Exploration of spatial confinement and ligand effects for the oxygen reduction reaction on Fe-Nx embedded hole-graphene.

In this work, we constructed theoretical models by embedding Fe-TCPP and Fe-(mIM)n (n = 2,3,4) active sites into hole-graphene, and the structural stability was evaluated using molecular dynamics simulations. Based on the theoretical models, we systematically studied the oxygen reduction reaction (ORR) mechanism and the effect of spatial confinement and ligands with DFT calculations. The analysis of the ORR reaction pathway shows that Fe-TCPP and Fe-(mIM)4 have good catalytic activity. Subsequently, the confinement effect (5-14 Å) was introduced to investigate its influence on the catalytic activity. The Fe-TCPP and Fe-(mIM)4 active sites have the lowest overpotential at an axial space of 8 Å and 9 Å, respectively. We select four ligands (bpy, pya, CH3, and bIm) to explore their effect on the catalytic activity of the Fe-TCPP active site. With the modification of bpy, pya, and bIm_N (Fe-N4 sites become Fe-N5 active sites), the overpotential decreases by 26-31%. In the present work, the best catalytic system is Fe-TCPP_pya, which is on the top of the volcano plot.

Preserving or peeling the inferior mesenteric arterial sheath during laparoscopic rectal cancer surgery: a prospective study of surgical outcomes.

BACKGROUND: We mainly evaluated whether preserving the inferior mesenteric artery (IMA) sheath to dissecting IMA root lymph nodes (also called No.253 lymph nodes) would benefit patients in terms of comparable lymph-node yield removed during operation and postoperative complications in laparoscopic radical resection of rectal cancer. METHODS: This is a prospective study included 141 rectal cancer patients who received laparoscopic radical resection during September 2018 to December 2020. All patients were randomly assigned to the preserved group (n = 71) and the peeled group (n = 70). The baseline characteristics, pathological features, intraoperative and postoperative data outcomes and complications were analyzed by independent samples t test, chi-square test or Fisher's exact test between the 2 groups. RESULTS: The baseline characteristic and pathological features had no statistical difference between the 2 groups. The preserved group had a shorter operative time (P = 0.002), a shorter lymph node dissection time (P < 0.001), less intraoperative bleeding (P = 0.004), an earlier time to first flatus (P = 0.013), an earlier time to fluid intake (P = 0.033) and a shorter length of hospitalization (P = 0.012) than the peeled group. The differences between the 2 groups were not statistically significant (P > 0.05) in regard to the total number of lymph nodes cleared, positive lymph nodes, bleeding, anastomotic leakage, pneumonia, wound infection, abscess, ileus, urinary retention, urinary tract infection and chyle leakage. CONCLUSION: Preserving of the IMA sheath in laparoscopic radical surgery for rectal cancer will reduce the total operation time and the length of hospitalization. This surgical method could lead to lower complication rate and faster recovery. TRIAL REGISTRATION: The study was approved by the Ethics Committee of The First Affiliated Hospital of Wannan Medical College and registered by the China Clinical Trials Registry (ChiCTR2200060830, Date of Registration:2022-06-12 -retrospective registration) http://www.chictr.org.cn/index.aspx .

Xanthones from Calophyllum Polyanthum Wallich ex Choisy with CYP1 Enzymes Inhibitory Activity.

Three new xanthone compounds, 1,3,5-trihydroxy-2-(2-hydroxy-3-methylbut-3-enyl)-4-(3-methylbut-2-enyl)xanthone (1), toxyloxanthone E (2), dehydrocycloguanandin B (3) along with 15 known xanthones (4-18) were isolated from the aerial parts of Calophyllum polyanthum Wall. ex Choisy. Their structures were fully characterised using spectroscopic data, as well as comparison with the previous literature data. All isolated compounds had inhibitory effects against CYP1A1, CYP1A2 and CYP1B1 enzymes at working concentration of 10 µM, 1 µM and 10 µM, respectively. Among them, compounds 10, 11, and 12 exhibited better CYP1A2 enzyme inhibitory effects than that of the positive control α-naphthoflavone, with 51.05 %, 56.82 % and 44.93 % inhibition, respectively.

Expeditious assembly of biuret-guanidine derivatives via the catalyst-free transformation.

We disclose a mild and practical catalyst-free transformation for the expeditious construction of biuret-guanidine derivatives using aromatic isocyanates. This synthetic transformation is featured with mild reaction conditions and high efficiency.

Quantitative prediction model for affinity of drug-target interactions based on molecular vibrations and overall system of ligand-receptor.

BACKGROUND: The study of drug-target interactions (DTIs) affinity plays an important role in safety assessment and pharmacology. Currently, quantitative structure-activity relationship (QSAR) and molecular docking (MD) are most common methods in research of DTIs affinity. However, they often built for a specific target or several targets, and most QSAR and MD methods were based either on structure of drug molecules or on structure of receptors with low accuracy and small scope of application. How to construct quantitative prediction models with high accuracy and wide applicability remains a challenge. To this end, this paper screened molecular descriptors based on molecular vibrations and took molecule-target as a whole system to construct prediction models with high accuracy-wide applicability based on dissociation constant (Kd) and concentration for 50% of maximal effect (EC50), and to provide reference for quantifying affinity of DTIs. RESULTS: After comprehensive comparison, the results showed that RF models are optimal models to analyze and predict DTIs affinity with coefficients of determination (R2) are all greater than 0.94. Compared to the quantitative models reported in literatures, the RF models developed in this paper have higher accuracy and wide applicability. In addition, E-state molecular descriptors associated with molecular vibrations and normalized Moreau-Broto autocorrelation (G3), Moran autocorrelation (G4), transition-distribution (G7) protein descriptors are of higher importance in the quantification of DTIs. CONCLUSION: Through screening molecular descriptors based on molecular vibrations and taking molecule-target as whole system, we obtained optimal models based on RF with more accurate-widely applicable, which indicated that selection of molecular descriptors associated with molecular vibrations and the use of molecular-target as whole system are reliable methods for improving performance of models. It can provide reference for quantifying affinity of DTIs.

Subarachnoid transplantation of human umbilical cord mesenchymal stem cell in rodent model with subacute incomplete spinal cord injury: Preclinical safety and efficacy study.

Functional multipotency renders human umbilical cord mesenchymal stem cell (hUC-MSC) a promising candidate for the treatment of spinal cord injury (SCI). However, its safety and efficacy have not been fully understood for clinical translation. In this study, we performed cellular, kinematic, physiological, and anatomical analyses, either in vitro or in vivo, to comprehensively evaluate the safety and efficacy associated with subarachnoid transplantation of hUC-MSCs in rats with subacute incomplete SCI. Concerning safety, hUC-MSCs were shown to have normal morphology, excellent viability, steady proliferation, typical biomarkers, stable karyotype in vitro, and no tumorigenicity both in vitro and in vivo. Following subarachnoid transplantation of hUC-MSCs in the subject rodents, the biodistribution of hUC-MSCs was restricted to the spinal cord, and no toxicity to immune system or organ function was observed. Body weight, organ weight, and the ratio of the latter upon the former between stem cell-transplanted rats and placebo-injected rats revealed no statistical differences. Regarding efficacy, hUC-MSCs could differentiate into osteoblasts, chondrocytes, adipocytes and neural progenitor cells in vitro. While in vivo studies revealed that subarachnoid transplantation of stem cells resulted in significant improvement in locomotion, earlier automatic micturition recovery and reduced lesion size, which correlated with increased regeneration of tracking fiber and reduced parenchymal inflammation. In vivo luminescence imaging showed that a few of the transplanted luciferase-labeled hUC-MSCs tended to migrate towards the lesion epicenter. Shortened latency and enhanced amplitude were also observed in both motor and sensory evoked potentials, indicating improved signal conduction in the damaged site. Immunofluorescent staining confirmed that a few of the administrated hUC-MSCs integrated into the spinal cord parenchyma and differentiated into astrocytes and oligodendrocytes, but not neurons. Moreover, decreased astrogliosis, increased remyelination, and neuron regeneration could be observed. To the best of our knowledge, this preclinical study provides detailed safety and efficacy evidence regarding intrathecal transplantation of hUC-MSCs in treating SCI for the first time and thus, supports its initiation in the following clinical trial.

RNA editing of SLC22A3 drives early tumor invasion and metastasis in familial esophageal cancer.

Like many complex human diseases, esophageal squamous cell carcinoma (ESCC) is known to cluster in families. Familial ESCC cases often show early onset and worse prognosis than the sporadic cases. However, the molecular genetic basis underlying the development of familial ESCC is mostly unknown. We reported that SLC22A3 is significantly down-regulated in nontumor esophageal tissues from patients with familial ESCC compared with tissues from patients with sporadic ESCCs. A-to-I RNA editing of the SLC22A3 gene results in its reduced expression in the nontumor esophageal tissues of familial ESCCs and is significantly correlated with lymph node metastasis. The RNA-editing enzyme ADAR2, a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of SLC22A3 Moreover, functional studies showed that SLC22A3 is a metastasis suppressor in ESCC, and deregulation of SLC22A3 facilitates cell invasion and filopodia formation by reducing its direct association with α-actinin-4 (ACTN4), leading to the increased actin-binding activity of ACTN4 in normal esophageal cells. Collectively, we now show that A-to-I RNA editing of SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals.

Base-promoted domino radical cyclization of 1,6-enynes.

A good regioselective, high atom-economical and transition-metal-free method for the synthesis of α-functionalized ether derivatives via the domino radical cyclization of 1,6-enynes is described. A series of α-functionalized ether derivatives could be easily obtained in good yields with wide functional group tolerance by using less toxic and inexpensive Cs2CO3 as the base. The control experiment results show that the reaction involves a radical process. This strategy provides a regioselective way toward the formation of dual C-C bonds in one step.

Silk Sericin Hydrolysate is a Potential Candidate as a Serum-Substitute in the Culture of Chinese Hamster Ovary and Henrietta Lacks Cells.

The silk sericin hydrolysate (SSH) from the waste of silk processing as a substitute of fetal bovine serum (FBS) was used for the culture of Chinese hamster ovary (CHO) cells and Henrietta Lacks (Hela) strain of human cervical cancer cells. The survival ratio of these cells cultured in SSH media were similar to or higher than those in FBS media. Especially after the serum was replaced by low concentration of SSH at 15.0 µg/ml for 5 d, the proliferation of both cells was also similar to or higher than that of FBS group; the percentages of CHO and Hela cells in S-phase were 28.9 and 28.0%, respectively. The former is nearly two times that of FBS group, the latter is also higher than the control group. Reverse transcription-polymerase chain reaction (RT-PCR) revealed that among the differentially expressed genes, the relative expression of CXCL12 gene of CHO cells in SSH group increased, was three times that of serum group, and the relative expression of LCN2 gene of Hela cells increased 2.8 times, indicating that these related genes were activated to promote cell growth and proliferation. These results fully illustrated the hydrolysated sericin has a potential use as serum substitutes in cell culture.

[Construction of theoretical model of traditional Chinese medicine intelligent manufacturing].

In the process of transforming and upgrading of traditional Chinese medicine( TCM) intelligent manufacturing,the TCM enterprises lack systematic and in-depth research on intelligent manufacturing of TCM,leading to insufficient understanding of relevant concepts,development direction,development content and other aspects,to some extent,causing fuzzy and chaotic phenomena. The theoretical model,as a higher expression level of scientific thinking,has the function of interpretation and prediction,and can provide theoretical basis as well as guide for scientific research. Therefore,this article aims to construct a theoretical model of TCM intelligent manufacturing based on the concept of flexible production and intelligent equipment for some unhealthy phenomena in the development process of TCM intelligent manufacturing. In the TCM intelligent manufacturing system,with theory model as the core,the new-generation information technology was integrated with the TCM manufacturing technology to realize the integration of informationization and industrilization as well as the landing of theoretical model. Then,a 3 D simulation model was established to provide a visual environment for intelligent manufacturing of TCM and simulate the virtual reality throughout the TCM intelligent manufacturing process. The new theoretical model in this paper,to a certain extent,can play a guiding role in the development of TCM intelligent manufacturing,and can also provide reference for the realization of TCM intelligent manufacturing.

Eukaryotic translation initiation factor 5A2 promotes metabolic reprogramming in hepatocellular carcinoma cells.

Reprogramming of intracellular metabolism is common in liver cancer cells. Understanding the mechanisms of cell metabolic reprogramming may present a new basis for liver cancer treatment. In our previous study, we reported that a novel oncogene eukaryotic translation initiation factor 5A2 (EIF5A2) promotes tumorigenesis under hypoxic condition. Here, we aim to investigate the role of EIF5A2 in cell metabolic reprogramming during hepatocellular carcinoma (HCC) development. In this study, we reported that the messenger RNA (mRNA) level of EIF5A2 was upregulated in 59 of 105 (56.2%) HCC clinical samples (P = 0.015), and EIF5A2 overexpression was significantly associated with shorter survival time of patients with HCC (P = 0.021). Ectopic expression of EIF5A2 in HCC cell lines significantly promoted cell growth and accelerated glucose utilization and lipogenesis rates. The high rates of glucose uptake and lactate secretion conferred by EIF5A2 revealed an abnormal activity of aerobic glycolysis in HCC cells. Several key enzymes involved in glycolysis including glucose transporter type 1 and 2, hexokinase 2, phosphofructokinase liver type, glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase M2 isoform, phosphoglycerate mutase 1 and lactate dehydrogenase A were upregulated by overexpression of EIF5A2. Moreover, EIF5A2 showed positive correlations with FASN and ACSS2, two key enzymes involved in the fatty acid de novo biosynthetic pathway, at both protein and mRNA levels in HCC. These results indicated that EIF5A2 may regulate fatty acid de novo biosynthesis by increasing the uptake of acetate. In conclusion, our findings demonstrate that EIF5A2 has a critical role in HCC cell metabolic reprogramming and may serve as a prominent novel therapeutic target for liver cancer treatment.

Effect of transcutaneous electrical stimulation treatment on lower urinary tract symptoms after class III radical hysterectomy in cervical cancer patients: study protocol for a multicentre, randomized controlled trial.

BACKGROUND: Class III radical hysterectomy (RH III)_plus pelvic lymphadenectomy is the standard surgery for early stage cervical cancer (CC) patients, the 5 year survival rate is about 90%, but pelvic floor disorders especially bladder dysfunction are common due to damaged vessels and nerve fibers following surgery. Transcutaneous electrical stimulation (TENS) treatment has been used to treat bladder disorders for many years, but its effect on cervical cancer patients, the best treatment time point and stimulated protocol, had never been assessed. The aim of this study is to investigate the efficacy of TENS treatment on lower urinary tract symptoms (LUTS) after RH III in CC patients. METHODS/DESIGN: The study will be conducted as a clinical, multicentre, randomised controlled trial with balanced randomisation (1:1). The planned sample size is 208 participants (at 1:1 ratio, 104 subjects in each group). At 5-7 days after RH III, patients are screened according to operative and pathological findings. Enrolled participants are randomised into an intervention group (TENS plus conventional clinical care) or control group (conventional clinical care), with stratification by menopausal status (menopause vs. non-menopause) and surgical modality (laparoscopic RH or abdominal RH). Participants in both groups will be followed up at 14 days, 21 days, 28 days, 3 months, 6 months, 12 months, 18 months and 24 months after surgery. The primary endpoint is improvement rate of urination function which is defined as recovery (residual urine ≤50 ml) or improvement (residual urine 50-100 ml). Secondary endpoints include urodynamic parameter, urinary incontinence, anorectal function, pelvic function, quality of life (QOL), disease-free survival and adverse events. Primary endpoint analyses will be carried out by Cochran-Mantel-Haenszel tests taking into center effect. DISCUSSION: To our knowledge this is the first trial to investigate the effect of TENS treatment on bladder function recovery after RH III among CC patients. This study will provide new information on TENS efficacy for bladder function recovery. Once confirmed, it may help to provide a new, non-invisive treatment for those postoperative CC patients with poor pelvic function, which would help improve their quality of life. TRIAL REGISTRATION: The study is registered to Clinical Trials.gov ( NCT02492542 ) on June 25, 2015.

The potential of silk sericin protein as a serum substitute or an additive in cell culture and cryopreservation.

Cell culture and cryopreservation are necessary for clinical therapy and cells storage. The addition of 10% (v/v) foetal bovine serum (FBS) to basal culture media has been common practice and is one of the most widely used methods. FBS media added with 10% DMSO (dimethyl sulfoxide) have also been used for cryopreservation cells. Ideally, FBS should be avoided because of high cost and bio-safety. Silk sericin has been used as a serum substitute and an additive due to its good hydrophilicity and biological safety. This article summarizes a few details about the processing of sericin and its application as a serum substitute or an additive for cell culture and cryopreservation media. Sericin can be a potential novel serum substitute or an additive for cell culture and cryopreservation media.

[Influence of different cultivation measures on the content of three free carbohydrates of Codonopsis Radix].

To provide a scientific evidence for the quality control of Codonopsis Radix, a method was established for determining the content of three free carbohydrates of Codonopsis Radix. The developed method showed good linearity. The calibration curves were linear within the range of 2.312 5-18.500 0 µg for sucrose, 1.500 0-12.000 0 µg for glucose, and 2.000 0-16.000 0 µg for fructose, resgectwely. The recoveries varied between 96.31%-101.8%. The method is simple, accurate and reproducible, and can be used for determining the content of sucrose, glucose and fructose of Codonopsis Radix. The results showed that different cultivation measures had an effect on the content of three free carbohydrates of Codonopsis Radix. According to the content of sucrose, using Zhuanggenling>not using Zhuanggenling. While, not pinching, shelving>not pinching, not shelving>pinching, not shelving>pinching, shelving. According to the content of glucose and fructose, not using Zhuanggenling>using Zhuanggenling. While, pinching, shelving>not pinching, not shelving>not pinching, shelving>pinching, not shelving. In consideration of the differences of sweetness and content of the three free carbohydrates in Codonopsis Radix, we recommend that the content of free carbohydrates could be considered as the marker to evaluate the quality of Codonopsis Radix.

Localization of neonatal Fc receptor for IgG in aggregated lymphoid nodules area in abomasum of Bactrian camels (Camelus bactrianus) of different ages.

BACKGROUND: The neonatal Fc receptor (FcRn) plays a crucial role in transporting IgG and associated antigens across polarized epithelial barriers in mucosal immunity. However, it was not clear that FcRn expression in aggregated lymphoid nodules area (ALNA) in abomasum, a unique and important mucosal immune structure discovered only in Bactrian camels. In the present study, 27 Alashan Bactrian camels were divided into the following five age groups: fetus (10-13 months of gestation), young (1-2 years), pubertal (3-5 years), middle-aged (6-16 years) and old (17-20 years). The FcRn expressions were observed and analyzed in detail with histology, immunohistochemistry, micro-image analysis and statistical methods. RESULTS: The results showed that the FcRn was expressed in mucosal epithelial cells of ALNA from the fetus to the old group, although the expression level rapidly declined in old group; moreover, after the ALNA maturated, the FcRn expression level in the non-follicle-associated epithelium (non-FAE) was significantly higher than that in FAE (P < 0.05). In addition, the FcRn was also expressed in the vessel endothelium, smooth muscle tissue, and macrophages and dendritic cells (DCs) of secondary lymphoid follicles (sLFs). CONCLUSIONS: It was demonstrated that FcRn was mainly expressed in non-FAE, the effector sites, although which was expressed in FAE, the inductive sites for mucosal immunity. And it was also expressed in DCs and macrophages in sLFs of all ages of Bactrian camels. The results provided a powerful evidence that IgG (including HCAb) could participate in mucosal immune response and tolerance in ALNA of Bactrian camels through FcRn transmembrane transport.

Discovery of Novel Allopurinol Derivatives with Anticancer Activity and Attenuated Xanthine Oxidase Inhibition.

A series of pyrazolo[3,4-d]pyrimidine derivatives related to allopurinol has been synthesized and evaluated for its cytotoxicity against a panel of three cancer cell lines as well as its xanthine oxidase (XOD) inhibitory activities. Among them, compound 4 showed potent cytotoxicity with IC50 values of 25.5 and 35.2 µM against human hepatoma carcinoma cell lines, BEL-7402 and SMMC-7221, respectively. The anticancer activity of 4 was comparable to that of Tanespimycin (17-N-allylamino-17-demethoxy geldanamycin, 17-AAG) that inhibited the growth of BEL-7402 and SMMC-7221 cells at IC50 values of 12.4 and 9.85 µM, respectively. However, unlike allopurinol, which is also a strong inhibitor of XOD, compound 4 is a much weaker XOD inhibitor, suggesting that the anticancer activities of the allopurinol derivatives may not be associated with XOD inhibition. Moreover, the cytotoxicity of 4 toward normal cells is significantly lower than that of 17-AAG, making 4 a promising lead compound for further optimization of structure-activity relationships that may lead to anticancer agents of clinical utility.

[Design, synthesis and evaluation of 4-pyridinylthiazole-2-amines as acetylcholinesterase inhibitors].

Alzheimer's disease (AD) is a degenerative disease of the nervous system. Compound I reported to have inhibitory activity on AChE was used as a lead compound in this study, and 4-pyridinylthiazole-2-amines were designed by optimizing compound I structure. The new compounds were synthesized from acetylpyridines through five-steps of reaction, and their inhibition activities on AChE were measured in vitro by Ellman method. The new compounds exhibited a clear inhibitory activity on AChE in vitro. The bioactivity of compound 13c was the best among them, and its IC(50) value was 0.15 µmol·L(-1), which was better than that of rivastigmine and compound I in the control. Meanwhile, it exhibited little inhibition on butyrylcholinesterase. So the selective inhibitory activities of 4-pyridinylthiazole-2-amines to acetylcholinesterase were worth of studying furtherly.

Increased expression of EIF5A2, via hypoxia or gene amplification, contributes to metastasis and angiogenesis of esophageal squamous cell carcinoma.

BACKGROUND & AIMS: Solid tumors often become hypoxic, leading to activation of hypoxia-response genes. We investigated the effects of overexpression of the hypoxia response genes eIF5A2 in esophageal squamous cell carcinoma (ESCC). METHODS: We used quantitative real-time polymerase chain reaction and immunohistochemistry analyses to compare expression of eIF5A2 between paired ESCC samples and nontumor esophageal tissues, and fluorescence in situ hybridization to detect gene copy-number alterations. Luciferase reporter and chromatin immunoprecipitation assays were used to study interactions between eIF5A2 and hypoxia-inducible factor-1α (HIF1α). We determined the effects of eIF5A2 overexpression and knockdown in ESCC cell lines and growth of ESCC xenograft tumors in nude mice. RESULTS: Levels of eIF5A2 messenger RNA and protein were increased in >40% of ESCC samples compared with matched nontumor tissues, along with levels of HIF1α and vascular endothelial growth factor. Increased levels of EIF5A2 were significantly associated with ESCC metastasis to lymph nodes (P < .001) and tissue invasion (P = .037), and shorter survival times of patients (P < .001). Amplification of eIF5A2 was detected in 35.14% of ESCC samples that overexpressed eIF5A2. Hypoxia increased expression of eIF5A2 4- to 8-fold in ESCC cell lines; we observed bidirectional regulation between eIF5A2 and HIF1α. Transient transfection of ESCC cell lines with eIF5A2 increased their migratory and invasive abilities and markers of the epithelial to mesenchymal transition, and eIF5A2 knockdown or HIFα inhibition reduced these. In mice, xenograft tumors grown from ESCC cells that expressed eIF5A2 formed tumors more rapidly than cells that expressed only vector (controls); they also expressed higher levels of HIF1α and vascular endothelial growth factor, and formed more microvessels than controls. Knockdown of eIF5A2 in ESCC cells with interfering RNAs reduced their growth as xenograft tumors in mice, particularly when mice were given docetaxel or cisplatin. CONCLUSIONS: eIF5A2 is overexpressed by gene amplification or hypoxia in ESCCs, and associated with up-regulation of HIF1α, metastasis, and shorter survival times of patients. Increased expression of eIF5A2 increases metastasis and angiogenesis in ESCC via the HIF1α-mediated signaling pathway.