KDM2A plays a dual role in regulating the expression of malignancy-related genes in esophageal squamous cell carcinoma.

KDM2A is a histone demethylase, which primarily catalyzes the demethylation of H3K36me2. Abnormal expression of KDM2A is observed in many types of cancers; however, the molecular events connected to KDM2A expression remain unclear. We report that KDM2A performs an oncogenic function in esophageal squamous cell carcinoma (ESCC) and is robustly expressed in ESCC cells. ShRNA-mediated knockdown of KDM2A resulted in a significant inhibition of the malignant phenotype of ESCC cell lines, whereas ectopic expression of KDM2A showed the opposite effect. We also analyzed the function of KDM2A using a CRISPR-CAS9 depletion system and subsequent rescue experiment, which also indicated a cancerous role of KDM2A. Interestingly, analysis of the gene expression network controlled by KDM2A using RNA-seq revealed an unexpected feature: KDM2A could induce expression of a set of well-documented oncogenic genes, including IL6 and LAT2, while simultaneously suppressing another set of oncogenes, including MAT2A and HMGCS1. Targeted inhibition of the upregulated oncogene in the KDM2A-depleted cells led to a synergistic suppressive effect on the malignant phenotype of ESCC cells. Our results revealed the dual role of KDM2A in ESCC cells, which may have therapeutic implications.

[A Single-Center Analysis of the Use of G-CSF Combined with Plerixafor to Mobilize Peripheral Blood Hematopoietic Stem Cell from Healthy Related Donors in Allogeneic Hematopoietic Stem Cell Transplantation].

OBJECTIVE: To study the effect and safety of G-CSF combined with Plerixafor on the mobilization of peripheral blood hematopoietic stem cells from healthy related donors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: It was analyzed retrospectively that the data of peripheral blood hematopoietic stem cells from 33 (observation group) related donors mobilized by G-CSF plus Plerixafor in Hebei Yanda Lu Daopei Hospital from April 2019 to April 2021. Bone marrow and peripheral blood hematopoietic stem cells (PBSCs) of these donors were respectively collected on the fourth and fifth day of G-CSF-induced mobilization. Following the administration of Plerixafor on the night of the fifth day, PBSCs were collected on the sixth day once again. 46 donors using "G-CSF only" mobilization method in the same period were randomly selected as the control and respectively analyzed the differences of CD34+ cell counts on the fifth and the sixth day in two groups. And the donors' adverse reaction to Plerixafor in the form of questionnaire was also observed. Then it was compared that the patients who underwent allo-HSCT in "G-CSF+Plerixafor" group and "G-CSF only" group in terms of acute GVHD at grade I-IV or III-IV, CMV reactivation and EBV reactivation. RESULTS: CD34+ cells count (M±Q) among PBSCs collected on the fifth and the sixth day in the observation group were (1.71±1.02)×106/kg and (4.23±2.33)×106/kg, respectively. CD34+ cell counts on the sixth day was significantly higher than that of the fifth day (P<0.001); While the counterparts in the control group were (2.47±1.60)×106/kg and (1.87±1.37)×106/kg, respectively. By statistical analysis, CD34+ cell counts on the sixth day was significantly less than that of the fifth day (P<0.001). The adverse reaction to Plerixafor for the donors in the study were all grade 1 or 2 (mild or moderate) according to CTCAE 5.0 and disappeared in a short time. The patients who underwent allo-HSCT in the "G-CSF+Plerixafor" group and "G-CSF only" group were not statistically significant in terms of acute GVHD at grade I-IV or III-IV, CMV reactivation and EBV reactivation (P>0.1). CONCLUSION: The cell mobilization program of G-CSF combined with Plerixafor is safe and effective for being applied to allo-HSCT. The addition of Plerixafor can significantly increase the number of CD34 postive cells in the PBSC collection. Key words　　; ;

Characterization of the complete chloroplast genome of Houttuynia cordata Thunb and phylogenetic relationships.

In this study, I presented the chloroplast genome of Houttuynia cordata Thunb using BGISEQ-500 sequencing data. Its chloroplast genome is 160,226 bp in size. It contains a pair of inverted repeat regions of 26,853 bp, each separating a small single copy region of 18,340 bp and a large single copy region of 88,180 bp. Totally, 112 unique genes, including 78 protein coding genes, 30 tRNAs and 4 rRNAs, were identified and annotated in the chloroplast genome. Phylogenetic maximum likelihood analysis indicated that H. cordata Thunb is closest to Piper cenocladu.

Effectiveness comparisons of traditional Chinese medicine on treating diabetic nephropathy proteinuria: A systematic review and meta-analysis.

BACKGROUND: Diabetic nephropathy (DN) is one of the microvascular complications of diabetes mellitus. Proteinuria is the most important clinical feature of DN and an independent risk factor for the progression of DN. Therefore, reducing urinary protein is the primary goal of DN treatment. Traditional Chinese medicine (TCM) has long been widely used in the treatment of DN. Therefore, this paper conducted a meta-analysis of the clinical efficacy of TCM in the treatment of DN proteinuria, to comprehensively analyze the role of TCM in the treatment of DN. METHODS: We will search for PubMed, Cochrane Library, AMED, EMbase, WorldSciNet, Nature, Science online and China Journal Full-text Database, China Biomedical Literature CD-ROM Database, and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to September 2019. We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the Revman 5.3 and Stata13.0 software for meta-analysis of the effectiveness, recurrence rate, and symptom scores of DN proteinuria. TRIAL REGISTRATION NUMBER: PROSPERO CRD42019139707.

Characterization of the complete chloroplast genome of a purple passion flower variety 'Pingtang No.1' (Passiflora edulia Sims) in China and phylogenetic relationships.

Passion flower (Passiflora edulia Sims) is an important fruit that is of great economic importance. In this study, we presented the chloroplast genome of a purple passion flower variety 'Pingtang No.1' in China using BGISEQ-500 sequencing. Its chloroplast genome is 152,621 bp in size. It contains a pair of inverted repeat regions of 25,989 bp, each separating a small single copy region of 13,352 bp and a large single copy region of 85,141 bp. Totally, 111 unique genes, including 77 protein coding genes, 30 tRNAs, and 4 rRNAs, were identified and annotated in the chloroplast genome. Phylogenetic maximum likelihood analysis based on chloroplast genomes of 35 plant species, mainly from the genus Passiflora indicated that 'Pingtang No.1' and yellow passion flower 'IAPAR-123' (Passiflora edulis) cluster together. The chloroplast genome can be used for a better understanding of the evolutionary relationships of plant species of the family Passifloraceae, especially the genus Passiflora.

Synthesis and evaluation of isoprenylation-resveratrol dimer derivatives against Alzheimer's disease.

A series of resveratrol dimer derivatives against Alzheimer's disease (AD) was obtained by structural modification and transformation using resveratrol as substrate. Biological analysis revealed that these derivatives had moderate inhibitory activity against human monoamine oxidase B (hMAO-B). In particular, 3 and 7 showed the better inhibitory activity for hMAO-B (IC50 = 3.91 ±â€¯0.23 µM, 0.90 ±â€¯0.01 µM) respectively. Compound 3 (IC50 = 46.95 ±â€¯0.21 µM for DPPH, 1.43 and 1.74 trolox equivalent by ABTS and FRAP method respectively), and 7 (IC50 = 35.33 ±â€¯0.15 µM for DPPH, 1.70 and 1.97 trolox equivalent by ABTS method and FRAP method respectively) have excellent antioxidant effects. Cellular assay shown that 3 and 7 had lower toxicity and were resistant to neurotoxicity induced by oxidative toxins (H2O2, rotenone and oligomycin-A). More importantly, the selected compounds have neuroprotective effects against ROS generation, H2O2-induced apoptosis and a significant in vitro anti-inflammatory activity. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that 3 and 7 would be predominant to cross the blood-brain barrier. In this study, mouse microglia BV2 cells were used to establish cell oxidative stress injury model with H2O2 and to explore the protective effect and mechanism of 3 and 7. In general, 3 and 7 can be considered candidates for potential treatment of AD.

Donepezil-butylated hydroxytoluene (BHT) hybrids as Anti-Alzheimer's disease agents with cholinergic, antioxidant, and neuroprotective properties.

The multifactorial nature of Alzheimer's disease (AD) calls for the development of multitarget agents addressing key pathogenic processes. A novel family of donepezil-butylated hydroxytoluene (BHT) hybrids were designed, synthesized and evaluated as multifunctional ligands against AD. The optimal compound 7d displayed a balanced multifunctional profile covering an intriguing acetylcholinesterase (AChE) inhibition (IC50, 0.075 µM for eeAChE and 0.75 µM for hAChE) and Monoamine oxidase B (MAO-B) inhibition (IC50, 7.4 µM for hMAO-B), excellent antioxidant activity (71.7 µM of IC50 by DPPH method, 0.82 and 1.62 trolox equivalent by ABTS method and ORAC method respectively), and inhibitory effects on self-induced, hAChE-induced Aß aggregation. Moreover, 7d possessed neuroprotective potency against H2O2-induced oxidative damage on PC12 cells and Lipopolysaccharides (LPS)-stimulated inflammation on BV2 cells. Compound 7d was capable of penetrating BBB and presented good liver microsomal metabolic stability. Importantly, compound 7d could dose-dependently reverse scopolamine-induced memory deficit in mice without acute toxicity. Taken together, those outstanding results highlight the donepezil-BHT hybrid 7d as a promising prototype in the research of innovative compound for AD.

Design, synthesis, and evaluation of salicyladimine derivatives as multitarget-directed ligands against Alzheimer's disease.

A series of salicyladimine derivatives were designed, synthesized and evaluated as multi-target-directed ligands for the treatment of Alzheimer's disease (AD). Biological activity results demonstrated that some derivatives possessed significant inhibitory activities against amyloid-ß (Aß) aggregation and human monoamine oxidase B (hMAO-B) as well as remarkable antioxidant effects and low cell toxicity. The optimal compound, 5, exhibited excellent potency for inhibition of self-induced Aß1-42 aggregation (91.3±2.1%, 25µM), inhibition of hMAO-B (IC50, 1.73±0.39µM), antioxidant effects (43.4±2.6µM of IC50 by DPPH method, 0.67±0.06 trolox equivalent by ABTS method), metal chelation and BBB penetration. Furthermore, compound 5 had neuroprotective effects against ROS generation, H2O2-induced apoptosis, 6-OHDA-induced cell injury, and a significant in vitro anti-inflammatory activity. Collectively, these findings highlighted that compound 5 was a potential balanced multifunctional neuroprotective agent for the development of anti-AD drugs.

Rational Design and Multibiological Profiling of Novel Donepezil-Trolox Hybrids against Alzheimer's Disease, with Cholinergic, Antioxidant, Neuroprotective, and Cognition Enhancing Properties.

A novel series of donepezil-trolox hybrids were designed, synthesized, and evaluated as multifunctional ligands against Alzheimer's disease (AD). Biological assays showed that these derivatives possessed moderate to good inhibitory activities against acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) as well as remarkable antioxidant effects. The optimal compound 6d exhibited balanced functions with good inhibition against hAChE (IC50 = 0.54 µM) and hMAO-B (IC50 = 4.3 µM), significant antioxidant activity (41.33 µM IC50 by DPPH method, 1.72 and 1.79 trolox equivalent by ABTS and ORAC methods), excellent copper chelation, and Aß1-42 aggregation inhibition effect. Furthermore, cellular tests indicated that 6d has very low toxicity and is capable of combating oxidative toxin (H2O2, rotenone, and oligomycin-A) induced neurotoxicity. Most importantly, oral administration of 6d demonstrated notable improvements on cognition and spatial memory against scopolamine-induced acute memory deficit as well as d-galactose (d-gal) and AlCl3 induced chronic oxidative stress in a mouse model without acute toxicity and hepatotoxicity. In summary, both in vitro and in vivo results suggested that 6d is a valuable candidate for the development of a safe and effective anti-Alzheimer's drug.

Novel cinnamamide-dibenzylamine hybrids: Potent neurogenic agents with antioxidant, cholinergic, and neuroprotective properties as innovative drugs for Alzheimer's disease.

By using fragments endowed with interesting and complementary properties for the treatment of Alzheimer's disease (AD), a novel series of cinnamamide-dibenzylamine hybrids have been designed, synthesized, and evaluated biologically. In vitro assay indicated that most of the target compounds exhibited a significant ability to inhibit ChEs, strong potency inhibitory of self-induced ß-amyloid (Aß) aggregation and to act as potential antioxidants and biometal chelators. A Lineweaver-Burk plot and molecular modeling study showed that compound 7f targeted both the CAS and PAS of AChE. In addition, compound 7f could chelate metal ions, reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Overall, all of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7f as the lead structure worthy of further investigation.

Design, synthesis and evaluation of coumarin-pargyline hybrids as novel dual inhibitors of monoamine oxidases and amyloid-ß aggregation for the treatment of Alzheimer's disease.

A series of coumarin-pargyline hybrids (4a-x) have been designed, synthesized and evaluated as novel dual inhibitors of Alzheimer's disease (AD). Most of the compounds exhibited a potent ability to inhibit amyloid-ß (Aß) aggregation and monoamine oxidases. In particular, compound 4x exhibited remarkable inhibitory activities against monoamine oxidases (IC50, 0.027 ± 0.004 µM for MAO-B; 3.275 ± 0.040 µM for MAO-A) and Aß1-42 aggregation (54.0 ± 1.1%, 25 µM). Moreover, compound 4x showed low toxicity according to in vitro cell toxicity test. The results of the parallel artificial membrane permeability assay for blood-brain barrier indicated that compound 4x would be potent to cross the blood-brain barrier. Collectively, these findings demonstrate that compound 4x was an effective and promising candidate for AD therapy.

Synthesis and pharmacological evaluation of novel chromone derivatives as balanced multifunctional agents against Alzheimer's disease.

In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer's disease (AD), a series of chromone derivatives were designed, synthesized and evaluated. In vitro assay indicated that most of the target compounds have both MAOs inhibition activities, antioxidant activity and biometal chelating ability. Especially, compound s19 exhibits good inhibitory potency for inhibition of MAOs (IC50 value of 5.12µM for hMAO-A and 0.816µM for hMAO-B), moderate inhibition of Aß aggregation (75.1% at 20µM), metal chelation, control of ROS generation and antioxidant activity (ORAC=3.62). In addition, s19 could reduce PC12 cells death induced by oxidative stress and penetrate the blood-brain barrier (BBB). Taken together, these results suggested that s19 might be a promising multitargeted compound for AD treatment.

Synthesis and pharmacological evaluation of multi-functional homoisoflavonoid derivatives as potent inhibitors of monoamine oxidase B and cholinesterase for the treatment of Alzheimer's disease.

A series of homoisoflavonoid derivatives was designed, synthesized and evaluated as potential multi-functional anti-Alzheimer's agents for their inhibitory activity on cholinesterase and monoamine oxidase. Among them, compound 16 showed moderate acetylcholinesterase (AChE) inhibitory activity (eeAChE IC50 = 0.89 ± 0.02 µM; hAChE IC50 = 0.657 ± 0.002 µM) and significant monoamine oxidase B (MAO-B) inhibitory activity (hMAO-B IC50 = 0.0372 ± 0.0002 µM). Kinetic analysis of AChE, MAO-B inhibition and molecular modeling studies revealed that compound 16 is a dual binding site inhibitor of AChE and noncompetitive inhibitor of MAO-B. Furthermore, 16 could penetrate through the blood-brain barrier (BBB) in vitro. Most importantly, oral administration of 16 demonstrated no marked signs of acute toxicity and it could significantly reverse scopolamine-induced memory impairment in mice. These results suggested that compound 16 is a promising multifunctional drug candidate with potential effect for the treatment of Alzheimer's disease.

Rational modification of donepezil as multifunctional acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

A series of novel donepezil derivatives was designed, synthesized and evaluated as multifunctional acetylcholinesterase (AChE) inhibitors for the treatment of Alzheimer's disease (AD). The screening results indicated that most of the compounds exhibited potent inhibition of AChE with IC50 values in the nanomolar range. Moreover, these derivatives displayed good antioxidant, Aß interaction, blood-brain barrier penetration (PAMPA-BBB+) and ADMET properties (in silico). Among them, 5c demonstrated excellent AChE inhibition (IC50: 85 nM for eeAChE, 73 nM for hAChE), metal chelation, and inhibitory effects on self-induced, hAChE-induced and Cu(2+)-induced Aß1-42 aggregation (18.5%, 72.4% and 46.3%, at 20 µM). Kinetic analysis and molecular modeling studies suggested that 5c could bind simultaneously to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. More importantly, 5c exhibited significant neuroprotective potency against Aß1-42-induced PC12 cell injury. Furthermore, the step-through passive avoidance test showed 5c significantly reversed scopolamine-induced memory deficit and no hepatotoxicity in mice. These results indicated that 5c might be a promising drug candidate for AD therapy.

[Preparation and properties of chitosan film as a drug sustained-release system].

OBJECTIVE: To develop a best chitosan film for using as a drug sustained-release system through the evaluation of the sustained-release property, degradation property, and cytotoxicity to osteoblast. METHODS: Orthogonal experiments were designed to determine the best combination of chitosan film preparations. Drug release rate was determined with Coomassie brilliant blue G250. In a separate study, chitosan films were placed into the test tubes with buffer solution and 10(7) U/L lysozyme. The degradation rate was calculated. Osteoblasts derived from fetal rat calvarial were cultured on chitosan films. Cell proliferation was tested by methyl thiazolyl tetrazolium (MTT) assay. The relative growth rate was calculated and the cytotoxicity was graded. RESULTS: The best processing condition was 1% acetic acid, chitosan concentration of 2 mg/mL, 6% sodium tripolyphosphate (STPP) concentration, and cross-linking time of one hour. The resulting chitosan film released 33.13% of bovine serum albumin (BSA) within 8 d, 36.73% of BSA within four weeks and the cytotoxicity grade was 0 or 1. CONCLUSION: This chitosan film possesses good sustained release property, and a good degradation rate.

[Simulation and analysis of ethanol concentration response to enzyme amount changes in Saccharomyces cerevisiae glycolysis pathway model].

Metabolome has become an important part of Systems Biology, and a large set of data has already gained by applying the methods of metabolome. How to deal with the data and how to combine data of metabolome with data of other omics are problems that can not be ignored. An Enzyme Amount Multiple Factor was imported into the enzyme kinetic equation. When the enzyme amount in the system changed, in silico model, it means to alter the Enzyme Amount Multiple Factor. In order to observe ethanol concentration response to enzyme amount changes in S. cerevisiae glycolysis pathway model, enzyme amount was separately set at high and low level, the corresponding Enzyme Amount Multiple Factor value was 10 and 0.1, relatively. Based on the result of simulation, twelve enzymes in pathway were separated into two classes, class I and class II by cluster analysis. The four enzymes belonging to class I, ADH, HK, PFK and PDC, all catalyze irreversible reactions. The six out of eight enzymes belonging to class II, ALD, GAPDH, GlcTrans, lpPEP, PGI and TIM, catalyze reversible reactions. The other two enzymes belonging to class II, lpGlyc and PK, catalyze irreversible reactions. Based on this method, data of metabolome and proteomics are easily integrated to accomplish relatively overall analysis of system properties.