Discovery of Novel Dual Inhibitors Targeting Mutant IDH1 and NAMPT for the Treatment of Glioma with IDH1Mutation.

The targeting of cancer cell intrinsic metabolism has emerged as a promising strategy for antitumor intervention. In the study, we identified the first-in-class small molecules that effectively inhibit both mutant isocitrate dehydrogenase 1 (mIDH1) and nicotinamide phosphoribosyltransferase (NAMPT), two crucial targets in cancer metabolism, through structure-based drug design. Notably, compound 23h exhibits excellent and balanced inhibitory activities against both mIDH1 (IC50 = 14.93 nM) and NAMPT (IC50 = 12.56 nM), leading to significant suppression of IDH1-mutated glioma cell (U87 MG-IDH1R132H) proliferation. Significantly, compound 23h has the ability to cross the blood-brain barrier (B/P ratio, 0.76) and demonstrates remarkable in vivo antitumor efficacy (20 mg/kg) in the U87 MG-IDH1R132H orthotopic transplantation mouse models without any notable toxicity. This proof-of-concept investigation substantiates the viability of discovering small molecules that concurrently target mIDH1 and NAMPT, providing valuable leads for the treatment of glioma and an efficient approach for the discovery of multitarget antitumor drugs.

Early results of the integrative epigenomic-transcriptomic landscape of colorectal adenoma and cancer.

BACKGROUND: Aberrant methylation is common during the initiation and progression of colorectal cancer (CRC), and detecting these changes that occur during early adenoma (ADE) formation and CRC progression has clinical value. AIM: To identify potential DNA methylation markers specific to ADE and CRC. METHODS: Here, we performed SeqCap targeted bisulfite sequencing and RNA-seq analysis of colorectal ADE and CRC samples to profile the epigenomic-transcriptomic landscape. RESULTS: Comparing 22 CRC and 25 ADE samples, global methylation was higher in the former, but both showed similar methylation patterns regarding differentially methylated gene positions, chromatin signatures, and repeated elements. High-grade CRC tended to exhibit elevated methylation levels in gene promoter regions compared to those in low-grade CRC. Combined with RNA-seq gene expression data, we identified 14 methylation-regulated differentially expressed genes, of which only AGTR1 and NECAB1 methylation had prognostic significance. CONCLUSION: Our results suggest that genome-wide alterations in DNA methylation occur during the early stages of CRC and demonstrate the methylation signatures associated with colorectal ADEs and CRC, suggesting prognostic biomarkers for CRC.

Drug discovery targeting nicotinamide phosphoribosyltransferase (NAMPT): Updated progress and perspectives.

Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway, primarily catalyzing the synthesis of nicotinamide mononucleotide (NMN) from nicotinamide (NAM), phosphoribosyl pyrophosphate (PRPP), and adenosine triphosphate (ATP). Metabolic diseases, aging-related diseases, inflammation, and cancers can lead to abnormal expression levels of NAMPT due to the pivotal role of NAD+ in redox metabolism, aging, the immune system, and DNA repair. In addition, NAMPT can be secreted by cells as a cytokine that binds to cell membrane receptors to regulate intracellular signaling pathways. Furthermore, NAMPT is able to reduce therapeutic efficacy by enhancing acquired resistance to chemotherapeutic agents. Recently, a few novel activators and inhibitors of NAMPT for neuroprotection and anti-tumor have been reported, respectively. However, NAMPT activators are still in preclinical studies, and only five NAMPT inhibitors have entered the clinical stage, unfortunately, three of which were terminated or withdrawn due to safety concerns. Novel drug design strategies such as proteolytic targeting chimera (PROTAC), antibody-drug conjugate (ADC), and dual-targeted inhibitors also provide new directions for the development of NAMPT inhibitors. In this perspective, we mainly discuss the structure, biological function, and role of NAMPT in diseases and the currently discovered activators and inhibitors. It is our hope that this work will provide some guidance for the future design and optimization of NAMPT activators and inhibitors.

The Optimization of the Synthesis Process and the Identification of Levobupivacaine Hydrochloride.

In this study, we not only optimized and improved the synthesis process of levobupivacaine hydrochloride (21) but also conducted a comprehensive exploration of critical industrial-scale production details, and a novel high-performance liquid chromatography (HPLC) analysis method was developed. Starting with the readily available and cost-effective (R,S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (28) as the initial material and utilizing l-(-)-dibenzoyl tartaric acid (29) for chiral separation, and then through substitution and a salting reaction, levobupivacaine hydrochloride (21) was obtained with high purity (chemical purity of 99.90% and enantiomeric excess (ee) values of 99.30%). The total yield of the three steps was 45%. Structures of intermediates and the final product were confirmed using nuclear magnetic resonance (NMR) (1H NMR, 13C NMR), mass spectrometry (MS), and elemental analysis. The crystal structure of the final product was determined through differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and X-ray diffraction (XRD). Furthermore, we evaluated the risk of the substitution reaction using a reaction calorimeter and accelerating rate calorimetry (ARC). This process offers the advantages of simple operation, greenness, safety, controllable quality, and cost-effectiveness. It provides reliable technical support for the industrial-scale production of levobupivacaine hydrochloride (21), which is of significant importance in meeting clinical demands. Pilot-scale production has already been successfully completed by China National Medicines Guorui Pharmaceutical Co., Ltd., with a production scale of 20 kg.

DNA barcoding of Chinese snakes reveals hidden diversity and conservation needs.

DNA barcoding has greatly facilitated studies of taxonomy, biodiversity, biological conservation, and ecology. Here, we establish a reliable DNA barcoding library for Chinese snakes, unveiling hidden diversity with implications for taxonomy, and provide a standardized tool for conservation management. Our comprehensive study includes 1638 cytochrome c oxidase subunit I (COI) sequences from Chinese snakes that correspond to 17 families, 65 genera, 228 named species (80.6% of named species) and 36 candidate species. A barcode gap analysis reveals gaps, where all nearest neighbour distances exceed maximum intraspecific distances, in 217 named species and all candidate species. Three species-delimitation methods (ABGD, sGMYC, and sPTP) recover 320 operational taxonomic units (OTUs), of which 192 OTUs correspond to named and candidate species. Twenty-eight other named species share OTUs, such as Azemiops feae and A. kharini, Gloydius halys, G. shedaoensis, and G. intermedius, and Bungarus multicinctus and B. candidus, representing inconsistencies most probably caused by imperfect taxonomy, recent and rapid speciation, weak taxonomic signal, introgressive hybridization, and/or inadequate phylogenetic signal. In contrast, 43 species and candidate species assign to two or more OTUs due to having large intraspecific distances. If most OTUs detected in this study reflect valid species, including the 36 candidate species, then 30% more species would exist than are currently recognized. Several OTU divergences associate with known biogeographic barriers, such as the Taiwan Strait. In addition to facilitating future studies, this reliable and relatively comprehensive reference database will play an important role in the future monitoring, conservation, and management of Chinese snakes.

Overview of Methionine Adenosyltransferase 2A (MAT2A) as an Anticancer Target: Structure, Function, and Inhibitors.

Methionine adenosyltransferase 2A (MAT2A) is a rate-limiting enzyme in the methionine cycle that primarily catalyzes the synthesis of S-adenosylmethionine (SAM) from methionine and adenosine triphosphate (ATP). MAT2A has been recognized as a therapeutic target for the treatment of cancers. Recently, a few MAT2A inhibitors have been reported, and three entered clinical trials to treat solid tumorsor lymphoma with MTAP loss. This review aims to summarize the current understanding of the roles of MAT2A in cancer and the discovery of MAT2A inhibitors. Furthermore, a perspective on the use of MAT2A inhibitors for the treatment of cancer is also discussed. We hope to provide guidance for future drug design and optimization via analysis of the binding modes of known MAT2A inhibitors.

Nicotinamide mononucleotide increases cell viability and restores tight junctions in high-glucose-treated human corneal epithelial cells via the SIRT1/Nrf2/HO-1 pathway.

BACKGROUND: Diabetes mellitus (DM)-related corneal epithelial dysfunction is a severe ocular disorder; however, the effects of nicotinamide mononucleotide (NMN) on high-glucose (HG)-treated human corneal epithelial cells (HCECs) remain unclear. METHODS: We conducted an in-vitro study to examine the effects of NMN treatment on HG-treated HCECs. Cell viability was measured using trypan blue stain, mitochondrial membrane potential was measured using JC-1 stain, and intracellular reactive oxygen species and apoptosis assays were conducted using flow cytometry. Transepithelial electrical resistance (TEER) and zonula occludens-1 (ZO-1) immunofluorescence for tight junction examinations were conducted. Immunoblot analyses were conducted to analyze the expression of silent information regulator-1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1) of the SIRT1/Nrf2/HO-1 pathway. RESULTS: NMN increased cell viability by reducing cell damage, reducing apoptosis, increasing cell migration, and restoring tight junctions in HG-treated HCECs. By analyzing the expressions of SIRT1, Nrf2, HO-1, NMN demonstrated protective effects via the SIRT1/Nrf2/HO-1 pathway. CONCLUSIONS: NMN increases cell viability by reversing cell damage, reducing apoptosis, increasing cell migration, and restoring tight junctions in HG-treated HCECs, and these effects may be mediated by the SIRT1/Nrf2/HO-1 pathway.

Molecular phylogeny and morphological comparisons of the genus Hebius Thompson, 1913 (Reptilia: Squamata: Colubridae) uncover a new taxon from Yunnan Province, China, and support revalidation of Hebius septemlineatus (Schmidt, 1925).

We describe a new species of the genus Hebius and provide evidence for the validity of H. septemlineatuscomb. nov. Morphological and molecular analyses of Hebius specimens collected in Yunnan Province, China, revealed three distinct lineages, namely the newly described Hebius weixiensissp. nov., as well as H. octolineatus (Boulenger, 1904), and H. septemlineatuscomb. nov. (Schmidt 1925), which is removed from synonymy with H. octolineatus. Based on mitochondrial genealogy, Hebius weixiensissp. nov. is sister to H. septemlineatuscomb. nov., while H. octolineatus is sister to H. bitaeniatus. The new species and H. septemlineatuscomb. nov. showed considerable genetic divergence from their recognized congeners (uncorrected P-distance ≥3.9%). Furthermore, the new species and H. septemlineatuscomb. nov. can be diagnosed from closely related congeners by a combination of pholidosis characters.

Imaging and anatomical parameters of the lacrimal punctum and vertical canaliculus using optical coherence tomography.

Purpose: The anatomical parameters of normal lacrimal puncta and vertical canaliculus using optical coherence tomography (OCT) and the OCT imaging features of punctal lesions were analyzed to provide a basis for clinical diagnosis and treatment. Methods: From June to September 2019, 40 volunteers (80 eyes) from Tongji Hospital were enrolled. The external punctal diameter (ELP) was measured using slit-lamp microscopy and OCT. The internal lacrimal punctal diameter (ILP) at 100 µm, vertical canalicular length (VCL), and tear meniscus depth were measured by OCT with open eyes. Twenty-eight volunteers (56 eyes) underwent the same examinations with their eyes closed. The OCT imaging features of 26 patients (27 eyes) with lacrimal lesions were examined. Results: The ELP of the right and left healthy eyes under slit-lamp microscopy were 564.40 and 555.40 µm respectively. Under OCT, the ELP, ILP, and VCL of the right and left eyes were 628.20 um and 616.85 µm, 343.40 µm and 346.95 µm, 731.95 um and 709.20 µm respectively. The ELP was larger when measured by OCT than slit-lamp microscopy (p<0.05). Twenty-eight volunteers (56 eyes) had measurements taken under different conditions. The ELP, ILP, and VCL of the open and closed right eyes were 667.54 and 567.21 µm, 369.18 and 303.18 µm, 715.00 and 417.14 µm, respectively. The ELP, ILP, and VCL of the open and closed left eyes were 655.86 um and 551.68 µm, 369.25 um and 313.54 µm, 719.96 um and 433.89 µm respectively. The anatomical parameters of the open eyes were greater than those of the closed eyes (p<0.05). Thus, we identified the imaging features of lacrimal stenosis, punctal obstruction, punctal tear, lacrimal atresia, and lacrimal mass using OCT. Conclusions: OCT can be used to measure the anatomical parameters of lacrimal puncta and vertical canaliculus in vivo. In addition, OCT can detect punctal lesions in vivo and provide an objective basis for the clinical diagnosis and treatment of punctal lesions.

Optimization, Characterization and in vivo Evaluation of Paclitaxel-Loaded Folate-Conjugated Superparamagnetic Iron Oxide Nanoparticles.

BACKGROUND: Paclitaxel (PTX) has interesting anticancer activity. However, it is insoluble in water, which seriously hinders its use in clinical. Superparamagnetic iron oxide nanoparticles (SPIONs) are used as an ideal drug delivery system. Therefore, we proposed a folic acid (FA) targeting drug-loaded SPIONs to reduce its adverse reaction. METHODS: To improve the hydrophilicity of PTX, the structure of PTX was modified by succinic anhydride to obtain 2'-succinate paclitaxel (SPTX). FA conjugated Polyethylene glycol (PEG)/polyethyleneimine (PEI)-SPIONs SPTX-loaded nanoparticles (SPTX@FA@PEG/PEI-SPIONs) were prepared by solvent volatilization and hydrogen bond adsorption, and the nano-formulation was optimized by response surface methodology (RSM). The characteristics, antitumor effect in vitro, pharmacokinetics, and biodistribution of SPTX@FA@PEG/PEI-SPIONs were evaluated. RESULTS: SPTX was successfully loaded on the surface of FA@PEG/PEI-SPIONs. The formation of SPTX@FA@PEG/PEI-SPIONs was exhibited water-dispersive monodispersity with high stability by RSM, and dynamic light scattering (DLS) was 178.1±3.12 nm, particle size observed in the transmission electron microscope (TEM) was 13.01±1.10 nm, and the encapsulation efficiency (EE) and loading efficiency (LE) were 81.1±1.66% and 14.8±1.46%, respectively. It enhanced the stability in normal physiological condition, accelerated drug release at tumorous pH, and preferentially prolonged the circulation time. In vitro, the SPTX@FA@PEG/PEI-SPIONs significantly targeted to folate receptor (FR) positive cancers cell (HNE-1) via the receptor-ligand mediated pathway, resulting in effective cytotoxic activity. Pharmacokinetic results demonstrated that SPTX@FA@PEG/PEI-SPIONs (t1/2=3.41 h) had longer than free SPTX or PTX (t1/2=1.67 h) in rats in vivo. Tissue distribution studies showed that SPTX@FA@PEG/PEI-SPIONs were present at high levels in the liver and help in targeting the folate receptors present on the kidneys. CONCLUSION: These results suggest that SPTX@FA@PEG/PEI-SPIONs offer a highly promising approach to control drug release, improve drug pharmacokinetics and actively target the nasopharyngeal carcinoma.

Plasma Free Amino Acids and Risk of Cardiovascular Disease in Chinese Patients With Type 2 Diabetes.

Objectives: This study aimed to explore associations between plasma free amino acids (PFAA) and risk of cardiovascular disease (CVD) in Chinese with Type 2 diabetes (T2D). Methods: We retrieved 741 inpatients with T2D consecutively from tertiary hospital. Twenty-three PFAA were measured. CVD was defined as having coronary heart disease (CHD) or stroke. Principal component analysis was used to extract factors of PFAA. Factors and their components were introduced into binary logistic regressions as continuous and tertiles to obtain OR (odds ratio) and 95% confidence interval (CI) for CVD (or its components) risk. Results: Of 741 inpatients, 282 (38.1%) had CVD (CHD alone: 122, stroke alone: 109, both: 51). Five factors were extracted, accounting for 65% of the total variance. Factor 3 composed of glutamate and tryptophan was associated with increased CVD risk (ORs, 95%CI of top vs. bottom tertiles: 1.60, 1.02-2.50 for CVD; 2.19, 1.17-4.07 for stroke, 1.51, 0.83-2.73 for CHD); the ORs (top vs. bottom tertiles) of glutamate were 2.62 (95%CI, 1.18-5.84) for stroke and 1.44 (0.80-2.61) for CHD; the ORs (top vs. bottom tertiles) of tryptophan were 1.50 (0.81-2.75) for stroke and 1.07 (0.58-1.97) for CHD. Comparable results were observed according to important confounders (all P for interaction >0.05). Conclusions: Elevated factor 3 composed of glutamate and tryptophan was associated with increased CVD, especially stroke in T2D in China.

Microbiological contamination in donor corneas preserved for medium-term.

To evaluate the characteristics of microbiological contamination in donor corneas preserved for medium-term. A total of 82 donated corneas from June 1, 2014 to November 30, 2014 were retrospectively analyzed. The corneas were preserved in cornea chambers medium-term solution at 4-8 °C for keratoplasty. After removal of the central corneas for transplantation, the corneoscleral rims were put back into the medium for 1 month at room temperature (20-25 °C). The suspicious contaminated storage solutions indicated with transparency or color change were examined with bacteria and fungi cultivation for strain identification. The data collected included gender, age, procurement site and causes of death of donors, and follow-up of recipients. Statistical analysis was performed using Microsoft Excel and SPSS 24.0. Significance level was set at a P value < 0.05. The overall pathogen positive rate was 9.8% (n = 8), including 7 (87.5%) fungi and 1 (12.5%) bacteria. They were 2 (2.44%) Fusarium, 2 (2.44%) Chromomycosis, 1 (1.22%) Candida albicans, 1 (1.22%) Aspergillus versicolor, 1 (1.22%) Acremonium species, and 1 (1.22%) Enterococcus. 5 contaminated corneas were used for penetrating keratoplasty; although four out of five (80%) had not been given antifungal drugs during more than 6 months following-up period, none of the recipients was infected with a graft. Donor age (P = 0.839), gender (P = 0.062), procurement sites (P = 0.713) and cause of death (P = 0.711) had no statistically significant influence on the contamination rate. All donor corneas have a possibility of microbiological contamination. Strict tissue preservation protocol but not antifungal drugs following keratoplasty seems necessary to prevent graft infection.

A New Isolation Method of Human Lacrimal Canaliculus Epithelial Stem Cells by Maintaining Close Association with Their Niche Cells.

Purpose: To investigate whether lacrimal canaliculus epithelial stem cells (LCESC) could be isolated and expanded in vitro. Methods: The lacrimal canaliculus epithelium of 6 patients with limbal stem cell deficiency (LSCD) caused by alkali burn or Stevens Johnson Syndrome were examined by lacrimal endoscope. Cadaveric eyelids were fixed and prepared for cross section and stained with HE and antibodies against PCK, Vim, p63α, SCF and c-Kit. Canaliculus tissue was separated under an operating microscope using a lacrimal probe as an indicator and digested with collagenase A. The clusters of epithelial cells with closely associated stroma were further digested with Trypsin/EDTA to obtain single cells for culture on Matrigel-coated plastic plates in MESCM media. The expression of SCF, c-Kit and p63α was determined by immunostaining. The colony-forming efficiency on 3T3 feeder layers was also measured by calculating the percentage of the clone number divided by the total number cells seeded. Results: The epithelial layers of five out of six inferior lacrimal canaliculi and all the six superior lacrimal canaliculi were visually normal in appearance. Five to fifteen layers of the epithelium in the human lacrimal canaliculi were present with a small, tightly compacted basal layer of cells expressing PCK, p63α, SCF and c-Kit. LCESC were isolated by collagenase A and obtained clonal growth in MESCM. The colony-forming efficiency of LCESC holoclones on a 3T3 feeder layer was 3.2%, compared to 1.9% for those of limbal stem cells (LSC). Conclusions: Herein, we first report that LCESCs can be isolated and have stem cell characteristics, similar to those of LSCs. Such a discovery raises a promising substrate resource of stem cells for LSC reconstruction in LSCD patients.

Comparative study of fungal culture and in vivo confocal microscopy in the diagnosis of non-primary fungal keratitis / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To compare fungal culture and in vivo confocal microscopy ( IVCM ) in the diagnosis of non- primary fungal keratitis.?METHODS:The clinical data of 31 cases (31 eyes) with non- primary fungaI keratitis from September 2016 to February 2017 in our HospitaI were retrospectiveIy reviewed. The positive rate of the two methods was compared by chi-square test.?RESULTS: The positive rate by fungal culture was 58％(18/31 ) and IVCM was 19％ ( 6/31 ); the positive rate comparison difference was statistically significant between fungal culture and IVCM (x2=7. 56,P<0. 01). In the 13 eyes with positive culture results, 2 eyes were positive by IVCM;in the 25 positive IVCM eyes, 14 eyes were positive in culture.?CONCLUSION: The positive rate of fungal culture in non-primary fungal keratitis is higher than that of IVCM. Fungal culture is an essential auxiliary examination in the diagnosis of non - primary fungal keratitis. With the characteristics of fast, noninvasive and repeatable, IVCM also plays an important role in the diagnosis of non-primary fungal keratitis. The combination of the two methods can improve the positive rate of diagnosis.

Danhong Huayu Koufuye Prevents Diabetic Retinopathy in Streptozotocin-Induced Diabetic Rats via Antioxidation and Anti-Inflammation.

Danhong Huayu Koufuye (DHK), a traditional Chinese prescription, is used to treat central retinal vein occlusion clinically. We previously reported that DHK prevented diabetic retinopathy (DR) in rats. Moreover, we found that it protected endothelial cells from hyperglycemia-induced apoptosis through antioxidation and anti-inflammation. Here, we investigated whether antioxidative and anti-inflammatory activities of DHK contributed to its therapeutic effect on DR in streptozotocin- (STZ-) induced diabetic rats. DHK significantly blocked the breakdown of the blood-retinal barrier (BRB) and increased the thickness of the inner nuclear layer (INL), as well as suppressed the swelling of the ganglion cell layer (GCL) in diabetic retinas. DHK remarkably increased the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in plasma, and decreased serum level of nitric oxide (NO). Moreover, DHK markedly reduced the serum levels of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1). Furthermore, DHK significantly downregulated protein expressions of VEGF and inducible NO synthase (iNOS) and mRNA expression of ICAM-1 in retinas. These results suggest that the antioxidative and anti-inflammatory activities of DHK may be important mechanisms involved in the protective effect of DHK on DR in STZ-induced diabetic rats.

Autologous limbus conjunctival flap transplantation for pterygium accompaniedwith conjunctival cyst / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To observe the efficacy of surgical excision combined with autologous limbus conjunctival flap transplantation in the treatment of pterygium accompanied with conjunctival cyst.METHODS: Totally 126 patients 188 eyes with pterygium were hospitalized in Department of Ophthalmology of Tongji Hospital of Huazhong University of Science and Technology during August 2013 and August 2015.The patients were divided into two groups: observation group (11 eyes of 11 patients) with pterygium accompanied with conjunctival cyst and control group (177 eyes of 115 patients) with primary pterygium.All patients underwent slit lamp microscope examination, anterior segment photography, and anterior segment optical coherence tomography(OCT).The size of pterygium was calculated by multiplying neck width and length of the covered corneal.All patients underwent excision combined with autologous conjunctival flap transplantation, and the resections were performed pathological section with hematoxylin and eosin staining.All patients were followed up postoperatively for 4-28mo.RESULTS: All cases in the observation group were confirmed by postoperative pathological examination.All cyst walls were complete, and containing single layer of epithelial cells.The mean size of pterygium of the observation group was 6.9±1.7mm2, and 6.3±1.8mm2 for the control group.There was no significant difference between the two groups (P>0.05).The mean postoperative healing time of observation group was 2.1±0.9d, and 1.9±0.8d for the control group.There was no significant difference between the two groups (P>0.05).Recurrence was seen in two eyes within the follow-up period in the control group, and no recurrence in the observation group.CONCLUSION: Surgical excision combined with autologous limbus conjunctival flap transplantation is a safe and effective treatment for pterygium accompanied with conjunctival cyst.

Association of catechol-O-methyltransferase Val(108/158) Met genetic polymorphism with schizophrenia, P50 sensory gating, and negative symptoms in a Chinese population.

Catechol-O-methyltransferase (COMT), an enzyme involved in the degradation and inactivation of the neurotransmitter dopamine, is associated with the sensory gating phenomenon, protecting the cerebral cortex from information overload. The COMT Val(108/158)Met polymorphism is essential for prefrontal cortex processing capacity and efficiency. The current study was designed to investigate the role of COMT Val(108/158)Met polymorphism in development, sensory gating deficit, and symptoms of schizophrenia in Han Chinese population. P50 gating was determined in 139 schizophrenic patients and 165 healthy controls. Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptomatology in 370 schizophrenic subjects. COMT Val(108/158)Met polymorphism was genotyped by PCR-restriction fragment length polymorphism (PCR-RFLP). No significant differences in COMT allele and genotype distributions were observed between schizophrenic patients and control groups. Although P50 deficits were present in patients, there was no evidence for an association between COMT Val(108/158)Met polymorphism and the P50 biomarker. Moreover, PANSS negative subscore was significantly higher in Val allele carriers than in Met/Met individuals. The present findings suggest that COMT Val(108/158)Met polymorphism may not contribute to the risk of schizophrenia and to the P50 deficits, but may contribute to the negative symptoms of schizophrenia among Han Chinese.

Danhong huayu koufuye prevents deep vein thrombosis through anti-inflammation in rats.

BACKGROUND: Danhong huayu koufuye (DHK) has traditionally been used clinically for a long time in China. This study was to evaluate the effect of DHK in treating deep vein thrombosis (DVT) in rats and explore its possible mechanism. METHODS: Forty-eight Sprague-Dawley rats were divided into four groups, performed with incomplete inferior vena cava ligation to induce DVT, and orally administered with DHK (3.20 mg/kg/d), warfarin (2.00 mg/kg/d), or vehicle for 7 days. The involved inferior vena cava and thrombi were collected and measured in size. The tissue specimens were performed for routine histopathologic evaluation and immunohistochemical staining with tissue factor and matrix metalloproteinases-9. Blood samples were collected for detecting coagulation function, blood cell count, and the levels of interleukin-6 and tumor necrosis factor-α. RESULTS: The treatment of DHK markedly reduced the size of thrombi by 49.26%, and the vein wall thickness by 47.86%. The recanalization rate was significant higher in the DHK-treated group than the vehicle-treated group (26.34 ± 6.53% versus 15.91 ± 3.93%, P < 0.01). Comparing to vehicle control, DHK significantly reduced neutrophils (P < 0.05) and lymphocytes (P < 0.05), serum tumor necrosis factor-α level (4.90 ± 1.14 pg/mL versus 6.60 ± 1.62 pg/mL, P < 0.01), and the expression of matrix metalloproteinases-9 and tissue factor (P < 0.05) in thrombi. CONCLUSIONS: DHK effectively prevented DVT through anti-inflammatory action in rats.

Clinical observation of 15 cases of corneal foreign body injuries caused by chestnut thorns / 国际眼科杂志(Guoji Yanke Zazhi)

Abstract?AIM:To investigate the effective treatment methods of corneal injury caused by chestnut thorns and the factors affecting the disease progression.?METHODS: From Jul.2014 to Oct.2015, the clinical data of 15 patients(15 eyes) with corneal injury caused by chestnut thorns in Ophthalmology Inpatient Department of Wuhan Tongji Hospital was retrospective analyzed. The patients without fungal keratitis were treated with the surgery of removing chestnut thorn from cornea and antifungal drugs. For the patients complicated with fungal keratitis, besides surgery of removing chestnut thorn and antifungal drugs, anterior chamber irrigation and corneal stroma injection with fluconazole solution were given to treat the disease.If necessary, amniotic membrane transplantation or keratoplasty was also given to the patients complicated with fungal keratitis. After that, the effectiveness of those methods and the factors affecting progression were analyzed.?RESULTS:For 11 patients without fungal keratitis, the average time between corneal injury and receiving treatment at Tongji Hospital was 1-7 (2.42±2.15) d and for 4 patients complicated with fungal keratitis, the average time was 3-30 (18.25±4.35)d.Among 15 cases, statistics suggested that the average number of chestnut thorn in patients complicated with fungal keratitis was 4.5, and all the chestnut thorn penetrated the cornea into the anterior chamber.The average number of chestnut thorn in patients without fungal keratitis was 3.5, and the proportion of chestnut thorn penetrated the cornea into the anterior chamber was 28.5%.After treatment, all patients had no new fungal keratitis or other complications.Those results indicated that the different treatments for the patients with or without fungal keratitis were all effective.?CONCLUSION:The factors affecting the progression of cornea foreign body injury caused by chestnut thorn are the number of chestnut thorn, whether chestnut thorn penetrate the cornea into the anterior chamber, time since injury, active anti -fungal therapy. If patients complicated with fungal keratitis could be treated with antifungal agents and anterior chamber irrigation or corneal stroma injection using fluconazole solution without delay, the progress of fungal keratitis could be effectively controlled, and favorable conditions for further therapy such as amniotic membrane transplantation or keratoplasty could be provided.

Complete sequence and detailed analysis of the first indigenous plasmid from Xanthomonas oryzae pv. oryzicola.

BACKGROUND: Bacterial plasmids have a major impact on metabolic function and adaptation of their hosts. An indigenous plasmid was identified in a Chinese isolate (GX01) of the invasive phytopathogen Xanthomonas oryzae pv. oryzicola (Xoc), the causal agent of rice bacterial leaf streak (BLS). To elucidate the biological functions of the plasmid, we have sequenced and comprehensively annotated the plasmid. METHODS: The plasmid DNA was extracted from Xoc strain GX01 by alkaline lysis and digested with restriction enzymes. The cloned and subcloned DNA fragments in pUC19 were sequenced by Sanger sequencing. Sequences were assembled by using Sequencher software. Gaps were closed by primer walking and sequencing, and multi-PCRs were conducted through the whole plasmid sequence for verification. BLAST, phylogenetic analysis and dinucleotide calculation were performed for gene annotation and DNA structure analysis. Transformation, transconjugation and stress tolerance tests were carried out for plasmid function assays. RESULTS: The indigenous plasmid from Xoc strain GX01, designated pXOCgx01, is 53,206-bp long and has been annotated to possess 64 open reading frames (ORFs), including genes encoding type IV secretion system, heavy metal exporter, plasmid stability factors, and DNA mobile factors, i.e., the Tn3-like transposon. Bioinformatics analysis showed that pXOCgx01 has a mosaic structure containing different genome contexts with distinct genomic heterogeneities. Phylogenetic analysis indicated that the closest relative of pXOCgx01 is pXAC64 from Xanthomonas axonopodis pv. citri str. 306. It was estimated that there are four copies of pXOCgx01 per cell of Xoc GX01 by PCR assay and the calculation of whole genome shotgun sequencing data. We demonstrate that pXOCgx01 is a self-transmissible plasmid and can replicate in some Xanthomonas spp. strains, but not in Escherichia coli DH5α. It could significantly enhance the tolerance of Xanthomonas oryzae pv. oryzae PXO99A to the stresses of heavy metal ions. The plasmid survey indicated that nine out of 257 Xoc Chinese isolates contain plasmids. CONCLUSIONS: pXOCgx01 is the first report of indigenous plasmid from Xanthomonas oryzae pv. oryzicola, and the first completely sequenced plasmid from Xanthomonas oryzae species. It is a self-transmissible plasmid and has a mosaic structure, containing genes for macromolecule secretion, heavy metal exportation, and DNA mobile factors, especially the Tn3-like transposon which may provide transposition function for mobile insertion cassette and play a major role in the spread of pathogenicity determinants. The results will be helpful to elucidate the biological significance of this cryptic plasmid and the adaptive evolution of Xoc.