Dual role of Nrf2/HO-1 pathway in Z-ligustilide-induced ferroptosis against AML cells.

BACKGROUND: The scarcity of drugs targeting AML cells poses a significant challenge in AML management. Z-Ligustilide (Z-LIG), a phthalide compound, shows promising pharmacological potential as a candidate for AML therapy. However, its precise selective mechanism remains unclear. PURPOSE: In order to assess the selective inducement effects of Z-LIG on ferroptosis in AML cells and explore the possible involvement of the Nrf2/HO-1 pathway in the regulation of ferroptosis. METHODS: Through in vitro cell proliferation and in vivo tumor growth tests, the evaluation of Z-LIG's anticancer activity was conducted. Ferroptosis was determined by the measurement of ROS and lipid peroxide levels using flow cytometry, as well as the observation of mitochondrial morphology. To analyze the iron-related factors, western blot analysis was employed. The up-regulation of the Nrf2/HO-1 axis was confirmed through various experimental techniques, including CRISPR/Cas9 gene knockout, fluorescent probe staining, and flow cytometry. The efficacy of Z-LIG in inducing ferroptosis was further validated in a xenograft nude mouse model. RESULTS: Our study revealed that Z-LIG specifically triggered lipid peroxidation-driven cell death in AML cells. Z-LIG downregulated the total protein and nuclear entrance levels of IRP2, resulting in upregulation of FTH1 and downregulation of TFR1. Z-LIG significantly increased the susceptibility to ferroptosis by upregulating ACSL4 levels and simultaneously suppressing the activity of GPX4. Notably, the Nrf2/HO-1 pathway displayed a twofold impact in the ferroptosis induced by Z-LIG. Mild activation suppressed ferroptosis, while excessive activation promoted it, mainly driven by ROS-induced labile iron pool (LIP) accumulation in AML cells, which was not observed in normal human cells. Additionally, Nrf2 knockout and HO-1 knockdown reversed iron imbalance and mitochondrial damage induced by Z-LIG in HL-60 cells. Z-LIG effectively inhibited the growth of AML xenografts in mice, and Nrf2 knockout partially weakened its antitumor effect by inhibiting ferroptosis. CONCLUSION: Our study presents biological proof indicating that the selective initiation of ferroptosis in leukemia cells is credited to the excessive activation of the Nrf2/HO-1 pathway triggered by Z-LIG.

A novel machine learning model to predict high on-treatment platelet reactivity on clopidogrel in Asian patients after percutaneous coronary intervention.

BACKGROUND: Various genetic and nongenetic variables influence the high on-treatment platelet reactivity (HTPR) in patients taking clopidogrel. AIM: This study aimed to develop a novel machine learning (ML) model to predict HTPR in Chinese patients after percutaneous coronary intervention (PCI). METHOD: This cohort study collected information on 507 patients taking clopidogrel. Data were randomly divided into a training set (90%) and a testing set (10%). Nine candidate Machine learning (ML) models and multiple logistic regression (LR) analysis were developed on the training set. Their performance was assessed according to the area under the receiver operating characteristic curve, precision, recall, F1 score, and accuracy on the test set. Model interpretations were generated using importance scores by transforming model variables into scaled features and representing in radar plots. Finally, we established a prediction platform for the prediction of HTPR. RESULTS: A total of 461 patients (HTPR rate: 19.52%) were enrolled in building the prediction model for HTPR. The XGBoost model had an optimized performance, with an AUC of 0.82, a precision of 0.80, a recall of 0.44, an F1 score of 0.57, and an accuracy of 0.87, which was superior to those of LR. Furthermore, the XGBoost method identified 7 main predictive variables. To facilitate the application of the model, we established an XGBoost prediction platform consisting of 7 variables and all variables for the HTPR prediction. CONCLUSION: A ML-based approach, such as XGBoost, showed optimum performance and might help predict HTPR on clopidogrel after PCI and guide clinical decision-making. Further validated studies will strengthen this finding.

IL-7 promotes CD19-directed CAR-T cells proliferation through miRNA-98-5p by targeting CDKN1A.

CAR-T targeting CD19 have achieved significant effects in the treatment of B-line leukemia and lymphoma. However, the treated patients frequently relapsed and could not achieve complete remission. Therefore, improving the proliferation and cytotoxicity of CAR-T cells, reducing exhaustion and enhancing infiltration capacity are still issues to be solved. The IL-7 has been shown to enhance the memory characteristics of CAR-T cells, but the specific mechanism has yet to be elaborated. miRNAs play an important role in T cell activity. However, whether miRNA is involved in the activation of CAR-T cells by IL-7 has not yet been reported. Our previous study had established the 3rd generation CAR-T cells. The present study further found that IL-7 significantly increased the proliferation of anti-CD19 CAR-T cells, the ratio of CD4 + CAR + cells and the S phase of cell cycle. In vivo study NAMALWA xenograft model showed that IL-7-stimulated CAR-T cells possessed stronger tumoricidal efficiency. Further we validated that IL-7 induced CAR-T cells had low expression of CDKN1A and high expression of miRNA-98-5p. Additionally, CDKN1A was associated with miRNA-98-5p. Our results, for the first time, suggested IL-7 could conspicuously enhance the proliferation of CAR-T cells through miRNA-98-5p targeting CDKN1A expression, which should be applied to CAR-T production.

Z-ligustilide preferentially caused mitochondrial dysfunction in AML HL-60 cells by activating nuclear receptors NUR77 and NOR1.

BACKGROUND: Nuclear receptors NUR77 and NOR1 were identified as critical targets in acute myeloid leukemia (AML) therapy. Previously, we showed that Z-ligustilide (Z-LIG) selectively targeted AML by restoring NUR77 and NOR1. However, its downstream mechanisms are yet to be elucidated. METHODS: SRB staining assay was used to measure cell viability. Cell apoptosis, mitochondrial membrane potential and mitochondrial reactive oxygen species were analyzed using flow cytometry. The potential targets of Z-LIG in AML HL-60 cells were evaluated by RNA sequencing. Changes in RNA levels were measured using quantitative RT-qPCR and western blot analysis was used to detect the expression of proteins. RESULTS: Z-LIG preferentially induced mitochondrial dysfunction in HL-60 cells compared with 293T cells. Furthermore, RNA sequencing revealed that mitochondrial transcription and translation might be potential Z-LIG targets inhibiting HL-60 cells. NUR77/NOR1 overexpression significantly reduced the mitochondrial ATP and mitochondrial membrane potential and increased mitochondrial reactive oxygen species in HL-60 cells but not in 293T cells. Moreover, Z-LIG induced mitochondrial dysfunction by restoring NUR77 and NOR1 in HL-60 cells. Compared with HL-60 cells, the apoptosis-inducing activities of NUR77/NOR1 and Z-LIG were significantly reduced in HL-60 ρ0 cells depleted in mitochondrial DNA (mt-DNA). Moreover, NUR77/NOR1 and Z-LIG downregulated mitochondrial transcription and translation related proteins in HL-60 cells. Notably, Z-LIG remarkably reduced mitochondrial ATP in primary AML cells and showed anti-AML activity in mouse models of human AML. CONCLUSIONS: Collectively, our findings suggested that Z-LIG selectively induces mitochondrial dysfunction in AML HL-60 cells by restoring NUR77 and NOR1, a process associated with interference in mtDNA transcription.

Development and validation of the thyroid cancer self-perceived discrimination scale to identify patients at high risk for psychological problems.

Objective: To develop a Thyroid Cancer Self-Perceived Discrimination Scale (TCSPDS) to identify patients at high risk for psychological problems and to test its reliability, validity and acceptability. Methods: Using classical test theory, a total of 176 thyroid cancer patients from November 2021 to October 2022 were recruited to develop the TCSPDS. Item analysis was used to improve the preliminary TCSPDS. Exploratory factor analysis (EFA), confirmatory factor analysis (CFA) and structural equation model (SEM) were used to test the construct validity of the final TCSPDS. Pearson correlation coefficient was used to analyze the validity coefficient between TCSPDS and EORTC QLQ-C30 to test the criterion-related validity (CRV) of the final TCSPDS. The internal consistency coefficient (Cronbach's alpha coefficient), split half reliability (Spearman-Brown coefficient) and test-retest reliability were used to verify the reliability of the final TCSPDS. The questionnaire completion time and effective response rate were used to validate the acceptability of the final TCSPDS. Results: The TCSPDS consisted of 20 items and was divided into 3 subscales: 8 items for stigma, 6 items for self-deprecation, and 6 items for social avoidance. The TCSPDS had good validity (χ2/df=1.971, RMSEA=0.074, GFI=0.921, CFI= 0.930, IFI=0.932, TLI=0.901, Validity coefficient=0.767), reliability (Cronbach's alpha=0.867, Spearman-Brown coefficient=0.828, test-retest reliability coefficient=0.981) and acceptability [average completion time (15.01 ± 1.348 minutes) and an effective response rate of 95.14%]. Patients with higher TCSPDS scores reported a lower quality of life (P<0.05). Conclusion: The TCSPDS could be used for early identification and assessment of the level of self-perceived discrimination in patients with thyroid cancer, which may provide a scientific basis for health education, social support and psychosocial oncology services in the future, especially in Southwest China.

TFP5-Mediated CDK5 Activity Inhibition Improves Diabetic Nephropathy via NGF/Sirt1 Regulating Axis.

Diabetic nephropathy (DN) is one of the leading causes of chronic kidney disease (CKD), during which hyperglycemia is composed of the major force for the deterioration to end-stage renal disease (ESRD). However, the underlying mechanism triggering the effect of hyperglycemia on DN is not very clear and the clinically available drug for hyperglycemia-induced DN is in need of urgent development. Here, we found that high glucose (HG) increased the activity of cyclin-dependent kinase 5 (CDK5) dependent on P35/25 and which upregulated the oxidative stress and apoptosis of mouse podocytes (MPC-5). TFP5, a 25-amino acid peptide inhibiting CDK5 activity, decreased the secretion of inflammation cytokines in serum and kidney, and effectively protected the kidney function in db/db mouse from hyperglycemia-induced kidney injuries. In addition, TFP5 treatment decreased HG-induced oxidative stress and cell apoptosis in MPC-5 cells and kidney tissue of db/db mouse. The principal component analysis (PCA) of RNA-seq data showed that MPC-5 cell cultured under HG, was well discriminated from that under low glucose (LG) conditions, indicating the profound influence of HG on the properties of podocytes. Furthermore, we found that HG significantly decreased the level of NGF and Sirt1, both of which correlated with CDK5 activity. Furthermore, knockdown of NGF was correlated with the decreased expression of Sirt1 while NGF overexpression leads to upregulated Sirt1 and decreased oxidative stress and apoptosis in MPC-5 cells, indicating the positive regulation between NGF and Sirt1 in podocytes. Finally, we found that K252a, an inhibitor of NGF treatment could undermine the protective role of TFP5 on hyperglycemia-induced DN in db/db mouse model. In conclusion, the CDK5-NGF/Sirt1 regulating axis may be the novel pathway to prevent DN progression and TFP5 may be a promising compound to improved hyperglycemia induced DN.

The prognosis biomarkers based on m6A-related lncRNAs for myeloid leukemia patients.

BACKGROUND: Chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) are two common malignant disorders in leukemia. Although potent drugs are emerging, CML and AML may still relapse after the drug treatment is stopped. N6-methyladenosine (m6A) and lncRNAs play certain roles in the occurrence and development of tumors, but m6A-modified LncRNAs in ML remain to be further investigated. METHODS: In this study, we extracted and analyzed the TCGA gene expression profile of 151 ML patients and the clinical data. On this basis, we then evaluated the immune infiltration capacity of ML and LASSO-penalized Cox analysis was applied to construct the prognostic model based on m6A related lncRNAs to verify the prognostic risk in clinical features of ML. Quantitative reverse transcription PCR was used to detect the expression level of LncRNA in in ML cell lines K562, MOLM13 and acute monocytic leukemia cell line THP-1. RESULTS: We found 70 m6A-related lncRNAs that were related to prognosis, and speculated that the content of stromal cells and immune cells would correlate with the survival of patients with ML. Next, Prognostic risk model of m6A-related lncRNAs was validated to have excellent consistency in clinical features of ML. Finally, we verified the expression levels of CRNDE, CHROMR and NARF-IT1 in ML cell lines K562, MOLM13 and acute monocytic leukemia cell line THP-1, which were significant. CONCLUSIONS: The research provides clues for the prognosis prediction of ML patients by using the m6A-related lncRNAs model we have created, and clarifies the accuracy and authenticity of it.

Efficacy of Enhanced Cytokine-Induced Killer Cells as an Adjuvant Immunotherapy for Renal Cell Carcinoma: Preclinical and Clinical Studies.

Cytokine-induced killer (CIK) cells have been proved to be an effective method of tumor immunotherapy in numerous preclinical and clinical studies. In our previous study, a new method was developed to prime and propagate CIK cells by the combination of IL-2 and IL-15, and this kind of CIK cells had enhanced antitumor effect on lung cancer. For renal cell carcinoma (RCC), immunotherapy plays an important role because of the poor efficacy of radiotherapy and chemotherapy. In this study, we further evaluated the antitumor effects of these enhanced CIK cells against RCC. Enhanced CIK cells were generated by IL-2 combined with IL-15 and identified by flow cytometry. HEK-293 and ACHN cell lines were used to verify the efficiency of CIK cells in vitro, and then the ACHN tumor xenograft model was also employed for in vivo study. In addition, the secreted cytokines including IFN-γ, granzyme B, TNF-α, and perforin, as well as the local microstructure were also studied. Subsequently, 20 patients with RCC were enrolled into our study, and 11 patients were randomly divided into the autologous CIK treatment group for clinical research. The results showed that enhanced CIK cells exert better antitumor effects in RCC in vitro (p < 0.01 in HEK-293 and p < 0.05 in ACHN）and in vivo (p < 0.05). Patients benefit overall survival from enhanced CIK therapy in our clinical study. Our present preclinical and clinical studies for the first time elucidated that these enhanced CIK cells would be used as an effective adjuvant therapy in the treatment of RCC.

Electrochemically Promoted Asymmetric Transfer Hydrogenation of 2,2,2-Trifluoroacetophenone.

The study reported an electrochemically promoted asymmetric hydrogen transfer reaction of 2,2,2-trifluoroacetophenone with a chiral Ru complex. (R)-α-(Trifluoromethyl) benzyl alcohol with a 96% yield and 94% ee could be obtained with only a 0.5 F mol-1 charge amount at room temperature and normal pressure.

Combined Biosynthetic Pathway Engineering and Storage Pool Expansion for High-Level Production of Ergosterol in Industrial Saccharomyces cerevisiae.

Ergosterol, a terpenoid compound produced by fungi, is an economically important metabolite serving as the direct precursor of steroid drugs. Herein, ergsosterol biosynthetic pathway modification combined with storage capacity enhancement was proposed to synergistically improve the production of ergosterol in Saccharomyces cerevisiae. S. cerevisiae strain S1 accumulated the highest amount of ergosterol [7.8 mg/g dry cell weight (DCW)] among the wild-type yeast strains tested and was first selected as the host for subsequent metabolic engineering studies. Then, the push and pull of ergosterol biosynthesis were engineered to increase the metabolic flux, overexpression of the sterol acyltransferase gene ARE2 increased ergosterol content to 10 mg/g DCW and additional overexpression of a global regulatory factor allele (UPC2-1) increased the ergosterol content to 16.7 mg/g DCW. Furthermore, considering the hydrophobicity sterol esters and accumulation in lipid droplets, the fatty acid biosynthetic pathway was enhanced to expand the storage pool for ergosterol. Overexpression of ACC1 coding for the acetyl-CoA carboxylase increased ergosterol content from 16.7 to 20.7 mg/g DCW. To address growth inhibition resulted from premature accumulation of ergosterol, auto-inducible promoters were employed to dynamically control the expression of ARE2, UPC2-1, and ACC1. Consequently, better cell growth led to an increase of ergosterol content to 40.6 mg/g DCW, which is 4.2-fold higher than that of the starting strain. Finally, a two-stage feeding strategy was employed for high-density cell fermentation, with an ergosterol yield of 2986.7 mg/L and content of 29.5 mg/g DCW. This study provided an effective approach for the production of ergosterol and other related terpenoid molecules.

Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Ameliorate HaCaT Cell Photo-Aging.

Umbilical cord mesenchymal stem cells (UCMSCs) have been identified as a potentially ideal cell type for use in regenerative therapeutic contexts owing to their excellent paracrine secretory abilities and other desirable properties. Previous work has shown that stem cell-derived exosomes can effectively reduce skin aging, but few studies have specifically focused on the role of UCMSC-derived exosomes in this context. In this study, we isolated exosomes derived from UCMSCs grown in a three-dimensional culture system and explored their ability to modulate the photo-aging of HaCaT keratinocytes. Cell viability and proliferation were assessed using CCK8 assay, whereas wound healing and transwell assays were used to assess cell migratory capabilities. UVB irradiation (60 mJ/cm2) was used to induce photo-aging of HaCaT cells. TUNEL and SA-ß-Gal staining were used to explore HaCaT cell apoptosis and senescence, respectively, whereas real-time quantitative PCR was used to assess the expression of relevant genes at the mRNA level. We found that UCMSC-derived exosomes were able to enhance normal HaCaT cell proliferation and migration while also inhibiting UVB-induced damage to these cells. These exosomes also reduced HaCaT cell apoptosis and senescence, increasing collagen type I expression and reducing matrix metalloproteinase (MMP1) expression in photo-aged HaCaT cells. Together, these findings indicate that UCMSC-derived exosomes have the potential to be used therapeutically to suppress skin aging.

Evaluation of piggyBac-mediated anti-CD19 CAR-T cells after ex vivo expansion with aAPCs or magnetic beads.

Adoptive immunotherapy is a new potential method of tumour therapy, among which anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T cell), is a typical treatment agent for haematological malignancies. Previous clinical trials showed that the quality and phenotype of CAR-T cells expanded ex vivo would seriously affect the tumour treatment efficacy. Although magnetic beads are currently widely used to expand CAR-T cells, the optimal expansion steps and methods have not been completely established. In this study, the differences between CAR-T cells expanded with anti-CD3/CD28 mAb-coated beads and those expanded with cell-based aAPCs expressing CD19/CD64/CD86/CD137L/mIL-15 counter-receptors were compared. The results showed that the number of CD19-specific CAR-T cells with a 4-1BB and CD28 co-stimulatory domain was much greater with stimulation by aAPCs than that with beads. In addition, the expression of memory marker CD45RO was higher, whereas expression of exhausted molecules was lower in CAR-T cells expanded with aAPCs comparing with the beads. Both CAR-T cells showed significant targeted tumoricidal effects. The CAR-T cells stimulated with aAPCs secreted apoptosis-related cytokines. Moreover, they also possessed marked anti-tumour effect on NAMALWA xenograft mouse model. The present findings provided evidence on the safety and advantage of two expansion methods for CAR-T cells genetically modified by piggyBac transposon system.

CRISPR-Assisted Multiplex Base Editing System in Pseudomonas putida KT2440.

Pseudomonas putida (P. putida) KT2440 is a paradigmatic environmental-bacterium that possesses significant potential in synthetic biology, metabolic engineering and biodegradation applications. However, most genome editing methods of P. putida KT2440 depend on heterologous repair proteins and the provision of donor DNA templates, which is laborious and inefficient. In this report, an efficient cytosine base editing system was established by using cytidine deaminase (APOBEC1), enhanced specificity Cas9 nickase (eSpCas9ppD10A) and the uracil DNA glycosylase inhibitor (UGI). This constructed base editor converts C-G into T-A in the absence of DNA strands breaks and donor DNA templates. By introducing a premature stop codon in target spacers, we successfully applied this system for gene inactivation with an efficiency of 25-100% in various Pseudomonas species, including P. putida KT2440, P. aeruginosa PAO1, P. fluorescens Pf-5 and P. entomophila L48. We engineered an eSpCas9ppD10A-NG variant with a NG protospacer adjacent motif to expand base editing candidate sites. By modifying the APOBEC1 domain, we successfully narrowed the editable window to increase gene inactivation efficiency in cytidine-rich spacers. Additionally, multiplex base editing in double and triple loci was achieved with mutation efficiencies of 90-100% and 25-35%, respectively. Taken together, the establishment of a fast, convenient and universal base editing system will accelerate the pace of future research undertaken with P. putida KT2440 and other Pseudomonas species.

Construction of an Efficient Nicotinate Dehydrogenase Expression System in Comamonas testosteroni CNB-2 with Multi-level N-Terminal Engineering.

Nicotinate dehydrogenase (NDHase) is a membrane protein with three subunits (ndhS, ndhL, and ndhM), which is difficult to express in a functional form using common hosts such as Escherichia coli, Bacillus subtilis, or Pichia pastoris. Comamonas testosteroni is a suitable microbial chassis for expressing multi-subunit membrane proteins. However, the expression of NDHase in C. testosteroni is extremely low. We have developed a systematic approach to create an efficient protein expression system in C. testosteroni CNB-2 using multi-level N-terminal engineering. We selected a strong promoter for the Mmp1 system that enables control of transcriptional strength in unconventional bacteria. This enhanced the expression of a green fluorescent reporter protein threefold. Following modification of the N-terminal Shine-Dalgarno sequence and rearrangement of amino acid sequence in the starting area of the gene encoding NDHase, enzyme activity increased from 90.6 to 165 U/L. These optimized N-terminal Shine-Dalgarno and amino acid sequences were used to enhance the expression of ndhL subunit and improve the balance expression of three subunits of NDHase, resulting in enzyme activity of 192 U/L that far surpasses the previously reported level. These results highlight a promising strategy for the development of other heterologous expression systems for challenging proteins using unconventional bacteria.

Analysis of nicotine-induced metabolic changes in Blakeslea trispora by GC-MS.

Blakeslea trispora is a natural source of carotenoids, including ß-carotene and lycopene, which have industrial applications. Therefore, classical selective breeding techniques have been applied to generate strains with increased productivity, and microencapsulated ß-carotene preparation has been used in food industry (Li et al., 2019). In B. trispora, lycopene is synthesized via the mevalonate pathway (Venkateshwaran et al., 2015). Lycopene cyclase, which is one of the key enzymes in this pathway, is a bifunctional enzyme that can catalyze the cyclization of lycopene to produce ß-carotene and exhibit phytoene synthase activity (He et al., 2017).

Efficient heterologous expression of nicotinate dehydrogenase in Comamonas testosteroni CNB-2 with transcriptional, folding enhancement strategy.

Nicotinate dehydrogenase (NDHase) from Comamonas testosteroni JA1 catalyzes the C6 hydroxylation of 3-cyanopyridine with high regional selectivity, which is a very difficult and complex reaction for chemical synthesis. However, because NDHase is a membrane protein with three subunits (ndhS, ndhL and ndhM), it is difficult to express the enzyme in a functional form using common hosts such as Escherichia coli, Bacilus subtilis or Pichia pastoris. Furthermore, the enzyme requires special electron transfer chains in the membrane system for proper catalytic activity. Thus, we investigated the expression of NDHase in non-model bacterial strains, which are evolutionarily similar to C. testosteroni JA1, using several broad-host plasmids with different copy numbers as expression vectors. We successfully expressed NDHase in soluble from using the pVLT33 vector in C. testosteroni CNB-2, and found the activity of enzyme to be 40.6 U/L. To further improve the expression of NDHase in C. testosteroni CNB-2, we trialed a T7-like MmP1 system, composed of MmP1 RNA polymerase and an MmP1 promoter, which is used for transcriptional control in non-model bacteria. This increased protein expression and enzyme activity doubled to 90.5 U/L. A molecular chaperone was co-expressed using pBBR1 MCS-5 in the same host to improve the efficiency of folding and assembly of multi-subunit structures. The maximum activity was 115 U/L using the molecular chaperone GroES-EL, far surpassing the previously reported level, although expression was almost equivalent. These results indicate that a strategy involving the construction of a T7-like system and co-expression of a molecular chaperone offers an efficient approach for heterologous expression of enzymes that are difficult to express in functional forms using conventional hosts.

Microencapsulated ß-carotene preparation using different drying treatments.

ß-Carotene is one of the most abundant natural pigments in foods; however, usage of ß-carotene is limited because of its instability. Microencapsulation techniques are usually applied to protect microencapsulated ß-carotene from oxidization. In this study, ß-carotene was microencapsulated using different drying processes: spray-drying, spray freeze-drying, coating, and spray granulation. The properties of morphology, particle size, water content, thermal characteristic, and chemical stability have been explored and compared. Scanning electron microscopy measurements showed that the coated powder had a dense surface surrounded by starch and suggested that the coating process gave a microencapsulated powder with the smallest bulk density and the best compressibility among the prepared powders. The chemical stabilities of microcapsules were evaluated during six months of storage at different temperatures. The coated powder had the highest mass fraction of ß-carotene, which indicated that the coating process was superior to the three other drying processes.

Effectiveness comparisons of acupuncture for psoriasis: A Bayesian network meta-analysis protocol.

BACKGROUND: Psoriasis is an immune-mediated polygenic hereditary skin disease quality of the patients' life because of the great trouble it causes to patients. Whereas there is variability when we regard the selection of acupuncture treatments in practice and most choices are made based on personal experience or preference of clinician. This study uses network meta-analysis to compare the effectiveness of different forms of acupuncture for psoriasis and assesses the evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. METHODS: We will search for PubMed, Cochrane Library, AMED, EMbase, WorldSciNet; Nature, Science online and China Journal Full-text Database (CNKI), China Biomedical Literature CD-ROM Database (CBM), and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to April 2019. The quality of the included RCTs will be evaluated by the risk of bias (ROB) tool and the evidence will be evaluated by GRADE. STATA 13.0 and WinBUGS 1.4.3 through the GeMTC package will be used to perform a network meta-analysis to synthesize direct and indirect evidence. RESULTS: The results of this network meta-analysis (NMA) will be submitted to a peer-reviewed journal for publication. TRIAL REGISTRATION NUMBER: PROSPERO CRD42019123437.

Advancement of multi-target drug discoveries and promising applications in the field of Alzheimer's disease.

Complex diseases (e.g., Alzheimer's disease) or infectious diseases are usually caused by complicated and varied factors, including environmental and genetic factors. Multi-target (polypharmacology) drugs have been suggested and have emerged as powerful and promising alternative paradigms in modern medicinal chemistry for the development of versatile chemotherapeutic agents to solve these medical challenges. The multifunctional agents capable of modulating multiple biological targets simultaneously display great advantages of higher efficacy, improved safety profile, and simpler administration compared to single-targeted agents. Therefore, multifunctional agents would certainly open novel avenues to rationally design the next generation of more effective but less toxic therapeutic agents. Herein, the authors review the recent progress made in the discovery and design processes of selective multi-targeted agents, especially the successful application of multi-target drugs for the treatment of Alzheimer's disease.

Prognostic Factors and Recurrence Patterns in T4 Gastric Cancer Patients after Curative Resection.

Background: To investigate prognostic factors and recurrence patterns in T4 gastric cancer (GC) patients after curative resection. Methods: Between January 2004 and December 2014, 249 patients with T4 gastric cancer undergoing curative resection were recruited. Patient characteristics, survival, prognostic factors and recurrence patterns were analyzed. Results: Our results showed that the median survival time (MST) for T4 gastric cancer after curative resection was 55.47 months, with 59.47 months for T4a (tumor perforating serosa) and 25.90 months for T4b (tumor invasion of the adjacent structure). Multivariate analysis indicated that age (hazard ratio [HR], 1.86; P = 0.006), location of tumor (HR, 1.25, 0.90 - 5.64; P < 0.001) and intraoperative blood loss (HR, 1.85; P = 0.010) were independent prognostic factors for overall survival (OS). After a median follow-up of 25.87 months, a total of 109 (43.8%) patients suffered from recurrence, and 90 patients had been observed specific recurrence sites, among which peritoneal metastasis was the most common recurrence pattern, 59.0% for T4a and 88.3% for T4b, respectively. Conclusions: For T4 gastric cancer patients after curative resection, older age, gastric cancer of the entire stomach and more intraoperative blood loss were associated with poor OS. The recurrence rate after curative resection for T4 was high, and the most common recurrence pattern was peritoneal metastasis.