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Background. Immunotherapy represented by PD-1 blockades had become the standard of care for advanced non-small cell lung cancer (NSCLC) gradually. Unfortunately, several PD-1 inhibitor-related studies excluded elderly patients with NSCLC over 75 years of age, resulting in relatively limited evidence regarding the efficacy and safety of PD-1 in elderly patients with NSCLC clinically. Objective. This study aimed to identify the effectiveness and safety of PD-1 blockade monotherapy among elderly patients with advanced NSCLC. Methods. Elderly patients with advanced NSCLC (≥65 years) who received PD-1 blockade monotherapy from September 2018 to December 2021 were screened retrospectively, and a total of 68 elderly patients with NSCLC were eligible for inclusion ultimately. The PD-1 blockades in the study were the available PD-1 monoclonal antibodies that had been approved for marketing in China, including camrelizumab, sintilimab, pembrolizumab, and nivolumab. The effectiveness and safety of the patients was collected retrospectively. Additionally, the correlation between prognosis and baseline characteristic subgroups was analyzed to identify the potential risk factors for progression-free survival (PFS). Results. The median age of the 68 elderly patients with advanced NSCLC was 73 years (range: 65–82 years). Best overall response during PD-1 blockade administration suggested that no patients were found with complete response, partial response was found in 14 patients, stable disease was noted in 29 patients, and 25 patients had progressive disease, yielding an objective response rate (ORR) of 20.6% (95%CI: 11.7%–32.1%) and a disease control rate (DCR) of 63.2% (95%CI: 50.7%–74.6%). Furthermore, prognostic analysis exhibited that the median progression-free survival (PFS) of the 68 patients with advanced NSCLC was 3.5 months (95%CI: 2.4–4.6) and the median overall survival (OS) was 10.5 months (95%CI: 6.3–14.7). Additionally, a total of 48 patients were observed with the treatment-related adverse reaction (70.6%) of the 68 elderly patients with NSCLC, and the incidence of grade 3 or above adverse reactions was 16.2%. Specifically, the most common adverse reactions were fatigue, diarrhea, rash, and abnormal liver function with the incidence of 25.0%, 22.1%, 16.2%, and 14.7%, respectively. Exploratory analysis between PFS and baseline characteristic subgroups suggested that ECOG performance status and number of metastatic lesions might be independent factors for PFS. Conclusion. PD-1 blockade monotherapy exhibited potential effectiveness and acceptable toxicity for elderly patients with NSCLC. ECOG performance status and number of metastatic lesions might be potential risk factors to predict the PFS of elderly patients with advanced NSCLC.

Centromere protein A (CENP-A) is a centromere-specific protein that determines kinetochore positioning and the accuracy of chromosome segregation. Despite its recognized importance in maintaining mitotic fidelity, the molecular details of CENP-A regulation in mitosis are still obscure. We performed a structure-activity relationship (SAR) study of the cell cycle-arresting indole terpenoid mimic JP18 and identified two more potent analogues, (+)-6-Br-JP18 and (+)-6-Cl-JP18. Tubulin was identified as a potential protein target of these two halogenated analogues by using the drug affinity responsive target stability (DARTS) based method. X-ray crystallographic analysis determined that (+)-6-Br-JP18 and (+)-6-Cl-JP18 bind to the colchicine-binding site of β-tubulin. We further found that treatment of cancer cells with microtubule-targeting agents (MTAs), including these two compounds, upregulated CENP-A by destabilizing Cdh1, an E3 ubiquitin ligase component. The mechanistic study revealed that Cdh1 mediates proteolysis of CENP-A in mitosis, specifying the role of Cdh1 in maintaining mitotic fidelity.

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PDF file - 94 KB, UV absorption spectra of HOEC. The UV absorption spectrum of HOEC (1, 10, 100, 1000, or 10000 micromol/L) was detected using a DU 800 spectrophotometer according to the manufacturer's protocol.

PDF file - 115 KB, HOEC suppresses solar UV-induced AKT, ATF2 and c-Fos phosphorylation levels and PCNA protein levels in mouse skin tissues. At week 30, all mice were sacrificed and skin tissue collected from mice treated or not treated with HOEC and solar UV. Tissues were immediately frozen and kept at -80 degrees C. Tissues were homogenized with lysis buffer and incubated for another 60 min and centrifuged twice. The supernatant fraction was collected for Western blot analysis as described in Materials and Methods. The levels of phosphorylated and total target proteins in mouse skin and tumor tissues were analyzed by Western blot. Representative results from 3 independent blots are shown (n = 6). The abundance of each band relative to its own total protein and/or beta-actin was quantified, respectively, and the means are labeled above each blot. The control levels were set at 1. The asterisk (*) indicates a significant difference (p < 0.05) between vehicle-treated and solar UV-induced phorphorylation levels. The asterisks (**) indicate a significant difference between untreated and HOEC-treated groups (p < 0.05).

PDF file - 126 KB, In vitro kinase profiling analysis (KinaseProfiler).

PDF file - 139 KB, The p110alpha, ERK1, ERK2, and p38alpha protein kinases are major targets of HOEC. (A) HOEC inhibits p110alpha (a), ERK1 (b), ERK2 (c), and p38alpha (d) kinase activities. In vitro p110alpha, ERK1, ERK2, and p38alpha kinase assays were performed as described in Materials and Methods. Equal loading controls are shown as a Coomassie Blue (C.B) stained panel below each experiment. (B) HOEC directly binds with p110alpha, ERK1, ERK2, and p38alpha in vitro (a) and ex vivo (b). In vitro and ex vivo pull-down assays were perfomed using active kinases and solar UV-treated JB6 Cl41 cell lysates with sepharose 4B beads only or HOEC-conjugated sepharose 4B beads as described in Materials and Methods. Lane 1 shows input control and representative blots from 3 independent experiments are shown. Equal loading controls are shown as a Coomassie Blue (C.B) stained panel below each experiment. (C) HOEC competitively binds with ATP to p110alpha, ERK1, ERK2, and p38alpha. In vitro ATP competitive pull-down assays were perfomed using active kinases with HOEC-conjugated-sepharose 4B or sepharose 4B beads only as described in Materials and Methods. The pulled down proteins were detected by Western blot analysis. All input controls were used as a standard for each protein in the first lane of the pull-down assay results. The relative abundance of each band normalized to its own control group (untreated, set at 1) was quantified and the value is shown above each respective lane in each blot.

For decades, skin cancer incidence has increased, mainly because of oncogenic signaling pathways activated by solar ultraviolet (UV) irradiation (i.e., sun exposure). Solar UV induces multiple signaling pathways that are critical in the development of skin cancer, and therefore the development of compounds capable of targeting multiple molecules for chemoprevention of skin carcinogenesis is urgently needed. Herein, we examined the chemopreventive effects and the molecular mechanism of (+)-2-(1-hydroxyl-4-oxocyclohexyl) ethyl caffeate (HOEC), isolated from Incarvillea mairei var. grandiflora (Wehrhahn) Grierson. HOEC strongly inhibited neoplastic transformation of JB6 Cl41 cells without toxicity. PI3K, ERK1/2, and p38 kinase activities were suppressed by direct binding with HOEC in vitro. Our in silico docking data showed that HOEC binds at the ATP-binding site of each kinase. The inhibition of solar UV-induced PI3K, ERK1/2, and p38 kinase activities resulted in suppression of their downstream signaling pathways and AP1 and NF-κB transactivation in JB6 cells. Furthermore, topical application of HOEC reduced skin cancer incidence and tumor volume in SKH-1 hairless mice chronically exposed to solar UV. In summary, our results show that HOEC exerts inhibitory effects on multiple kinase targets and their downstream pathways activated by solar UV in vitro and in vivo. These findings suggest that HOEC is a potent chemopreventive compound against skin carcinogenesis caused by solar UV exposure. Cancer Prev Res; 7(8); 856–65. ©2014 AACR.

XLS file 35K, Chromosomal aberrations of the EPT3-M1.

XLS file 2928K, Changed gene expression in D5HS comparing to EPT2-D5 cells

XLS file 30K, Accumulation of chromosomal aberrations in stepwise generated cell lines.

Eleven undescribed ent-kaurane-type diterpenoid acids, namely noueinsiancins A–K (1–11), together with sixteen related known analogs (12–27) were isolated from Nouelia insignis Franch.

Synergistic Pd/Cu catalysis was used to achieve regio- and stereoselective borylation of allenylic carbonates, offering a straightforward strategy to produce 2-boryl 1,3-butadienes.

A chemical investigation on Gerbera anandria (Linn) Sch-Bip led to the isolation and identification of six coumarin derivatives, named Gerberdriasins A–F (1–6). Their structures and absolute configurations were determined by NMR, HR-ESI-MS, QM-NMR, Mosher's method and ECD.

All-hydrocarbon stapling strategy has been widely applied for enhancing the proteolytic stability of peptides. However, two major technical hurdles to some extent limit the development of stapled peptides for therapeutic usage: rational selection of the stapling sites and the corresponding deletion of the native side chains. Previously we described the development of the olefin-terminated amino acids with the retention of native side chains and successfully applied them in the synthesis of hydrocarbon stapled peptides with single side-chain retention. Here, we explored the feasibility and effectiveness of hydrocarbon stapling strategy characterized as double side-chains retention. Modeled after a lengthy human immunodeficiency virus-1 (HIV-1) fusion inhibitor SC34EK, Leui, Seri+4 and Lysi, Leui+4 stapled peptides with the retention of double side-chains were effectively obtained. Our complementary study provided a convenient alternative to address where to install the staple in sequence for conventional all-hydrocarbon peptide stapling. Furthermore, this method not only conferred conformational reinforcement for SC34EK with high α-helicity and protease resistance, but also preserved the structural characteristic (key peripheral residues, charge and solubility) of the linear peptide to the maximum, which are crucial for anti-HIV-1 activity.

The pandemic of acute respiratory disease in 2019 caused by highly pathogenic and infectious SARS-CoV-2 has seriously endangered human public safety. The 6-HB (HR1-HR2 complex) formation occurring in the process of spike protein-mediated membrane fusion could serve as a conserved and potential target for the design of fusion inhibitors. Based on the HR2 domain of 6-HB, we designed and synthesized 32 stapled peptides using an all-hydrocarbon peptide stapling strategy. Owing to the improved proteolytic stability and higher helical contents, the optimized stapled peptides termed SCH2-1-20 and SCH2-1-27 showed better inhibitory activities against pseudo and authentic SARS-CoV-2 compared to the linear counterpart. Of note, SCH2-1-20 and SCH2-1-27 were proved to interfere with S protein-mediated membrane fusion. Structural modeling indicated similar binding modes between SCH2-1-20 and the linear peptide. These optimized stapled peptides could serve as potent fusion inhibitors in treating and preventing SARS-CoV-2, and the corresponding SAR could facilitate further optimization.

A green and efficient method for the synthesis of β-sulfonyl aliphatic sulfonyl fluorides was developed. This reaction works in aqueous media under mild and environmentally benign conditions without any ligand...

Alternative antibacterial therapies refractory to existing mechanisms of antibiotic resistance are urgently needed. One such attractive therapy is to inhibit bacterial adhesion and colonization. Ser O-heptosylation (Ser O-Hep) on autotransporters of Gram-negative bacteria is a novel glycosylation and has been proven to be essential for bacterial colonization. Herein, we chemically synthesized glycopeptides containing this atypical glycan structure and an absolute C6 configuration through the assembly of Ser O-Hep building blocks. Using glycopeptides as haptens, we generated first-in-class poly- and monoclonal antibodies, termed Anti-Ser

Two previously undescribed 3(4), 8(9), 9(10)-trisecocycloartane triterpene dilactones with a featured eleven-membered ring, pseudoladilactones A and B (1-2), together with three known ones (4-5), were isolated from the 80 % ethanol extract of the cones of Pseudolarix amabilis. The structures of compounds 1 and 2 were determined on the basis of analysis of 1D- and 2D-NMR spectroscopic data. The absolute configuration of pseudoladilactones A (1) was elucidated by single crystal X-ray diffraction (CuKα). All isolates were tested for cytototoxicity against four human tumor cell lines A549, HCT116, SK-BR-3, and HepG2.

Dimeric sesquiterpenoids possessing densely substituted 7-norbornenone/7-norbornenol motifs pose a considerable challenge for chemical synthesis. From a strategic perspective, one could envision intermolecular Diels−Alder cycloaddition as a straightforward method for assembling alkyl-substituted 7-norbornenones. However, this approach is hindered by lability of the required dienes, namely alkyl-substituted cyclopentadienones. Here we report a one-pot protocol for construction of alkyl-substituted 7-norbornenones from electron-deficient olefins and a cyclopentenone derivative. DDQ was found to be an effective oxidant for generating a cyclopentadienone intermediate in situ from the enone. A series of sterically congested 7-norbornenone-containing polycyclic compounds were prepared by using this protocol.

Bo Yang,1– 3,* Lin-Lin Ji,1,2,* Hong-Liang Xu,1,* Xiao-Ping Li,3 Hong-Gang Zhou,4 Ting Xiao,4 Xiao-He Li,4 Zhou-Yong Gao,1,2 Jian-Zhong Li,5 Wei-Dong Zhang,3 Guang-Shun Wang,1 Ming-Jiang Li3 1Department of Thoracic Surgery, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, 301800, People’s Republic of China; 2State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing, 102206, People’s Republic of China; 3Department of Thoracic Surgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, People’s Republic of China; 4State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key, Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, People’s Republic of China; 5Department of Thoracic Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guang-Shun WangDepartment of Thoracic Surgery, Tianjin Baodi Hospital, Baodi Clinical College of Tianjin Medical University, Tianjin, 301800, People’s Republic of ChinaEmail wgs@bddhospital.comMing-Jiang LiDepartment of Thoracic Surgery, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, People’s Republic of ChinaEmail mingjiangli@nankai.edu.cnBackground: Zc3h12d is a negative regulator which plays a crucial role in immune modulation. However, the role of zc3h12d in lung adenocarcinoma (LUAD) remains unclear. We aim to explore the prognostic of zc3h12d and investigate the relationship between zc3h12d expression and immune infiltration in LUAD.Methods: TIMER site was used to analyze the expression of zc3h12d in LUAD. The zc3h12d protein levels in patient tissue samples were detected by immunohistochemistry staining assays. Meanwhile, based on UALCAN database and samples’ data from our cohort, we explored the relationship of clinicopathological features and zc3h12d expression to determine the clinical effect of zc3h12d in LUAD. Several databases including GEPIA, Kaplan–Meier plotter and our samples’ data were used to explore the prognostic value of zc3h12d in LUAD. Cox regression analysis was established to further evaluate the prognostic value of zc3h12d in LUAD. In addition, zc3h12d promoter methylation was analyzed by UALCAN database. Genetic alteration analysis was observed in the cBioPortal web. GO and KEGG analyses were conducted to elucidate the underlying mechanisms. Finally, the correlation between zc3h12d and tumor-infiltrating immune cells in LUAD was investigated by TIMER database. The B cells level was investigated by flow cytometry analysis of peripheral blood from our LUAD cohort.Results: Zc3h12d expression was significantly higher in LUAD, compared with adjacent normal tissues. The clinical data from the UALCAN database demonstrated that zc3h12d expression was closely related with cancer stage and nodal metastasis. However, patient sample detection revealed that zc3h12d expression was closely related to pathological N (p = 0.0431) and grade (p = 0.004). Moreover, low zc3h12d expression was associated with poorer overall survival in LUAD. We analyzed the methylation level of zc3h12d in LUAD and found that the methylation levels of zc3h12d promoter in LUAD were significantly reduced. In addition, zc3h12d genetic alterations, including deep deletion, could be found in LUAD. GO and KEGG pathway analysis results indicated that zc3h12d has a certain value in immune infiltration. We investigated the expression of zc3h12d in tumor-immune interactions. It was found that zc3h12d might be associated with the immune infiltration and markers of infiltrating immune cells of LUAD. The results of patient sample detection confirmed that B cells level was significantly lower in the patients with low zc3h12d expression than those in the patients with high zc3h12d expression.Conclusion: zc3h12d might be considered as a potential biomarker for determining prognosis and immune-related therapeutic target in LUAD.Keywords: zc3h12d, lung adenocarcinoma, hypomethylation, tumor microenvironment, prognosis

BACKGROUND Endoscopic thyroidectomy via areola approach (ETA) has been widely used in thyroidectomy for many years as it can effectively avoid a scar in the neck. Transoral endoscopic thyroidectomy vestibular approach (TOETVA) is newly applied and has gained popularity quickly. This study is to compare the safety and effectiveness of TOETVA and ETA. MATERIALS AND METHODS A total of 95 patients who underwent TOETVA or ETA with unilateral papillary thyroid carcinoma were enrolled in this study from March 2019 to February 2020. The basic information (such as gender, age), intraoperative hemorrhage, postoperative drainage volume, hospital durations, intraoperative and postoperative complications, operative time, central lymph node dissection time, total number of central lymph nodes, and number of metastatic central lymph nodes were compared. RESULTS The operative time of the TOETVA group was significantly longer than the ETA group (148.11±19.78 vs. 135.90±12.77 min, P

A cross-sectional study was conducted to estimate the age-stratified normal levels and age-related changes in the risk predictors of benign prostatic hyperplasia (BPH) progression. A total of 4706 male participants aged 40 years or older in Zhengzhou (China) were enrolled. The values of the International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA), prostate volume (PV), and postvoid residual urine volume (PVR) significantly increased with age. Nonlinear relationships between age and IPSS scores ≥8 (P for nonlinearity = 0.046), PSA level ≥1.6 ng ml

Abundant cellulose and insoluble protein were contained in the Se-enriched peanut leaf residue, a by-product from leaf protein extraction. Ionic liquids (ILs) were used to extract the cellulose-protein complexes (CPCs) from Se-enriched peanut leaf residue. The effects of various ILs as extractants and organic solvents as regenerant on the physicochemical properties of CPCs were compared. The results showed that the yield of CPCs and recovery yield of [AMIM]Cl (1-allyl-3-methylimidazole chloride) were better than those of [BMIM]Cl (1-butyl-3-methylimidazolium chloride). Simultaneously, it could be seen from the infrared absorption peaks and secondary structure fitting results that [BMIM]Cl seemed stronger than [AMIM]Cl in destroying the secondary structure of CPCs. Scanning electron microscope (SEM) showed that the CPCs extracted by [BMIM]Cl were lamellate with holes on the surface, and the CPCs extracted by [AMIM]Cl were rough, almost without holes on the surface. Furthermore, the transmittance and tensile strength of the film which contained BA-CPC ([BMIM]Cl as extractant and acetonitrile as regenerant) film were better than those contained AA-CPC ([AMIM]Cl as extractant and acetonitrile as regenerant) film, which might be mainly because the types of ILs and regenerants affect the particle size of CPCs, thereby influencing the mechanical properties of the film.

Sulfide-based all-solid-state lithium-ion batteries (ASSLIBs) are promising candidates in the next generation of energy storage technology; the voltage mismatch and the resulting side reactions at the interface between the cathode and the solid electrolyte, however, dramatically deteriorate their cycling performance. Herein, for the first time, we report that the chemical interaction between LiCoO2 (LCO) and TiO2 can be regulated by two additives, carbon and Li2CO3, which in situ form a continuous ultrathin pure-phase Li2CoTi3O8 (LCTO) layer with a stable 3D network of spinel structures, relatively low electronic conductivity (2.5 × 10−8 S cm−1) and high lithium diffusion coefficient (DLi+ = 8.22 × 10−7 cm2 s−1) on the surface of LCO. When assembled in ASSLIBs, such an LCTO layer functions as an interlayer between the LCO and the Li10GeP2S12 solid electrolyte (LGPS). As a consequence, the original interface LCO/LGPS is substituted by two new interfaces LCO/LCTO and LCTO/LGPS. DFT calculations indicate that, compared with the LCO/LGPS, the new interfaces are not only thermodynamically and electrochemically more compatible, but also have higher interfacial affinity. Therefore, the relevant ASSLIB exhibits evidently reduced interfacial impedance, and it also displays a high initial capacity of 140 mA h g−1 and a reversible discharge specific capacity of 116 mA h g−1 after 200 cycles at room temperature (0.1C). In comparison, the ASSLIB assembled without the LCTO interlayer delivers an initial capacity of 98 mA h g−1 and only retains 22.4% capacity after 100 cycles (0.1C). Even at a high cutoff voltage (4.5 V vs. Li/Li+), the ASSLIB with the LCTO interlayer could also exhibit a high initial capacity of 180 mA h g−1 and a remarkable retention of 132 mA h g−1 after 100 cycles.

Abstract Four new 3,4-secocycloartane triterpenoids, pseudolactones A–D (1–4), were isolated from the ethanol extract of the cones of Pseudol arixamabilis. Their structures were established by extensive 1D- and 2D-NMR experiments. The cones of P. arixamabilis are enriched in the ring-expanded or cleaved cycloartane triterpenoids. This work provides new insight into cycloartane triterpenoids from the cones of P. arixamabilis. Graphic Abstract

Endoplasmic reticulum (ER) homeostasis is regulated by ER-resident E3 ubiquitin ligase Hrd1, which has been implicated in inflammatory bowel disease (IBD). Ginsenoside Rb1 (GRb1) is the major ginsenoside in ginseng with multiple pharmacological activities. In this study we investigated the role of Hrd1 in IBD and its regulation by GRb1. Two mouse colitis models were established to mimic human IBD: drinking water containing dextran sodium sulfate (DSS) as well as intra-colonic infusion of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). Colitis mice were treated with GRb1 (20, 40 mg·kg(−1)·d(−1), ig) or a positive control drug sulfasalazine (500 mg·kg(−1)·d(−1), ig) for 7 days. The model mice showed typical colitis symptoms and pathological changes in colon tissue. In addition to significant inflammatory responses and cell apoptosis in colon tissue, colon epithelial expression of Hrd1 was significantly decreased, the expression of ER stress markers GRP78, PERK, CHOP, and caspase 12 was increased, and the expression of Fas was increased (Fas was removed by Hrd1-induced ubiquitination). These changes were partially, or completely, reversed by GRb1 administration, whereas injection of Hrd1 inhibitor LS102 (50 mg·kg(−1)· d(−1), ip, for 6 days) exacerbated colitis symptoms in colitis mice. GRb1 administration not only normalized Hrd1 expression at both the mRNA and protein levels, but also alleviated the ER stress response, Fas-related apoptosis, and other colitis symptoms. In intestinal cell line IEC-6, the expression of Hrd1 was significantly decreased by LPS treatment, but was normalized by GRb1 (200 μM). GRb1 alleviated LPS-induced ER stress and cell apoptosis in IEC-6 cells, and GRb1 action was inhibited by knockdown of Hrd1 using small interfering RNA. In summary, these results reveal a pathological role of Hrd1 in colitis, and provide a novel insight into alternative treatment of colitis using GRb1 activating Hrd1 signaling pathway.

A large proportion of protein-protein interactions (PPIs) occur between a short peptide and a globular protein domain; the peptides involved in surface interactions play important roles, and there is great promise for using peptide motifs to interfere with protein interactions. Peptide inhibitors show more promise in blocking large surface protein interactions compared to small molecule inhibitors. However, peptides have drawbacks including poor stability against circulating proteolytic enzymes and an intrinsic inability to penetrate cell membranes. Stapled helical peptides, by adopting a preformed, stable α-helical conformation, exhibit improved proteolytic stability and membrane permeability compared to linear bioactive peptides. In this review, we summarize the broad aspects of peptide stapling for chemistry, biophysics, and biological applications and specifically highlight the methodology by providing an inventory of different anchoring residues categorized into two natural amino acids, two nonnatural amino acids, or a combination of natural and nonnatural amino acids. Additional advantages of specific peptide stapling techniques, including but not limited to reversibility, bio-orthogonal reactivity, and photoisomerization, are also discussed individually. This review is expected to provide a broad reference for the rational design of druggable stapled peptides targeting therapeutic proteins, particularly those involved in PPIs, by considering the impact of anchoring residues, functional cross-linkers, physical staple length, staple components, and the staple motif on the biophysical properties of the peptides.

Objectives To screen the cytotoxic activity of six secondary metabolites isolated from soil fungus Aspergillus niger. Importantly, to investigate the mechanism that pyoluteorin induced human triple-negative breast cancer MDA-MB-231 cells apoptosis in vitro. Methods The cell viability assay was tested with CTG assay. Cell cycle, apoptosis and intracellular reactive oxygen species (ROS) production assay were tested with flow cytometry. Additionally, intracellular ROS production assay and mitochondrial membrane potential assay were determined with laser scanning confocal microscopy. The expression of apoptosis-related proteins was determined with Western blot. Key findings Pyoluteorin displayed significantly selective cytotoxicity against human triple-negative breast cancer MDA-MB-231 cells (IC50 = 0.97 µm) with low toxicity against human breast epithelial cell MCF-10A. It was found that pyoluteorin could arrest MDA-MB-231 cells cycle at G2/M phase and induce cell apoptosis. Further experiments demonstrated that the apoptosis-inducing effect of pyoluteorin was related to reduction of mitochondrial membrane potential, accumulation of ROS and change of apoptosis-related protein expressions. Conclusion Our studies revealed that pyoluteorin had potent proliferation inhibition against MDA-MB-231 cells through arresting cell cycle at G2/M phase and inducing caspase-3-dependent apoptosis by mitochondrial pathway, implying that pyoluteorin may be a potential lead compound for drug discovery of human triple-negative breast cancer.

Background and objectives Formononetin has protective effect against ischemic stroke. It’s unclear whether it can restore the nerve functions after stroke. Methods SD rats were subjected with middle cerebral artery occlusion (MCAO), and divided into sham, model and formononetin (30 mg/kg) groups. Neurobehavioral tests (modified Neurological Severity Score [mNSS] and rotarod) were performed before and at 1, 3, 7 and 14 days after MCAO. Then, the rats were sacrificed and the brain sections were processed for neuronal differentiation and synaptic plasticity. Results Compared with the sham group, the scores of mNSS were significantly increased, and the residence time on the rotating drum was significantly decreased in the MCAO rats. Compared with the model group, the scores of mNSS were significantly decreased, and the residence time on the rotating drum was increased in the formononetin (30 mg/kg) group. Formononetin significantly increased the number of neuronal dendritic spines and the expression of β III-tubulin, GAP-43, NGF, BDNF, p-Trk A, p-Trk B, p-AKT and p-ERK 1/2. Conclusions Formononetin recovered injured nerve functions after ischemic stroke. PI3K/AKT/ERK pathway might involve in the beneficial effect of formononetin on the neuronal differentiation and synaptic plasticity.

The LiCoO2 (LCO) cathode has been widely used in material markets, especially in conventional lithium ion batteries, due to its stable electrochemical performance. Increasing the working cutoff pot...

Bile duct injury remains the most serious complication of laparoscopic cholecystectomy (LC), the main cause was misidentification of cystic duct (CD). The aim of this study was to evaluate the effectiveness and security of retrograde tracing along "cystic duct" (RTACD) method for the prevention of biliary misidentification injury in LC. The conception of RTACD method was first described and then illustrated by simulation dissection with extrahepatic biliary structure charts. A total of 840 patients undergoing LC were selected. After the "CD" was separated during operation, its authenticity was identified by RTACD method according to its course and origin. The "CD" can be clipped/divided only when it was identified to be true CD. Among 840 patients, the initially separated "CD" was identified as actual CD in 831 cases, common hepatic (bile) duct in six cases, accessory right posterior sectoral duct in two cases, and right haptic duct in one case. LCs were successfully finished in 837 patients, and converted to open cholecystectomy in three cases. The average operation time was 64.23 min (range 25-225 min), and the average blood loss was 8.07 ml (range 2-200 ml). No biliary misidentification injury was found. All patients recovered smoothly. No jaundice or abdominal pain was noted in the patients during 1-19 months follow-up. RTACD method is a safe and effective new technique of preventing biliary misidentification injury.

As our ongoing interest to search bioactive dimeric sesquiterpenes from the genus Vladimiria (Asteraceae), the plant of Vladimiria souliei was studied. Based on the repetitive chromatographic fractionation, a chemical investigation on the roots of Vladimiria souliei led to the isolation and the identification of four previously undescribed sesquiterpene dimers, vlasouliodes A-D (1-4). Their chemical structures were elucidated by comprehensive analysis of spectroscopic data, including HRESIMS, 1D and 2D NMR spectroscopic data. The absolute configurations of them were unambiguously established by the experimental and calculated ECD data. In the in vitro biological activity evaluation, 1 and 3 displayed pronounced inhibitory activity against human breast adenocarcinoma cell lines (MCF-7) with IC

Based on the basic information of the Second National Pollution Source Census and the VOCs source profiles of industrial industries, we established the speciated emission inventory of major industrial sources in Chongqing in 2017, estimated their ozone formation potential (OFP), and identified the key control species of industrial VOCs and their sources. The results showed that the total VOCs emission from industrial sources and their OFPs were 144.12 kt and 477.34 kt, respectively. Automobile manufacturing, equipment manufacturing, plastic manufacturing, and chemical raw materials and chemical products were all industries that contributed significantly to VOCs emissions and OFP, with VOCs emissions of 37.18, 33.09, 19.47, and 18.14 kt and OFP of 191.43, 153.69, 27.21, and 57.51 kt, respectively. Aromatics were the components with the largest contribution to VOCs emissions and OFP, accounting for 62.55% of the total VOCs emissions and 82.15% of the total OFP, mainly from metal surface coating and petrochemical industries. The major reactive species of industrial source VOCs were

Eleven undescribed

Dingkun Pill (DKP), a traditional Chinese medicine prescription, was modified from Bujing decoction and Xusijiangsheng pill by the imperial physician in the Qing dynasty (1700' s). It was believed to treat various gynecological diseases by nourishing qi and blood. Accumulating evidence indicates that it is effective in treating polycystic ovary syndrome (PCOS). However, the therapeutic efficacy and mechanism of action DKP against PCOS need to be further elucidated.To investigate the therapeutic effect and action mechanism of DKP against PCOS using an integrated approach of metabolomics and network pharmacology.The rat model of PCOS was established by dehydroepiandrosterone. An integrated metabolomics and network pharmacology strategy was applied to systemically clarify the mechanism of DKP against PCOS. Theca cells were prepared to evaluate the effect of DKP and its ingredients on testosterone synthesis in vitro.The pharmacological experiments demonstrated that DKP could effectively convert the disordered estrous cyclicity, decrease the level of testosterone and the luteinizing hormone/follicle stimulating hormone ratio, and inhibit abnormal follicle formation in PCOS rats. By metabolomics analysis, 164 serum endogenous differential metabolites and 172 urine endogenous differential metabolites were tentatively identified. Steroid hormone biosynthesis and ovarian steroidogenesis were the most significantly impacted pathways. Based on network pharmacology and metabolomics studies, the ingredient-target-pathway network of DKP in the treatment of PCOS was constructed. Among the 10 key targets, CYP17A1, CYP19A1, STS, AR, ESR1, and MYC were closely involved in ovarian androgen synthesis. In theca cell-based assay of testosterone synthesis, DKP and its two active compounds (ligustilide and picrocrocin) showed inhibitory effects.DKP effectively improved symptoms in rats with dehydroepiandrosterone-induced PCOS. The mechanism of DKP in the treatment of PCOS is related to the CYP17A1 enzyme required for androgen synthesis.

Background. Whether more tumor numbers detected in surgery compared to preoperative image affecting survival of colorectal liver metastases (CRLM) patients after hepatectomy combined with microwave ablation (MWA) remains unclear. Methods. From 2013 to 2018, 85 CRLM patients who underwent hepatectomy combined with MWA were retrospectively assessed. Compared to the tumor numbers in preoperative image, patients with equal intraoperative tumor numbers were defined as the equal number group ( n = 45 ); patients detected more tumor numbers in surgery were defined as the more number group ( n = 40 ). Clinicopathological factors and prognosis were compared between two groups. Results. Compared to the equal number group, the more number group was characterized by more lymphatic metastasis, synchronous metastasis of liver lesion, and tumor numbers over 5 (all P < 0.05 ). Median survival time was 46.7 months and 26.8 months in the equal and more number group. Significantly worse overall survival (OS) was found in more number group to the equal number group ( P = 0.027 ). In Cox analysis, more tumor number than image and high level of carbohydrate antigen 19-9 (CA19-9) were poor prognostic factors for OS. Conclusion. In patients receiving hepatectomy combined with MWA, detecting more liver metastases in surgery than preoperative image indicates poor long-term survival. These patients were characterized by more lymphatic metastasis, synchronous metastasis of liver lesion, and tumor numbers over 5. Intensive follow-up to detect early recurrence and potent postoperative therapy to improve survival may be justified in patients detected more tumor numbers in surgery with a high CA19-9 level.

Naringin has been shown to exert protective effects in an animal model of ulcerative colitis, but detailed mechanisms remain unclear. This study aimed to investigate function and signaling mechanisms underlying naringin-induced therapeutic effects on colitis. Two mouse models were established to mimic human Inflammatory bowel disease (IBD) by treating drinking water with dextran sodium sulphate or intra-colonic administration of 2, 4, 6-trinitrobenzene sulfonic acid. Transcriptomics combined with functional experiments were used to investigate underlying mechanisms. Colitis symptoms, including weight loss and high disease activity index were significantly reversed by naringin. The inflammatory response, oxidative reactions, and epithelial cell apoptosis that occur with colitis were also alleviated by naringin. After naringin treatment, transcriptomics results identified 753 differentially expressed mRNAs that were enriched in signaling pathways, including the neuroactive ligand-receptor interaction, calcium signaling, and peroxisome proliferator-activated receptor (PPAR) signaling. The naringin-induced alleviation of colitis was significantly inhibited by the PPAR-γ inhibitor BADGE. In IEC-6 and RAW264.7 cells incubated with lipopolysaccharide (LPS), NF-κB-p65, a downstream protein of PPAR-γ, was significantly increased. Naringin suppressed LPS-induced high expression of NF-κB-p65, which was inhibited by small interfering RNA targeting PPAR-γ. Our study clarifies detailed mechanisms underlying naringin-induced therapeutic effects on mice colitis, and PPAR-γ was found to be the main target of naringin by functional experiments both in vivo and in vitro. Our study supplies new scientific information for the use of naringin in colitis treatment.