Chloroxine inhibits pancreatic cancer progression through targeted antagonization of the PI3K/AKT/mTOR signaling pathway / La cloroxina inhibe la progresión del cáncer de páncreas mediante la antagonización dirigida de la vía de señalización PI3K/AKT/mTOR

Background: Patients with pancreatic cancer have a dismal prognosis due to tumor cell infiltration and metastasis. Many reports have documented that EMT and PI3K–AKT–mTOR axis control pancreatic cancer cell infiltration and metastasis. Chloroxine is an artificially synthesized antibacterial compound that demonstrated anti-pancreatic cancer effects in our previous drug-screening trial. We have explored the impact of chloroxine on pancreatic cancer growth, infiltration, migration, and apoptosis. Methods: The proliferation of pancreatic cancer cell lines (PCCs) treated with chloroxine was assessed through real-time cell analysis (RTCA), colony formation assay, CCK-8 assay, as well as immunofluorescence. Chloroxine effects on the infiltrative and migratory capacities of PCCs were assessed via Transwell invasion and scratch experiments. To assess the contents of EMT- and apoptosis-associated proteins in tumor cells, we adopted Western immunoblotting as well as immunofluorescence assays, and flow cytometry to determine chloroxine effects on PCCs apoptosis. The in vivo chloroxine antineoplastic effects were explored in nude mice xenografts. Results: Chloroxine repressed pancreatic cancer cell growth, migration, and infiltration in vitro, as well as in vivo, and stimulated apoptosis of the PCCs. Chloroxine appeared to inhibit PCC growth by Ki67 downregulation; this targeted and inhibited aberrant stimulation of the PI3K–AKT–mTOR signaling cascade, triggered apoptosis in PCC via mitochondria-dependent apoptosis, and modulated the EMT to inhibit PCC infiltration and migration. Conclusions: Chloroxine targeted and inhibited the PI3K–AKT–mTOR cascade to repress PCCs growth, migration, as well as invasion, and triggered cellular apoptosis. Therefore, chloroxine may constitute a potential antineoplastic drug for the treatment of pancreatic cancer.(AU)

Traditional Chinese medicine bufalin inhibits infectious hematopoietic necrosis virus infection in vitro and in vivo.

Infectious hematopoietic necrosis virus (IHNV) causes infectious hematopoietic necrosis and severe economic losses to salmon and trout aquaculture worldwide. Currently, the only commercial vaccine against IHNV is a DNA vaccine with some biosafety concerns. Hence, more effective vaccines and antiviral drugs are needed to prevent IHNV infection. In this study, 1,483 compounds were screened from a traditional Chinese medicine monomer library, and bufalin showed potential antiviral activity against IHNV. The 50% cytotoxic concentration of bufalin was >20 µM, and the 50% inhibitory concentration was 0.1223 µΜ against IHNV. Bufalin showed the inhibition of diverse IHNV strains in vitro, which confirmed that it had an inhibitory effect against all IHNV strains, rather than random activity against a single strain. The bufalin-mediated block of IHNV infection occurred at the viral attachment and RNA replication stages, but not internalization. Bufalin also inhibited IHNV infection in vivo and significantly increased the survival of rainbow trout compared with the mock drug-treated group, and this was confirmed by in vivo viral load monitoring. Our data showed that the anti-IHNV activity of bufalin was proportional to extracellular Na+ concentration and inversely proportional to extracellular K+ concentration, and bufalin may inhibit IHNV infection by targeting Na+/K+-ATPase. The in vitro and in vivo studies showed that bufalin significantly inhibited IHNV infection and may be a promising candidate drug against the disease in rainbow trout. IMPORTANCE: Infectious hematopoietic necrosis virus (IHNV) is the pathogen of infectious hematopoietic necrosis (IHN) which outbreak often causes huge economic losses and hampers the healthy development of salmon and trout farming. Currently, there is only one approved DNA vaccine for IHN worldwide, but it faces some biosafety problems. Hence, more effective vaccines and antiviral drugs are needed to prevent IHNV infection. In this study, we report that bufalin, a traditional Chinese medicine, shows potential antiviral activity against IHNV both in vitro and in vivo. The bufalin-mediated block of IHNV infection occurred at the viral attachment and RNA replication stages, but not internalization, and bufalin inhibited IHNV infection by targeting Na+/K+-ATPase. The in vitro and in vivo studies showed that bufalin significantly inhibited IHNV infection and may be a promising candidate drug against the disease in rainbow trout.

A new avialan theropod from an emerging Jurassic terrestrial fauna.

Birds are descended from non-avialan theropod dinosaurs of the Late Jurassic period, but the earliest phase of this evolutionary process remains unclear owing to the exceedingly sparse and spatio-temporally restricted fossil record1-5. Information about the early-diverging species along the avialan line is crucial to understand the evolution of the characteristic bird bauplan, and to reconcile phylogenetic controversies over the origin of birds3,4. Here we describe one of the stratigraphically youngest and geographically southernmost Jurassic avialans, Fujianvenator prodigiosus gen. et sp. nov., from the Tithonian age of China. This specimen exhibits an unusual set of morphological features that are shared with other stem avialans, troodontids and dromaeosaurids, showing the effects of evolutionary mosaicism in deep avialan phylogeny. F. prodigiosus is distinct from all other Mesozoic avialan and non-avialan theropods in having a particularly elongated hindlimb, suggestive of a terrestrial or wading lifestyle-in contrast with other early avialans, which exhibit morphological adaptations to arboreal or aerial environments. During our fieldwork in Zhenghe where F. prodigiosus was found, we discovered a diverse assemblage of vertebrates dominated by aquatic and semi-aquatic species, including teleosts, testudines and choristoderes. Using in situ radioisotopic dating and stratigraphic surveys, we were able to date the fossil-containing horizons in this locality-which we name the Zhenghe Fauna-to 148-150 million years ago. The diversity of the Zhenghe Fauna and its precise chronological framework will provide key insights into terrestrial ecosystems of the Late Jurassic.

Supplementation of Dietary Crude Lentinan Improves the Intestinal Microbiota and Immune Barrier in Rainbow Trout (Oncorhynchus mykiss) Infected by Infectious Hematopoietic Necrosis Virus.

The effects of crude lentinan (CLNT) on the intestinal microbiota and the immune barrier were evaluated in rainbow trout (Oncorhynchus mykiss) infected by infectious hematopoietic necrosis virus (IHNV). The results showed that supplementary CLNT declined the rainbow trout mortality caused by IHNV, which suggested that CLNT has preventive effects on IHNV infection. IHNV destroyed intestinal integrity, as well as caused the intestinal oxidative and damage in rainbow trout. Supplementary CLNT significantly strengthened the intestinal immune barrier by declining intestinal permeability, as well as enhancing intestinal antioxidant and anti-inflammatory abilities in IHNV-infected rainbow trout (P<0.05). In addition, CLNT modified the aberrant changes of intestinal microbiota induced by IHNV, mainly represented by promoting the growths of Carnobacterium and Deefgea and inhibiting Mycobacterium and Nannocystis. Especially, supplementing with CLNT significantly promoted the growth of short-chain fatty acid-producing bacteria (P<0.05) and consequently increased the production of acetic acid, butanoic acid, and hexanoic acid in the intestine of IHNV-infected rainbow trout. Furthermore, it was speculated that CLNT could regulate the self-serving metabolic pathways of intestinal microbiota induced by IHNV, such as fatty acid metabolism and amino acid metabolism. Together, CLNT played the antiviral effects on IHNV infection through strengthening the intestinal immune barrier, as well as regulating intestinal microbiota and SCFA metabolism in rainbow trout. The present data revealed that CLNT exerted a promising prebiotic role in preventing the rainbow trout from IHNV infection.

Etiological Diagnosis of Linear-Array Endoscopic Ultrasonography in Distal Common Bile Duct Dilatation.

ABSTRACT: The etiology of distal common bile duct (CBD) dilatation is complex. Linear-array endoscopic ultrasonography (EUS) can not only visualize the distal and surrounding structures of the bile duct closely but also obtain pathological specimens by fine-needle aspiration, which provides an important basis for the diagnosis and differential diagnosis. The purpose of this study was to evaluate the diagnostic value of linear-array EUS in the etiology of distal CBD dilatation. Patients with distal CBD dilatation underwent linear-array EUS in the endoscopic center of The Second Affiliated Hospital of Soochow University and Traditional Chinese Medicine Hospital of Kunshan were collected from January 2015 to June 2019. The pathology results after surgery, endoscopic pathology, computed tomography (CT), and magnetic resonance imaging (MRI) results were retrospectively analyzed. The diagnostic accuracy of linear-array EUS and CT or MRI was compared. For the diagnosis of choledocholithiasis, the diagnostic accuracy of linear-array EUS was 97.5%, which was significantly higher than that of MRI (86.36%) and CT (89.74) (P < 0.001 and 0.006, respectively). The diagnostic accuracy of linear-array EUS for periampullary tumors was 93.75%, which was higher than MRI and CT with an accuracy of 82.73% and 80.34% (P = 0.004 and 0.001, respectively). Linear EUS was effective for the etiological diagnosis of distal CBD dilatation.

Stratification of lung adenocarcinoma patients for d-limonene intervention based on the expression signature genes.

Globally, lung cancer ranks as the most lethal malignant neoplasm. d-Limonene, a plant extract enriched with essential oils, has been reported to exert anti-cancer effects both in vitro and in vivo; however, its clinical effect on humans remains elusive. Therefore, the present study aimed to investigate the gene expression signature that would potentially stratify lung adenocarcinoma (LUAD) patients who may benefit from d-limonene intervention, thus facilitating the development of newer treatment strategies for LUAD. In total, 1877 significant differentially expressed genes (DEGs) were identified. These genes were mainly associated with the metabolism of terpenoids and polyketides, lipid metabolism, endocrine system, carbohydrate metabolism, and cell growth and death pathways. Three genes, including antioncogenes FZD3 and MTURN, and oncogene PRC1, which were regulated by d-limonene were identified based on survival analysis of TCGA-LUAD data and were validated by both in vitro and in vivo experiments. High-risk patients screened by the model exhibited a significantly poor prognosis. In conclusion, three gene expression signatures (FZD3, MTURN, and PRC1) were validated by both in vitro and in vivo experiments and identified to help stratify candidate lung adenocarcinoma patients who may benefit from d-limonene intervention. Although further studies are warranted, this study highlighted a potential strategy to improve the treatment outcomes of LUAD patients.

Astragalus polysaccharides attenuate pulmonary fibrosis by inhibiting the epithelial-mesenchymal transition and NF-κB pathway activation.

Astragalus polysaccharides (APS), the active ingredients isolated from the plant Astragalus, have been reported to have numerous biological activities, including anti­inflammatory and antitumor activities. However, the effect of APS on pulmonary fibrosis (PF) remains unknown. The present study aimed to evaluate the protective effect of APS against PF and to explore its underlying mechanisms by using in vivo and in vitro models. A mouse in vivo model of bleomycin­induced PF and an in vitro model of transforming growth factor ß1 (TGF­ß1)­stimulated human lung epithelial A549 cells were established. Histopathologic examination and collagen deposition were investigated by hematoxylin and eosin staining and Masson staining, and by detecting the hydroxyproline content. The expression of related genes was analyzed by western blotting, reverse transcription­quantitative (RT­q) PCR, immunofluorescence and immunohistochemistry. The results from the in vivo mouse model demonstrated that treatment with APS could ameliorate collagen deposition and reduce fibrotic area and hydroxyproline content in the matrix. Furthermore, APS significantly inhibited the epithelial­mesenchymal transition (EMT), as evidenced by an increased level of E­cadherin and a decreased expression of vimentin and alpha smooth muscle actin. Furthermore, APS treatment significantly decreased TGF­ß1­induced EMT and NF­κB pathway activation in vitro. The results from the present study provided new insights on PF regression via the anti­fibrotic effects of APS.

[Effects of head down tilt on intra-ocular pressure, near vision, and visual field and the protection effect of Chinese herbs].

Objective. To observe the influences of 21 d head down tilt (HDT) bed rest on the intra-ocular pressure, visual field and near vision in human and to study the countermeasure of Chinese herb against weightlessness. Method. Ten subjects were randomly divided into control group and Chinese herb group. -6 degrees HDT was used to simulate weightlessness. Intra-ocular pressure, near vision and vision field were measured before, during and after bed rest in both groups. Result. Intra-ocular pressure and near vision showed a wave-like decrease change during bed rest, and there exists a certain coherence between them. Visual field showed no obvious changes. Taking Chinese herb was able to antagonize the decreasing of intra-ocular pressure and near vision during various phases of bed rest. Conclusion. 1) Bed rest could lead to the decreasing of intra-ocular pressure and near vision; 2) Taking Chinese herb was able to antagonize the negative influences of bed rest on visual function.