, and down-regulating the secretion level of inflammatory factors.

Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma.

Janus kinases (JAKs) classically signal by activating STAT transcription factors but can also regulate gene expression by epigenetically phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated B-cell (ABC) subtype and is triggered by autocrine production of IL-6 and IL-10. Whether this signaling involves STAT activation, epigenetic modification of chromatin, or both mechanisms is unknown. Here we use genetic and pharmacological inhibition to show that JAK1 signaling sustains the survival of ABC DLBCL cells. Whereas STAT3 contributed to the survival of ABC DLBCL cell lines, forced STAT3 activity could not protect these cells from death following JAK1 inhibition, suggesting epigenetic JAK1 action. JAK1 regulated the expression of nearly 3,000 genes in ABC DLBCL cells, and the chromatin surrounding many of these genes was modified by H3Y41-P marks that were diminished by JAK1 inhibition. These JAK1 epigenetic target genes encode important regulators of ABC DLBCL proliferation and survival, including IRF4, MYD88, and MYC. A small molecule JAK1 inhibitor cooperated with the BTK inhibitor ibrutinib in reducing IRF4 levels and acted synergistically to kill ABC DLBCL cells, suggesting that this combination should be evaluated in clinical trials.

Molecular characterization and juvenile hormone-regulated transcription of the vitellogenin receptor in the cabbage beetle Colaphellus bowringi.

The vitellogenin receptor (VgR) is highly expressed in the ovaries where it is responsible for vitellogenin (Vg) deposition during oogenesis in insects. Therefore, identifying the VgR of insect pests, and understanding the mechanism regulating its expression, could lead to the development of pest management strategies based on disrupting reproduction. We cloned and identified VgR in the cabbage beetle, Colaphellus bowringi, which is a serious pest of cruciferous vegetables in Asia. The regulation of VgR transcription by juvenile hormone (JH) was also investigated. The results show that C. bowringi VgR cDNA contains an open reading frame of 5310 bp encoding 1769 amino acid residues. Protein domain prediction indicates that C. bowringi VgR belongs to the LDLR gene superfamily, having the same group of structural domains that has been well characterized in other insects. VgR mRNA was highly expressed in the ovaries of reproductive female cabbage beetles. Knockdown of VgR reduced yolk deposition in the ovaries, increased the accumulation of Vg proteins in the hemolymph and decreased the transcription of Vg1 and Vg2 in the fat body. RNA interference and hormone challenge experiments showed that JH induced VgR transcription via the JH intracellular receptor methoprene-tolerant (Met) and the JH-responsive transcription factor Krüppel homolog 1 (Kr-h1). Our results suggest that there is a feedback loop between VgR transcription in the ovaries and Vg transcription in the fat body. JH acting through Met-Kr-h1 pathway induces the transcription of the VgR that is essential for Vg uptake and reproductive development. These findings not only reveal the potential JH signaling mechanism regulating VgR transcription, but may also contribute to the development of pest control strategies based on disrupting endocrine-regulated reproduction.

Applications of excipients in the field of 3D printed pharmaceuticals.

The aim of this study was to determine the effect of varying excipient content on the formation and physical properties of 3 D printed tablets. Fifteen different excipient preparations were formed into tablets with radii of 5 mm and thickness of 2 mm, using binder jetting (BJ). The tablets were analyzed by assessing visual and microstructural appearance, friability, hardness, and disintegration time. We found that filling agents with high water solubility (e.g. D-sucrose), binding agents with a high viscosity in solution (e.g. polyethylene glycol 4000) and moistening agent with higher water content can increase the bonding strength and hardness of the 3 D printed tablets and prolonged their disintegration time. This work has demonstrated that the type of excipient and its concentration affects the properties of the 3 D printed tablet. This article may be used as a guide for elucidation of the effects of using conventional tablet excipients in the field of 3 D printed pharmaceuticals. The present work should enable the identification of excipients that satisfy requirements, reduce analysis time, and improve efficiency.

[Study on blood enrichment mechanism of steamed notoginseng based on metabolomics method].

In this paper,ultra performance liquid chromatography coupled with time-of-flight mass spectrometry( UPLC-Q-TOFMS) technique was used to study the effects of steamed notoginseng on endogenous markers in plasma of rats with hemolytic anemia induced by N-acetyl phenyl hydrazine( APH). The aim was to find out the potential biomarkers and possible blood enriching mechanism of steamed notoginseng on hemolytic anemia rats. In the experiment,steamed notoginseng medicine pair( steamed notoginseng-ginseng)and compound medicines( Sanqi Yangxue Capsules) were used respectively to intervene in APH-induced hemolytic anemia model rats.Then blood routine indexes such as red blood cells( RBC),hemoglobin( Hb) and related organ indexes were determined. As compared with the blank group,the RBC and Hb levels in the model group were substantially decreased( P< 0. 01),while the liver and spleen organ indexes were increased( P< 0. 05). The results of blood routine and organ index demonstrated that the blood deficiency model was successfully established. Steamed notoginseng can significantly increase the RBC level of rats( P<0. 01),and the related indicators of each drug group had a trend of returning to normal levels,verifying the blood enriching effect of steamed notoginseng. The UPLC-Q-TOF-MS technique,principal component analysis( PCA) and partial least squares-discrimination analysis( PLS-DA) were used to analyze the metabolic profiles between the normal group and the model group. Twenty-six potential biomarkers for hemolytic anemia were screened in plasma. Nine metabolites such as retinol,L-valine,and arachidonic acid were down-regulated in the blood deficiency rats,and 17 metabolites such as protoporphyrin Ⅸ and niacinamide were up-regulated. The metabolic level of biomarkers could be changed to a normal state after rats were given with steamed notoginseng,drug pairs,and compound prescriptions. It can be speculated that steamed notoginseng may play a role of blood tonifying by improving biosynthesis of valine,leucine and isoleucine,as well as metabolic pathways such as retinol metabolism and arachidonic acid metabolism.

The gut bacteria across life stages in the synanthropic fly Chrysomya megacephala.

BACKGROUND: Gut bacteria are closely associated with host. Chrysomya megacephala, as a vector and resource insect, can transmit various pathogenic bacteria and consume manure to produce biofertilizer and larva biomass. However, the gut bacteria composition and abundance of C. megacephala remain unclear. RESULTS: Illumina MiSeq platform was used to compare composition of gut bacterial community in eggs, 1-day-old larvae, 5-day-old larvae, pupae, adult females and males by sequencing with variation in V4 region of 16S ribosomal DNA gene. In total, 928 operational taxonomic units (OTUs) were obtained. These OTUs were annotated into 19 phyla, 42 classes, 77 orders, 153 families and 289 genera. More than 0.5% abundance of 32 OTU core genera were found across all life stages. At class level, Alphaproteobacteria, Bacilli, Bacteroidia, Betaproteobacteria, Flavobacteriia and Gammaproteobacteria were the most abundant in C. megacephala. Eight species were identified to have significantly different abundance between 1-d-larvae and 5-day-larvae and took 28.95% of shared species between these two groups. Sex-specific bacterial species were identified that Faecalibacterium prausnitzii was merely present in females, while Rhodococcus fascians was merely present in males. CONCLUSION: Gut bacteria of C. megacephala varied across life stages. The composition and community structure of the bacterial community differed from young larvae to mature larvae, while that were similar in adult females and males. These data will provide an overall view of bacterial community across life stages in C. megacephala with attention on manure associated and pathogenic bacteria.

Oral disintegrating patient-tailored tablets of warfarin sodium produced by 3D printing.

Individualized medicine is a new direction in the field of modern pharmacy. In this study, we assessed the feasibility and accuracy of 3D printing techniques for the preparation of individualized doses of mouth-disintegrating tablets of warfarin. Warfarin sodium, D-sucrose, pregelatinized starch, povidone K30, microcrystalline cellulose, and silicon dioxide (at a ratio of 1:42.45:46.15:5.1:4.9:0.4) were mixed and used as the printing powder in the 3D printer; preset parameters were used. The dosage of the tablet was controlled by the number of printing layers. The content, dose uniformity, dose accuracy, hardness, friability, disintegration time, dissolution, and the microstructural and overall appearance were determined to evaluate the printed tablets. For the doses of 3, 2, and 1 mg that were produced in the experiment, the disintegration times were 50.0 ± 5.2, 35.7 ± 4.3, and 11.0 ± 2.2 s, respectively, and the relative errors of the dose were -2.33, -1.50, and 0%, respectively. The other indicators were consistent with the preparation requirements of pharmaceutical tablets. It is possible to prepare tablets with excellent properties and controlled drug doses by using 3D printing techniques. This technology will be an important means to achieve individualized medicine.

Biotransformation of ginsenosides F4 and Rg6 in zebrafish.

Ginsenosides F4 and Rg6 (GF4 and GRg6), two main active components of steamed notoginseng or red ginseng, are dehydrated disaccharide saponins. In this work, biotransformation of ginsenosides F4 and Rg6 in zebrafish was investigated by qualitatively identifying their metabolites and then proposing their possible metabolic pathways. The prediction of possible metabolism of ginsenosides F4 and Rg6 using zebrafish model which can effectively simulate existing mammals model was early and quickly performed. Metabolites of ginsenosides F4 and Rg6 after exposing to zebrafish for 24 h were identified by Ultraperformance Liquid Chromatography/Quadrupole-Time-of-Flight Mass Spectrometry. A total of 8 and 6 metabolites of ginsenosides F4 and Rg6 were identified in zebrafish, respectively. Of these, 7 and 5, including M1, M3-M5, M7-M9 and N1 (N5), N2, N4 (N9), N7-N8 were reported for the first time as far as we know. The mechanisms of their biotransformation involved were further deduced to be desugarization, glucuronidation, sulfation, dehydroxylation, loss of C-17 and/or C-23 residue pathways. It was concluded that loss of rhamnose at position C-6 and glucuronidation at position C-3 in zebrafish were considered as the main physiologic and metabolic processes of ginsenosides F4 and ginsenosides Rg6, respectively.

[Identification of saponins from Panax notoginseng in metabolites of rats].

UPLC-QTOF-MS/MS was used to identify metabolites in rat blood, urine and feces after the administration of n-butanol extract derived from steamed notoginseng. The metabolic process of saponins came from steamed notoginseng was analyzed. The metabolites were processed by PeakView software, and identified according to the structural characteristics of prototype compounds and the accurate qualitative and quantitative changes of common metabolic pathways. Four saponins metabolites were identified based on MS/MS information of metabolites, namely ginsenoside Rh4, Rk3, Rk1, Rg5,and their 15 metabolites were verified. The metabolic pathways of the four ginsenosides in n-butanol extract included glucuronidation, desugar, sulfation, dehydromethylation, and branch loss. The metabolites of main active saponin components derived from steamed Panax notoginseng were analyzed from the perspective of qualitative analysis. And the material basis for the efficacy of steamed notoginseng was further clarified.

Bone-marrow-derived mesenchymal stem cells inhibit gastric aspiration lung injury and inflammation in rats.

Gastric aspiration lung injury is one of the most common clinical events. This study investigated the effects of bone-marrow-derived mesenchymal stem cells (BMSCs) on combined acid plus small non-acidified particle (CASP)-induced aspiration lung injury. Enhanced green fluorescent protein (EGFP(+) ) or EGFP(-) BMSCs or 15d-PGJ2 were injected via the tail vein into rats immediately after CASP-induced aspiration lung injury. Pathological changes in lung tissues, blood gas analysis, the wet/dry weight ratio (W/D) of the lung, levels of total proteins and number of total cells and neutrophils in bronchoalveolar lavage fluid (BALF) were determined. The cytokine levels were measured using ELISA. Protein expression was determined by Western blot. Bone-marrow-derived mesenchymal stem cells treatment significantly reduced alveolar oedema, exudation and lung inflammation; increased the arterial partial pressure of oxygen; and decreased the W/D of the lung, the levels of total proteins and the number of total cells and neutrophils in BALF in the rats with CASP-induced lung injury. Bone-marrow-derived mesenchymal stem cells treatment decreased the levels of tumour necrosis factor-α and Cytokine-induced neutrophil chemoattractant (CINC)-1 and the expression of p-p65 and increased the levels of interleukin-10 and 15d-PGJ2 and the expression of peroxisome proliferator-activated receptor (PPAR)-γ in the lung tissue in CASP-induced rats. Tumour necrosis factor-α stimulated BMSCs to secrete 15d-PGJ2 . A tracking experiment showed that EGFP(+) BMSCs were able to migrate to local lung tissues. Treatment with 15d-PGJ2 also significantly inhibited CASP-induced lung inflammation and the production of pro-inflammatory cytokines. Our results show that BMSCs can protect lung tissues from gastric aspiration injury and inhibit lung inflammation in rats. A beneficial effect might be achieved through BMSC-derived 15d-PGJ2 activation of the PPAR-γ receptor, reducing the production of proinflammatory cytokines.