Adult ovarian and sellar region mixed germ cell tumor: a case report and literature review.

Mixed germ cell tumors (mGCTs) involving both the ovaries and sellar region have been rarely reported; thus, they pose significant challenges in clinical management. Our report of a case of a 26-year-old female with left ovarian mGCTs (dysgerminoma + yolk sac tumor) who presented with postoperative headaches and blurred vision contributes new information to the literature on treating mGCTs, which can lead to standardized regimens and sequencing guidelines. A physical examination revealed right temporal hemianopia, and elevated levels of alpha-fetoprotein were detected in serum and cerebrospinal fluid. Magnetic resonance imaging (MRI) of the sellar region revealed a space-occupying lesion. Pathological examination of the tumor after endoscopic transnasal resection confirmed the diagnosis of mGCTs (germinomas + yolk sac tumor). The patient received adjuvant chemotherapy and radiotherapy at reduced dosages. During follow-up, tumor markers remained within normal limits, and there was no evidence of tumor recurrence on sellar region MRI. This case highlights the rarity of the simultaneous occurrence of ovarian and sellar region mGCTs and emphasizes the importance of accurate diagnosis and multidisciplinary management.

Tracheal replacement with aortic grafts: Bench to clinical practice.

Tracheal reconstruction following extensive resection for malignant or benign lesions remains a major challenge in thoracic surgery. Numerous studies have attempted to identify the optimal tracheal replacement with different biological or prosthetic materials, such as various homologous and autologous tissues, with no encouraging outcomes. Recently, a few clinical studies reported attaining favorable outcomes using in vitro or stem cell-based airway engineering and also with tracheal allograft implantation following heterotopic revascularization. However, none of the relevant studies offered a standardized technology for airway replacement. In 1997, a novel approach to airway reconstruction was proposed, which involved using aortic grafts as the biological matrix. Studies on animal models reported achieving in-vivo cartilage and epithelial regeneration using this approach. These encouraging results inspired the subsequent application of cryopreserved aortic allografts in humans for the first time. Cryopreserved aortic allografts offered further advantages, such as easy availability in tissue banks and no requirement for immunosuppressive treatments. Currently, stented aortic matrix-based airway replacement has emerged as a standard approach, and its effectiveness was also verified in the recently reported TRITON-01 study. In this context, the present review aims to summarize the current status of the application of aortic grafts in tracheal replacement, including the latest advancements in experimental and clinical practice.

The role of PKN1 in glioma pathogenesis and the antiglioma effect of raloxifene targeting PKN1.

PKN1 (protein kinase N1), a serine/threonine protein kinase family member, is associated with various cancers. However, the role of PKN1 in gliomas has rarely been studied. We suggest that PKN1 expression in glioma specimens is considerably upregulated and positively correlates with the histopathological grading of gliomas. Knocking down PKN1 expression in glioblastoma (GBM) cells inhibits GBM cell proliferation, invasion and migration and promotes apoptosis. In addition, yes-associated protein (YAP) expression, an essential effector of the Hippo pathway contributing to the oncogenic role of gliomagenesis, was also downregulated. In contrast, PKN1 upregulation enhances the malignant characteristics of GBM cells and simultaneously upregulates YAP expression. Therefore, PKN1 is a promising therapeutic target for gliomas. Raloxifene (Ralo), a commonly used selective oestrogen-receptor modulator to treat osteoporosis in postmenopausal women, was predicted to target PKN1 according to the bioinformatics team from the School of Mathematics, Tianjin Nankai University. We showed that Ralo effectively targets PKN1, inhibits GBM cells proliferation and migration and sensitizes GBM cells to the major chemotherapeutic drug, Temozolomide. Ralo also reverses the effect of PKN1 on YAP activation. Thus, we confirm that PKN1 contributes to the pathogenesis of gliomas and may be a potential target for Ralo adjuvant glioma therapy.

Hyperhubeins A-I, Bioactive Sesquiterpenes with Diverse Skeletons from Hypericum hubeiense.

Nine new sesquiterpenes, hyperhubeins A-I (1-9), and 14 known analogues (10-23) were isolated from the aerial portions of Hypericum hubeiense. Their structures and absolute configurations were determined unambiguously via spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1-3 possess an unprecedented sesquiterpene carbon skeleton. Further, a plausible biosynthetic pathway from farnesyl diphosphate (FPP) is proposed. The isolated phytochemicals were evaluated for neuroprotective and anti-neuroinflammatory properties in vitro. Compounds 1, 2, 5-8, 14, and 21 displayed notable neuroprotective activity against hydrogen peroxide (H2O2)-induced lesions in PC-12 cells at 10 µM. Additionally, compounds 1, 2, 12, and 13 exhibited inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV-2 microglial cells, with their IC50 values ranging from 4.92 to 6.81 µM. Possible interactions between these bioactive compounds and inducible nitric oxide synthase (iNOS) were predicted via molecular docking. Moreover, Western blotting indicated that compound 12 exerted anti-neuroinflammatory activity by suppressing LPS-stimulated expression of toll-like receptor-4 (TLR-4) and inhibiting consequent activation of nuclear factor-kappa-B (NF-κB) signaling.

Bioassay-guided separation and identification of the anticancer composition from Curcuma longa L. by the combination strategy of methanol gradient countercurrent chromatography and ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry.

In this study, a combined strategy with methanol gradient countercurrent chromatography and ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry was introduced for the fractionation and identification of active constituents from Curcuma longa L. The gradient countercurrent chromatography separation was performed using the heptane-ethyl acetate-methanol-water (5:5:2:8, v/v) solvent system, in which the lower phase and methanol were used as the mobile phases. Constituents of turmeric with large partition coefficients were well resolved. Subsequent cytotoxicity analysis showed that the fractions 10, 11, 12, and 15 expressed significantly higher cytotoxicity against B16 mouse melanoma than the other fractions. Four compounds with potent activity, curcumin, demethoxycurcumin, and bisdemethoxycurcumin from fraction 11 and galanal A from fraction 15, were purified, and the half-maximal inhibitory concentrations were 18.5 ± 1.3, 7.8 ± 0.4, 20.4 ± 1.3, and 14.1 ± 0.8 µM, respectively. Ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry was then applied for compound identification from fraction 10 with constituents in very low content. A total of 14 diarylheptanoids were identified, which are supposed to be cytotoxic constituents. It proved that the strategy based on the combination of bioassay-guided methanol gradient countercurrent chromatography separation and ultra-high-performance liquid chromatography coupled with tandem mass spectrometry-assisted peak identification could be an efficient method for natural product screening and new drug discovery.

miR-19a/b promote EMT and proliferation in glioma cells via SEPT7-AKT-NF-κB pathway.

miR-19a/b belong to the miR-17-92 family. We have demonstrated previously that miR-19a/b are overexpressed in glioma and glioma cell lines. However, the role of miR-19a/b in glioma remains unclear. In the present study, we aim to identify the biological function and molecular mechanism of miR-19a/b in glioma cell proliferation and epithelial-mesenchymal transition (EMT). Knocking down miR-19a/b in LN308 glioblastoma (GBM) cells with higher expression of miR-19a/b inhibits cell proliferation and invasion, induces apoptosis, and suppresses EMT by downregulating the expression of Akt, phosphorylated p-Akt, nuclear factor κB (NF-κB), Snail, N-cadherin, and Vimentin and upregulating E-cadherin in vitro and in vivo. Enhanced proliferation and EMT are also observed when miR-19a/b are transfected into SNB19 GBM cells, with lowered expression of miR-19a/b. miR-19a is more effective than miR-19b in the regulation of biological behavior of glioma cells. miR-19a/b modulate molecular events for the promotion of EMT via the Akt-NF-κB pathway. SEPT7 has been confirmed as the target gene of miR-19a/b. The effect of miR-19a/b on proliferation and EMT of glioma cells and the Akt-NF-κB pathway could be reversed by transfection with SEPT7. Our study strongly suggests that miR-19a/b play a significant role in glioma progression and EMT through regulating target gene-SEPT7 and the SEPT7-Akt-NF-κB pathway.

Cytotoxic Diterpenoids from Euphorbia fischeriana.

Five new diterpenoids, named euphorfischerins A-E, were isolated from the roots of Euphorbia fischeriana. Their chemical structures and absolute configurations were determined by interpretation of NMR, HR-ESI-MS, ECD and X-ray diffraction data. Euphorfischerin A showed cytotoxicity against the human cancer cell lines HeLa, H460 and Namalwa with IC50 values of 4.6, 11.5 and 16.4 µM, respectively, while euphorfischerin B gave comparable IC50 values of 9.5, 17.4 and 13.3 µM against the three cancer cell lines, respectively.

Red Blood Cell Distribution Width Predicts Postoperative Death of Infective Endocarditis.

Infectious endocarditis (IE) is a rare disease with high mortality rate. Recently, red cell distribution width (RDW) has drawn special attention for predicting cardiovascular disease. This study aims to explore the relationship between RDW value and postoperative death of IE patients.Clinical records of patients with definite IE from Chinese People's Liberation Army General Hospital department of cardiovascular surgery were collected and analyzed. Clinical, echocardiographic, and biochemical variables were evaluated along with RDW.Results: A total of 158 consecutive IE patients (mean age 47.0 ± 16.3 years, male 61.4%) were enrolled in this study. According to receiver operating characteristic (ROC) curve analysis, the optimal RDW cutoff value for predicting mortality was 15.45% (area under the curve 0.913, P < 0.001). A total of 28 patients (17.8%) died postoperatively; of these, 89.3% had RDW value >15.45%. Binary regression analysis showed that aging, multiple valvular involved, valvular vegetation formation, pulmonary hypertension, and high RDW are strong predictors of postoperative death. Multiple regression analysis revealed that high RDW value was independent predictors of postoperative mortality in patients with IE (ß: 3.704, 95% confidence interval (95%CI): 2.729-604.692, P < 0.05).IE has a high inhospital mortality rate, and increased RDW is an independent predictor of postoperative death in these patients.

Meroterpene-Like α-Glucosidase Inhibitors Based on Biomimetic Reactions Starting from ß-Caryophyllene.

BACKGROUND: Natural meroterpenes derived from phloroglucinols and ß-caryophyllene have shown high inhibitory activity against α-glucosidase or cancer cells, however, the chemical diversity of this type of skeletons in Nature is limited. METHODS: To expand the chemical space and explore their inhibitory activities against α-glucosidase (EC 3.2.1.20), we employed ß-caryophyllene and some natural moieties (4-hydroxycoumarins, lawsone or syncarpic acid) to synthesize new types of meroterpene-like skeletons. All the products (including side products) were isolated and characterized by NMR, HR-MS, and ECD. RESULTS: In total, 17 products (representing seven scaffolds) were generated through a one-pot procedure. Most products (12 compounds) showed more potential activity (IC50 < 25 µM) than the positive controls (acarbose and genistein, IC50 58.19, and 54.74 µM, respectively). Compound 7 exhibited the most potent inhibition of α-glucosidase (IC50 3.56 µM) in a mixed-type manner. The CD analysis indicated that compound 7 could bind to α-glucosidase and influence the enzyme's secondary structure. CONCLUSIONS: Compound 7 could serve as a new type of template compound to develop α-glucosidase inhibitors. Full investigation of a biomimic reaction can be used as a concise strategy to explore diverse natural-like skeletons and search for novel lead compounds.

Structure-antifungal relationships and preventive effects of 1-(2,4-dihydroxyphenyl)-2-methylpropan-1-one derivatives as potential inhibitors of class-II fructose-1,6-bisphosphate aldolase.

Emerging fungal phytodiseases are a food security threat and novel fungicides are in an urgent need. Herein, a series of isobutyrophenone derivatives were designed and synthesized. The derivatives exhibited excellent fungicidal activities against seven fungi. The structure-activity relationship (SAR) study indicated that the introduction of a bromo group at the position 3 or 5 of the phenyl ring, as well as esterification of the 4-hydroxy with a chloroacetyl group, could substantially increase the antifungal activity and spectrum of the compounds. Among all 23 compounds, 2-bromo-3-hydroxy-4-isobutyryl-6-methylphenyl 2-chloroacetate (12b) showed the highest fungicidal activity against all seven tested fungal pathogens with EC50 values ranging from 1.22 to 39.94 µg/mL and exhibited the most potent inhibition against class II fructose-1,6-bisphosphate aldolase with an IC50 of 3.63 µM. The lead compounds were proven to be safe to NIH3T3/293 T cells and silkworm larvae, and relatively stable under different harsh conditions. Detached fruit tests showed the practical potential of lead compounds for fruit (or plant) protection. Taken together, our results indicated that the isobutyrophenone derivatives could be further optimized and developed as advanced leads for new fungicides.

PLK4 is a determinant of temozolomide sensitivity through phosphorylation of IKBKE in glioblastoma.

Despite the clinical success of temozolomide (TMZ), its sensitivity remains a major challenge in glioblastoma (GBM). Here, we show that PLK4 affects TMZ sensitivity by regulating the IKBKE/NF-κB axis. The mRNA level of PLK4 was significantly associated with glioma grade progression and inversely correlated with overall survival (OS) in patients with high-grade gliomas (HGG). Further analyses indicated that GBM patients with low PLK4 expression levels gained greater survival benefits from chemotherapy than did those with high PLK4 expression. In GBM cells, TMZ sensitivity was decreased by ectopic expression of PLK4 and enhanced by depletion of PLK4. In the GBM mice model, inhibiting PLK4 in combination with chemotherapy slowed tumor growth and provided a significant survival benefit. Furthermore, PLK4 interacted with and phosphorylated IKBKE, leading to an increase in NF-κB transcriptional activity and anti-apoptosis. Notably, the PLK4 inhibitor CFI400945, which is currently in clinical trials, had a synergistic effect with TMZ, increasing TMZ sensitivity in xenografts from patient-derived primary GBMs. Our work describes the PLK4-IKBKE signaling axis that influences GBM proliferation and chemosensitivity, and can enhance the anti-tumor effects of chemotherapy via therapeutic targeting.

Copper-catalyzed diastereoselective synthesis of ß-boryl-α-quaternary carbon carboxylic esters.

Cu(i)-Catalyzed diastereoselective carboboration of α-alkyl-substituted α,ß-unsaturated carboxylic esters to produce ß-boryl-α-quaternary carbon esters was developed. The carbon skeletons of dialkyl sulfates, primary allyl halides, and benzyl bromides were transferred to the α-position of the substrates to provide products in moderate to good yields with a diastereoselectivity of >95% in most cases. Substrates bearing a ß-(hetero)aryl substituent gave higher diastereoselectivities than those bearing a linear ß-alkyl substituent. The crystal structure of the potassium trifluoroborate derivative shows that the reactions probably go through a copper(i) enolate intermediate and the diastereoselectivity arises from the electrophilic attack of electrophiles to the less hindered side of the enolates.

Synthesis, Antifungal Activities and Molecular Docking Studies of Benzoxazole and Benzothiazole Derivatives.

Based on benzoxazole and benzothiazole scaffold as an important pharmacophore, two series of 2-(aryloxymethyl) benzoxazole and benzothiazole derivatives were synthesized and their antifungal effects against eight phytopathogenic fungi were evaluated. Compounds 5a, 5b, 5h, and 5i exhibited significant antifungal activities against most of the pathogens tested. Especially 5a, 5b, 5h, 5i, 5j, and 6h inhibited the growth of F. solani with IC50 of 4.34⁻17.61 µg/mL, which were stronger than that of the positive control, hymexazol (IC50 of 38.92 µg/mL). 5h was the most potent inhibitor (IC50 of 4.34 µg/mL) against F. Solani, which was about nine times more potent than hymexazol. Most of the test compounds displayed significant antifungal effects against B. cinerea (IC50 of 19.92⁻77.41 µg/mL), among them, 5a was the best one (IC50 of 19.92 µg/mL). The structure-activity relationships (SARs) were compared and analyzed. The result indicates that the electron-drawing ability and position of the substituents have a significant impact on biological activities. Furthermore, docking studies were carried out on the lipid transfer protein sec14p from S. cerevisiae, and preliminarily verified the antifungal activities. Taken together, these results provide 2-(phenoxymethyl)benzo[d]oxazole as an encouraging framework that could lead to the development of potent novel antifungal agents.

The emerging role of miR-19 in glioma.

Glioma has been regarded as the most common, highly proliferative and invasive brain tumour. Advances in research of miRNAs in glioma are toward further understanding of the pathogenesis of glioma. MiR-19, a member of miR-17~92 cluster, was reported to play an oncogenic role in tumourigenesis. Here we review the identified data about the effect of miR-19 on proliferation, apoptosis, migration and invasion of glioma cells, the target genes regulated by miR-19, and correlation of miR-19 with the sensitivity of glioma cells to chemotherapy and radiotherapy. It is concluded that miR-19 plays an important role in the pathogenesis of glioma and can be a potential target for gene therapy of glioma.

Natural products as sources of new fungicides (V): Design and synthesis of acetophenone derivatives against phytopathogenic fungi in vitro and in vivo.

A series of acetophenone derivatives (10a-10i, 11, 12a-12g, 13a-13g, 14a-14d and 15a-15l) were designed, synthesized and evaluated for antifungal activities in vitro and in vivo. The antifungal activities of 53 compounds were tested against several plant pathogens, and their structure-activity relationship was summarized. Compounds 10a-10f displayed better antifungal effects than two reference fungicides. Interestingly, the most potent compound 10d exhibited antifungal properties against Cytospora sp., Botrytis cinerea, Magnaporthe grisea, with IC50 values of 6.0-22.6 µg/mL, especially Cytospora sp. (IC50 = 6.0 µg/mL). In the in vivo antifungal assays, 10d displayed the significant protective efficacy of 55.3% to Botrytis cinerea and 73.1% to Cytospora sp. The findings indicated that 10d may act as a potential pesticide lead compound that merits further investigation.

RUNX3 inhibits glioma survival and invasion via suppression of the ß-catenin/TCF-4 signaling pathway.

INTRODUCTION: Runt-related transcription factor 3 (RUNX3) exerts a tumor suppressor gene associated with gastric and other cancers, including glioma. However, how its anti-tumor mechanism in functions glioma is unclear. METHODS: We assayed expression of RUNX3 with a tissue microarray (TMA), frozen cancer tissues and malignant glioma cell lines using immunohistochemistry, qRT-PCR and Western bolt analysis. Cell proliferation, invasion, cell cycle distribution and apoptosis were also examined to confirm the effect of RUNX3 medicated malignant phenotype. TOP/FOP experiment was used to detect the ß-catenin/Tcf-4 transcription activity by RUNX3. RESULTS: Enforced RUNX3 expression inhibited proliferation and invasion, induced cell cycle arrest and promoted apoptosis in vitro and in vivo, Bim siRNA partically reversed the effect of RUNX3-induced apoptosis in LN229 and U87 cells, suggesting a dependent role of Bim-caspase pathway. Moreover, Mechanism investigations revealed that restoration of RUNX3 suppressed ß-catenin/Tcf-4 transcription activity. CONCLUSIONS: RUNX3 plays a pivotal role in glioma initiation and progression as a tumor suppressor via attenuation of Wnt signaling, highlighting it as a potential therapeutic target for glioma.

Effects of miR-200a and FH535 combined with taxol on proliferation and invasion of gastric cancer.

Gastric cancer is one of the most common cancers in the world; taxol displayed modest efficacy as first-line chemotherapy for gastric cancer, conversely, it has limitations used alone. ß-catenin is a multifunctional oncogenic protein and the elevation in expression and activity of ß-catenin has been implicated in many cancers. Therefore, we assume that the inhibition of ß-catenin can enhanced the efficacy of taxol. The purpose of this study was to investigate the inhibitory effect of miR-200a mimics, FH535 combined with taxol on proliferation and invasion of human gastric cancer cell lines SGC-7901 and BGC-823. In the current study, we identified that the combination of FH535 and miR-200a with taxol had potent growth-inhibitory and pro-apoptotic effects. Further, similar results were also observed in vivo, intratumoral injection of FH535, taxol and miR-200a mimics which also delayed tumor growth in nude mice harboring subcutaneous SGC-7901 xenografts. Collectively, miR-200a and FH535 can enhance the inhibitory effect of taxol on cell proliferation and moderate the invasion of human gastric cancer.

Natural products as sources of new fungicides (IV): Synthesis and biological evaluation of isobutyrophenone analogs as potential inhibitors of class-II fructose-1,6-bisphosphate aldolase.

Several recently identified antifungal compounds share the backbone structure of acetophenones. The aim of the present study was to develop new isobutyrophenone analogs as new antifungal agents. A series of new 2,4-dihydroxy-5-methyl isobutyrophenone derivatives were prepared and characterized by 1H, 13C NMR and MS spectroscopic data. These products were evaluated for in vitro antifungal activities against seven plant fungal pathogens by the mycelial growth inhibitory rate assay. Compounds 3, 4a, 5a, 5b, 5e, 5f and 5g showed a broad-spectrum high antifungal activity. On the other hand, for the first time, these compounds were also assayed as potential inhibitors against Class II fructose-1,6-bisphosphate aldolase (Fba) from the rice blast fungus, Magnaporthe grisea. Compounds 5e and 5g were found to exhibit the inhibition constants (Ki) for 15.12 and 14.27 µM, respectively, as the strongest competitive inhibitors against Fba activity. The possible binding-modes of compounds 5e and 5g were further analyzed by molecular docking algorithms. The results strongly suggested that compound 5g could be a promising lead for the discovery of new fungicides via targeting Class II Fba.

Structural Diversity and Biological Activity of the Genus Pieris Terpenoids.

Secondary metabolites, particularly the grayanane diterpenoids produced by the members of genus Pieris, have been investigated in past decades for their remarkable antifeedant and insecticidal activities and toxicity. Grayanoids exhibit diverse biological properties such as antifeedant, insecticidal, cAMP regulatory, and sodium-channel-modulating activities. Structural complexity and diverse bioactivity of grayanoids have made them attractive targets for chemical, biological, and synthetic purposes. The current review synthesized findings published from 1966 to 2017, which include 135 reports that describe 130 terpenoids, including 103 grayanoids. The distribution, structure, skeleton, as well as the antifeedant and insecticidal activity of terpenoids, particularly the grayanane diterpenoids, are discussed in detail in this review. In cases where sufficient information is available, the structure-activity relationships of their antifeedant activity are also presented. We hope that this contribution will prompt more scientists to pay attention to these diterpenoids, which may be potentially applied in the agricultural field.