Construction and validation of a neovascular glaucoma nomogram in patients with diabetic retinopathy after pars plana vitrectomy.

BACKGROUND: Neovascular glaucoma (NVG) is likely to occur after pars plana vitrectomy (PPV) for diabetic retinopathy (DR) in some patients, thus reducing the expected benefit. Understanding the risk factors for NVG occurrence and building effective risk prediction models are currently required for clinical research. AIM: To develop a visual risk profile model to explore factors influencing DR after surgery. METHODS: We retrospectively selected 151 patients with DR undergoing PPV. The patients were divided into the NVG (NVG occurrence) and No-NVG (No NVG occurrence) groups according to the occurrence of NVG within 6 months after surgery. Independent risk factors for postoperative NVG were screened by logistic regression. A nomogram prediction model was established using R software, and the model's prediction accuracy was verified internally and externally, involving the receiver operator characteristic curve and correction curve. RESULTS: After importing the data into a logistic regression model, we concluded that a posterior capsular defect, preoperative vascular endothelial growth factor ≥ 302.90 pg/mL, glycosylated hemoglobin ≥ 9.05%, aqueous fluid interleukin 6 (IL-6) ≥ 53.27 pg/mL, and aqueous fluid IL-10 ≥ 9.11 pg/mL were independent risk factors for postoperative NVG in patients with DR (P < 0.05). A nomogram model was established based on the aforementioned independent risk factors, and a computer simulation repeated sampling method was used to internally and externally verify the nomogram model. The area under the curve (AUC), sensitivity, and specificity of the model were 0.962 [95% confidence interval (95%CI): 0.932-0.991], 91.5%, and 82.3%, respectively. The AUC, sensitivity, and specificity of the external validation were 0.878 (95%CI: 0.746-0.982), 66.7%, and 95.7%, respectively. CONCLUSION: A nomogram constructed based on the risk factors for postoperative NVG in patients with DR has a high prediction accuracy. This study can help formulate relevant preventive and treatment measures.

Roflumilast: Modulating neuroinflammation and improving motor function and depressive symptoms in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease causing central nervous system demyelination, often associated with depression. Current treatments for MS do not effectively address both physical disability and depression. Roflumilast, a phosphodiesterase-4 inhibitor with anti-inflammatory properties, has shown promise for autoimmune diseases. METHODS: We used an experimental autoimmune encephalomyelitis (EAE) rat model to study roflumilast's effects. Motor dysfunction and depression symptoms were assessed, and histopathological analysis evaluated its anti-inflammatory properties. Flow cytometry examined the drug's impact on brain microglia. TNF-α, IL-1ß, and IL-6 levels in hippocampal tissue were assessed using ELISA kits. RESULTS: Roflumilast improved motor dysfunction and depression symptoms in EAE rats. Histopathological analysis revealed reduced inflammation, demyelination, and axonal loss in the spinal cord. Roflumilast suppressed microglial cell activation and conversion to pro-inflammatory M1-type cells. Flow cytometry showed roflumilast inhibited inflammatory marker expression in microglia and their activation in the hippocampus. IL-6 was identified as a roflumilast target for suppressing hippocampal inflammation. LIMITATIONS: This study used an animal model and did not assess long-term or potential side effects of roflumilast treatment. CONCLUSIONS: Roflumilast holds promise as a treatment for depression and motor impairment in MS. Its anti-inflammatory properties, reducing inflammation and inhibiting microglial activation, suggest its potential for MS therapy. However, further research is needed to evaluate long-term effects and safety in MS patients.

Widely targeted metabolic profiling provides insights into variations in bioactive compounds and antioxidant activity of sesame, soybean, peanut, and perilla.

Oilseeds are important sources of diversified nutraceuticals with marked health attributes. Thus, a better understanding of metabolome differences between common oilseeds will be conducive to the food pharmacy. This study aimed to compare the metabolite profiles and antioxidant activity of sesame, soybean, peanut, and perilla seeds and reveal the variation in bioactive compounds. LC-MS-based widely targeted metabolic profiling identified a total of 975 metabolites, of which 753 were common to the four crops. Multivariate analyses unveiled a crop-specific accumulation of metabolites, with 298-388 DAMs (differentially accumulated metabolites) identified. Amino acid metabolism, phenylpropanoid biosynthesis, flavonoid biosynthesis, and lipid metabolism were the most differentially regulated pathways. Furthermore, we revealed the variation in the relative content of 48, 20, 18, 9, 18, 11, and 6 differentially accumulated bioactive flavonoids, phenolic acids, amino acids, vitamins, terpenoids, alkaloids, and coumarins, respectively. Most of the flavonoids accumulated highly in soybean, followed by perilla. Sesame exhibited a better amino acid profile than other oilseeds. DPPH and FRAP assays showed that the antioxidant activity of perilla seed extracts was the highest, followed by soybean, peanut, and sesame. Our results provide data support for the comprehensive use of sesame, perilla, soybean, and peanut seeds in food, and pharmaceutical industries.

Ginsenosides: a potential natural medicine to protect the lungs from lung cancer and inflammatory lung disease.

Lung cancer is the malignancy with the highest morbidity and mortality. Additionally, pulmonary inflammatory diseases, such as pneumonia, acute lung injury, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis (PF), also have high mortality rates and can promote the development and progression of lung cancer. Unfortunately, available treatments for them are limited, so it is critical to search for effective drugs and treatment strategies to protect the lungs. Ginsenosides, the main active components of ginseng, have been shown to have anti-cancer and anti-inflammatory activities. In this paper, we focus on the beneficial effects of ginsenosides on lung diseases and their molecular mechanisms. Firstly, the molecular mechanism of ginsenosides against lung cancer was summarized in detail, mainly from the points of view of proliferation, apoptosis, autophagy, angiogenesis, metastasis, drug resistance and immunity. In in vivo and in vitro lung cancer models, ginsenosides Rg3, Rh2 and CK were reported to have strong anti-lung cancer effects. Then, in the models of pneumonia and acute lung injury, the protective effect of Rb1 was particularly remarkable, followed by Rg3 and Rg1, and its molecular mechanism was mainly associated with targeting NF-κB, Nrf2, MAPK and PI3K/Akt pathways to alleviate inflammation, oxidative stress and apoptosis. Additionally, ginsenosides may also have a potential health-promoting effect in the improvement of COPD, asthma and PF. Furthermore, to overcome the low bioavailability of CK and Rh2, the development of nanoparticles, micelles, liposomes and other nanomedicine delivery systems can significantly improve the efficacy of targeted lung cancer treatment. To conclude, ginsenosides can be used as both anti-lung cancer and lung protective agents or adjuvants and have great potential for future clinical applications.

Retrospective Analysis of the Clinical Features and Pregnancy Outcomes in 124 Pregnant Patients with Non-Obstetric Acute Abdomen.

Objective: To retrospectively analyze the clinical characteristics and pregnancy outcomes of patients with the non-obstetric acute abdomen (AAD) during pregnancy. Methods: A total of 124 patients with non-obstetric AAD during pregnancy were selected, including acute gastroenteritis (n = 42), acute appendicitis (n = 24), pedicle torsion of ovarian tumor (n = 21), acute pancreatitis (n = 10), urinary stones (n = 8), acute cholecystitis (n = 5), ruptured ovarian cyst (n = 6), red degeneration of hysteromyoma (n = 4), pedicle torsion of subserosal hysteromyoma (n = 3) and intestinal obstruction (n = 1). The clinical data of included patients were collected, and their clinical manifestations, clinical diagnosis, treatment modalities, and pregnancy outcomes were analyzed. Results: Common clinical manifestations included abdominal pain, nausea, vomiting, fever, elevated leukocytes, and neutrophil count. Clinical diagnosis analysis revealed acute gastroenteritis (n = 42), acute appendicitis (n = 24), pedicle torsion of ovarian tumor (n = 21), acute pancreatitis (n = 10), urinary stones (n = 8), acute cholecystitis (n = 5), ruptured ovarian cyst (n = 6), red degeneration of hysteromyoma (n = 4), pedicle torsion of subserosal hysteromyoma (n = 3) and intestinal obstruction (n = 1) in patients. Surgery was performed for conditions such as acute appendicitis and ovarian tumor torsion, while conservative treatment was preferred for cases of acute gastroenteritis. 65 patients received surgery and 59 patients received conservative treatment. The pregnancy outcomes indicated 113 patients with full-term delivery, 5 with premature delivery, 6 with miscarriage and 1 with fetal death. Pregnancy outcomes varied, with 113 patients achieving full-term delivery, 5 experiencing premature delivery, 6 undergoing miscarriage, and 1 case of fetal death. Conclusion: Non-obstetric AAD during pregnancy manifests clinically as nausea and vomiting, abdominal pain, elevated body temperature, and leukocytes, all of which have pregnancy outcomes. Pregnant patients with non-obstetric AAD should be diagnosed according to their clinical manifestations, physical examinations, and relevant imaging examinations, and appropriate treatment modalities should be selected to achieve a better pregnancy outcome and ensure the safety of the mother and baby during the clinical diagnosis and treatment process. This study underscores the need for prompt and accurate diagnosis in pregnant patients with non-obstetric AAD, to optimize pregnancy outcomes and ensure maternal-fetal safety.

Application of four-dimensional cone beam computed tomography in lung cancer radiotherapy.

OBJECTIVE: This study explored the application of four-dimensional cone beam computed tomography (4D CBCT) in lung cancer patients, seeking to improve the accuracy of radiotherapy and to establish a uniform protocol for the application of 4D CBCT in radiotherapy for lung cancer. METHODS: 4D CBCT was applied to evaluate tumor volume response (TVR), motion, and center coordinates during radiotherapy in 67 eligible individuals with lung cancer diagnoses. The differences between 4D CBCT and 3D CBCT in different registration methods were compared. RESULTS: TVR was observed during treatment in 41% of patients (28/67), with a mean volume reduction of 41.7% and a median time to TVR of 19 days. Tumor motion was obvious in 16 patients, with a mean value of 0.52 cm (0.22 to 1.34 cm), and in 3 of 6 tumors close to the diaphragm (0.28 to 0.66 cm). Gray value registration based on mean density projection could still achieve close results to the 4D gray value registration. However, when the registration was based on bone alone, partial off-targeting occurred in the treatment in 41.8% of cases. The off-target rate was 19.0% when the tumor motion was ≤ 0.5 cm and 52.2% when the motion was > 0.5 cm. CONCLUSION: Tumor volume and motion of intrapulmonary lesions in individuals diagnosed with lung cancer varied significantly in the third week of radiotherapy. 4D CBCT may be more advantageous for isolated lesions without reference to relative anatomical structures or those near the diaphragm. Grayscale registration based on mean density projection is feasible.

Nano-emulsification essential oil of Monarda didyma L. to improve its preservation effect on postharvest blueberry.

The reduction in blueberry harvest due to pathogen infection was reported to reach 80%. Essential oil (EO) can provide a new way to preserve blueberry. Here, in search for plants volatiles with preservation ability, a novel device was designed for the screening of aromatic plants led to the discovery of hit plant Monarda didyma L. Consequently, antifungi activity of M. didyma EO (MEO) and its nano-emulsion (MNE) were tested. 2 species of pathogenic fungi were isolated from blueberries, namely Alternaria sp. and Colletotrichum sp. were used as the target strains. In the in vitro activity test, the pathogenic were completely inhibited when the EO was 4 µL or 1.0 µL/mL. Compared with EO, MNE exhibited superior antimicrobial activity. Moreover, MNE can cause serious morphological changes and result in a decrease in the rot and weightlessness rate of blueberry. Hence, NME represents a promising agent for the preservation of postharvest blueberry.

Silicate Ions Derived from Calcium Silicate Extract Decelerate Ang II-Induced Cardiac Remodeling.

BACKGROUND: Pathological cardiac hypertrophy is one of the main activators of heart failure. Currently, no drug can completely reverse or inhibit the development of pathological cardiac hypertrophy. To this end, we proposed a silicate ion therapy based on extract derived from calcium silicate (CS) bioceramics for the treatment of angiotensin II (Ang II) induced cardiac hypertrophy. METHODS: In this study, the Ang II induced cardiac hypertrophy mouse model was established, and the silicate ion extract was injected to mice intravenously. The cardiac function was evaluated by using a high-resolution Vevo 3100 small animal ultrasound imaging system. Wheat germ Agglutinin, Fluo4-AM staining and immunofluorescent staining was conducted to assess the cardiac hypertrophy, intracellular calcium and angiogenesis of heart tissue, respectively. RESULTS: The in vitro results showed that silicate ions could inhibit the cell size of cardiomyocytes, reduce cardiac hypertrophic gene expression, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ß-myosin heavy chain (ß-MHC), decrease the content of intracellular calcium induced by Ang II. In vivo experiments in mice confirmed that intravenous injection of silicate ions could remarkably inhibit the cardiac hypertrophy and promote the formation of capillaries, further alleviating Ang II-induced cardiac function disorder. CONCLUSION: This study demonstrated that the released silicate ions from CS possessed potential value as a novel therapeutic strategy of pathological cardiac hypertrophy, which provided a new insight for clinical trials.

A tyrosine, histidine-selective bifunctional cross-linker for protein structure analysis.

Chemical cross-linking mass spectrometry (XL-MS) significantly contributes to the analysis of protein structures and the elucidation of protein-protein interactions. Currently available cross-linkers mainly target N-terminus, lysine, glutamate, aspartate, and cysteine residues in protein. Herein, a bifunctional cross-linker, named [4,4'-(disulfanediylbis(ethane-2,1-diyl)) bis(1-methyl-1,2,4-triazolidine-3,5-dione)] (DBMT) has been designed and characterized aiming to extremely expand the application of XL-MS approach. DBMT is capable of selectively targeting tyrosine residue in protein via an electrochemical click reaction, and/or targeting histidine residue in protein in the presence of 1O2 generated under photocatalytic reaction. A novel cross-linking strategy based on this cross-linker has been developed and demonstrated using model proteins, which provides a complementary XL-MS tool analyzing protein structure, protein complexes, protein-protein interactions, and even protein dynamics.

A Cascade Targeted and Mitochondrion-Dysfunctional Nanomedicine Capable of Overcoming Drug Resistance in Hepatocellular Carcinoma.

Chemoresistance is a formidable issue in clinical anticancer therapy and is pertinent to the lowered efficacies of chemotherapeutics and the activated tumor self-repairing proceedings. Herein, bifunctional amphiphiles containing galactose ligands and high-density disulfide are synthesized for encapsulating mitochondrion-targeting tetravalent platinum prodrugs to construct a cascade targeted and mitochondrion-dysfunctional nanomedicine (Gal-NP@TPt). Subsequent investigations verify that Gal-NP@TPt with sequential targeting functions toward tumors and mitochondria improved the spatiotemporal level of platinum. In addition, glutathione depletion by Gal-NP@TPt appear to substantially inhibit the proceedings of platinum detoxification, inducing the susceptibility to the mitochondrial platinum. Moreover, the strategic transportation of platinum to mitochondria lacking DNA repair machinery by Gal-NP@TPt lowers the possibility of platinum deactivation. Eventually, Gal-NP@TPt demonstrates appreciable antitumor effects for the systemic treatment of patient-derived tumor xenografts of hepatocellular carcinoma. Note that these strategies in overcoming drug resistance have also been confirmed to be valid based on genome-wide analysis via RNA-sequencing. Therefore, an intriguing multifunctional nanomedicine capable of resolving formidable chemoresistance is achieved, which should be greatly emphasized in practical applications for the treatment of intractable tumors.

The wild allotetraploid sesame genome provides novel insights into evolution and lignan biosynthesis.

INTRODUCTION: The wild tetraploid sesame (Sesamum schinzianum), an ancestral relative of diploid cultivated sesame, grows in the tropical desert of the African Plateau. As a valuable seed resource, wild sesame has several advantageous traits, such as strong environmental adaptability and an extremely high content of sesamolin in its seeds. High-quality genome assembly is essential for a detailed understanding of genome structure, genome evolution and crop improvement. OBJECTIVES: Here, we generated two high-quality chromosome-scale genomes from S. schinzianum and a cultivated diploid elite sesame (Sesamum indicum L.) to investigate the potential genetic basis underlying these traits of wild sesame. METHODS: The long-read data from PacBio Sequel II platform and high-throughput chromosome conformation capture (Hi-C) data were used to construct high-quality sesame genome. Then dissecting the molecular mechanisms of sesame evolution and lignan biosynthesis through comparative genomics and transcriptomics. RESULTS: We found evidence of divergent evolution that involved differences in the number, sequence and expression level of homologous genes between the two sets of subgenomes from allotetraploids in S. schinzianum, all of which might be driven by subfunctionalization after polyploidization. Furthermore, it was found that a great number of genes involved in the stress response have undergone positive selection and resulted from gene family expansion in the wild sesame genome compared with the cultivated sesame genome, which, overall, is associated with adaptative evolution to the environment. We hypothesized that the sole functional member CYP92B14 (SscC22g35272) could be associated with high content of sesamolin in wild sesame seeds. CONCLUSION: This study provides high-quality wild allotetraploid sesame and cultivated sesame genomes, reveals evolutionary features of the allotetraploid genome and provides novel insights into lignan synthesis pathways. Meanwhile, the wild sesame genome will be an important resource to conduct comparative genomic and evolutionary studies and plant improvement programmes.

Effect of a strong CYP3A4 inhibitor and inducer on the pharmacokinetics of senaparib (IMP4297) in healthy volunteers: A drug-drug interaction study.

AIMS: A phase I open-label study assessed the effect of multiple oral doses of a potent CYP3A4 inhibitor (itraconazole) and inducer (rifampicin) on the pharmacokinetic profile of a single oral dose of senaparib, a novel, highly potent poly-(ADP-ribose) polymerase 1/2 inhibitor and CYP3A4 substrate, in Chinese healthy male volunteers (HMV). METHODS: Adult HMV were enrolled to the itraconazole or rifampicin group (n = 16 each). In Period 1, all participants received a single oral dose of senaparib 40 mg (itraconazole group) or 100 mg (rifampicin group). In Period 2, the same dose was coadministered with itraconazole (200 mg) and rifampicin (600 mg), respectively. The primary endpoints were senaparib exposure parameters. RESULTS: Coadministration with itraconazole significantly increased exposure of senaparib and decreased that of its major metabolites M9 and M14. Maximum plasma senaparib concentration (Cmax ) was increased by ~79% and area under the concentration-time curve (AUC) increased by ~2.8-fold. Coadministration with rifampicin significantly reduced the Cmax and AUC of senaparib by ~59 and 83%, respectively. The Cmax for both M9 and M14 was slightly increased, although AUC was decreased. All treatment-emergent adverse events were grade ≤2, regardless of the treatment administered. CONCLUSION: In Chinese HMV, the exposure of senaparib was significantly increased when coadministered with itraconazole and significantly decreased when coadministered with rifampicin. It is recommended to avoid concomitant use of senaparib and strong inhibitors or inducers of CYP3A4.

Investigation of the pharmacological effect and mechanism of mountain-cultivated ginseng and garden ginseng in cardiovascular diseases based on network pharmacology and zebrafish experiments.

Ginseng (Panax ginseng C.A. Mey) is a kind of perennial herb of the Panax genus in the Araliaceae family. The secondary metabolites of mountain-cultivated ginseng (MCG) and garden ginseng (GG) vary greatly due to their different growth environments. To date, the differences in their pharmacological effects on cardiovascular diseases (CVDs) and their clinical applications remain unclear. To distinguish between the components of MCG and GG, ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was performed. Next, the relationship between the expression of metabolites and the categories of the sample were analyzed using supervised partial least squares discriminant analysis and orthogonal partial least squares discriminant analysis. A network-based pharmacology approach was developed and applied to determine the underlying mechanism of different metabolites in CVD. In the present study, the role of MCG and GG in angiogenesis and their protective effects on damaged blood vessels in a vascular injury model of zebrafish were investigated. Using UPLC-Q-TOF/MS, 11 different metabolites between MCG and GG were identified. In addition, 149 common target genes associated with the metabolites and CVD were obtained; these targets were related to tumor protein P53, proto-oncogene tyrosine-protein kinase Src, human ubiquitin-52 amino acid fusion protein, ubiquitin-40S ribosomal protein S27a, polyubiquitin B, signal transducer and activator of transcription 3, isocitrate dehydrogenase 1, vascular endothelial growth factor A, glycose synthase kinase-3B, and coagulation factor II and were associated with the regulation of the phosphoinositide 3-kinase-Akt signaling pathway, the tumor necrosis factor signaling pathway, and the hypoxia-inducible factor-1 (HIF-1) signaling pathway, which play important roles in the curative effect in CVD treatment. Both types of ginseng can promote the growth of the subintestinal vessel plexus and protect injured intersegmental vessels through the HIF-1α/vascular endothelial growth factor signaling pathway in a dose-dependent manner. In addition, MCG has a stronger impact than GG. This is the first time metabolomics and network pharmacology methods were combined to study the difference between MCG and GG on CVDs, which provides a significant theoretical basis for the clinical treatment of CVD with two kinds of ginseng.

A mHealth-based nursing model for assessing the health outcomes of the discharged patients with nasopharyngeal carcinoma: a pilot RCT.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies, having a high incidence in Guangxi, China. Although chemoradiotherapy offers more effective cancer treatment, it also causes a variety of acute and chronic side effects, seriously affecting the quality of life. NPC has evolved into a chronic disease with most patients opting for home-based rehabilitation. Therefore, efforts on improving the home-based extended care services to improve the quality of life of patients are booming. The Chinese government encourages the use of internet technology for expanding the prospect of nursing. This study aimed to evaluate the impact of a mHealth-based care model on the health outcomes of discharged patients with nasopharyngeal carcinoma. METHODS: An experimental design was applied for this study. The study enrolled 116 discharged patients who were re-examined in the Radiotherapy Department of the First Affiliated Hospital of Guangxi Medical University from November 2019 to February 2020. These patients were randomized into control and intervention groups (n = 58 per group), but during the implementation of the project, there was one dropout in the control group due to the loss of follow-up, and one dropout in the intervention group due to distant metastasis. In the end, 57 patients in the control and intervention groups completed the trial. The control group was subjected to routine discharge guidance and follow-up, while the experimental group was implemented with a mobile health (mHealth)-based continuous nursing intervention model. The scores of the side effects, cancer fatigue, and quality of life were compared between the two groups of patients for 3, 6, and 12 months, respectively after discharge from the hospital. RESULTS: This study included 114 patients and there were no significant differences in the baseline data between the two groups. After 6 and 12 months of intervention, the severity of radiation toxicity and side effects, the scores of cancer-related fatigue, and quality of life (symptom field) of the patients in the interventional group were significantly lowered statistically compared to those in the control group. CONCLUSION: This study is based on the mHealth continuous nursing intervention model, which can reduce the side effects of radiotherapy and cancer fatigue, and improve the quality of life. TRIAL REGISTRATION: This study was retrospectively registered as a randomized controlled trial in the Chinese Clinical Trial Center. Registration Date: January 12, 2021, Registration Number: ChiCTR2100042027.

Difference of body surface temperature in stable chronic obstructive pulmonary disease patients with different degree of airflow limitation.

BACKGROUND: This study aimed to investigate the changes of body surface temperature of stable chronic obstructive pulmonary disease (COPD) patients and explore its clinical significance for the progression of COPD. OBJECTIVES: The aim of this study was to explore the correlation between body surface temperature and disease severity in COPD patients. METHODS: From May 2015 to May 2016, the patients who were diagnosed as COPD at stable phase (n = 148) were enrolled in this study. The subjects in control group (n = 49) were healthy people. The patients' general condition modified Medical Research Council (mMRC) dyspnea scale and the COPD assessment test (CAT) score were recorded, and pulmonary function of patients was determined. Back average temperature measurement was made using a thermal infrared imager (DT-9875, CEM, China). RESULTS: Patients in the COPD group had significantly lower mean temperatures of the back than those in the control group. The mean temperature of the back presented a decreased tendency with the aggravation of airflow limitation. Correlation analysis revealed that in the COPD group, the back temperature was negatively correlated with smoking index and mMRC score. FEV1%, FVC% and FEV1/FVC were positively correlated with pulmonary function. Smoking showed a tendency to lower the back temperature of COPD patients. CONCLUSIONS: This study preliminarily suggested that the body surface temperature of COPD patients decreased compared with that of healthy people, which may be associated with the dysfunction of autonomic nerve, increased basal metabolic rate, metabolic syndrome and peripheral nerve injury in COPD patients.

Bioactive Monomer and Polymer Polyketides from Edible Mushroom Cortinarius caerulescens as Glutamate Dehydrogenase Inhibitors and Antioxidants.

Two new polyketides named rufoolivacin E and viocristin B, a new natural product named 1-hydroxy-3,6,8-trimethoxyanthraquinone, and 13 known compounds were isolated from edible mushroom Cortinarius purpurascens in this work. Their structures were assigned on the basis of high-resolution electrospray ionization mass spectrometry, 1D and 2D nuclear magnetic resonance, and electronic circular dichroism data. Notably, the enzyme activity test on glutamate dehydrogenase indicated that 1, 3, 4, 5, 6, 10, 11, and 15 displayed an excellent inhibition effect. Further kinetic studies showed that the most potent compounds, 4 and 10, possess great potential as competitive inhibitors of glutamate dehydrogenase. Molecular docking and computational chemistry were applied to illustrate the binding mechanism in detail. 2,2-Diphenyl-1-picrylhydrazyl and reactive oxygen species assay results showed that compounds 1, 2, 3, and 8 exhibited significant antioxidant activities with IC50 values of 7.0 ± 0.3, 8.6 ± 0.1, 7.5 ± 0.1, and 2.8 ± 0.2 µg mL-1, respectively. Thus, Cortinarius caerulescens represents a novel resource of these polyketides to be utilized in food selection and drug discovery.

The significance of the neuregulin-1/ErbB signaling pathway and its effect on Sox10 expression in the development of terminally differentiated Schwann cells in vitro.

PURPOSE: The purpose of this study was to explore the significance of the neuregulin-1/ErbB signaling pathway and its effect on Sox10 expression in the course of the differentiation of mouse bone marrow mesenchymal stem cells into Schwann-like cells in vitro. MATERIALS AND METHODS: The experiment was conducted with three groups-control, TAK 165, and HRG-off. In the control group, we used the classical induction method of adding ß-ME, RA, FSK, b-FGF, PDGF, and neuregulin (HRG); the cells were collected on the 7th day. Using the same basic protocol as the control group, the specific ErbB2 inhibitor mubritinib (TAK 165) was added to block the neuregulin-1/ErbB pathway in the TAK 165 group, while HRG was not added in the HRG-off group. We detected the degree of differentiation of stem cells into Schwann-like cells by using RT-PCR to examine the expression of Sox10, NRG-1, ErbB2, ErbB3, and ErbB4 and by using immunofluorescence staining to examine the Schwann cell marker S100B, Glial Fibrillary Acidic Protein (GFAP) and P75. RESULTS: Our results showed that the proliferation of Schwann cells was reduced and apoptosis was increased in the TAK 165 group and the HRG-off group. Sox10 was stably expressed and NRG-1, ErbB2, and ErbB3 increased in the control group. However, the expression of Sox10 in the TAK 165 group was obviously decreased at the end of induced differentiation; meanwhile, the degree of stem cell differentiation also decreased. CONCLUSIONS: the neuregulin-1/ErbB signaling pathway plays an important role in the differentiation of bone marrow mesenchymal stem cells into Schwann-like cells and can promote the maintenance of Sox10 。.

CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. METHODS: Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer. RESULTS: We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. CONCLUSIONS: Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche.