Novel integrated Omics based computational approach for drug repurposing for non-muscle invasive bladder cancer (NMIBC).

Non-muscle invasive bladder cancer (NMIBC) refers to a subtype of bladder carcinoma where cancer is localized in the inner lining of bladder. NMIBC consider as one of most costly malignancy and requires significant surgical and therapeutic measure. However, recurrence and progression of tumor is common in treated patients. Here we presented an integrated OMICs approach for the identification and inhibition of NMIBC specific genes. We utilized a case study where three group of patients were compared: 1) Relapsed tumors 2) recurrent tumors and 3) tumor in progression. Common transcriptome signature between patients facing recurrence and progression allowed us to identify three NMIBC specific genes FLT-1, WHSC-1 and CD34. We further utilized novel approach of Co-expressed gene-set enrichment analysis (COGENA) on the differentially expressed genes of this case study. Three drugs (paroxetine, adiphenine and H-89) with role of receptors inhibition were identified and predicted as repurposed drugs for the inhibition NMIBC specific genes. We further tested this hypothesis by performing molecular docking and simulation analysis between cancer specific proteins and drugs. FLT-1 have shown significant stable interaction with both drugs paroxetine and adiphenine whereas WHSC-1 have shown compact interaction with adiphenine and H-89. In the light of these evidence, we suggest that adiphenine could be repositioned as alternate targeted medicine for the treatment of NMIBC. In the future, this study will help for strengthening the strategies development at the molecular level for the control of carcinomas at early as well as detection of active and binding site, receptor-ligand interaction and also make drug repurposing for the early treatment of the carcinomas.Communicated by Ramaswamy H. Sarma.

Identification of potential phytochemical for the inhibition of non-muscle invasive bladder cancer (NMIBC).

Non-muscle invasive bladder cancer (NMIBC) is one of the most common type of bladder cancer. Here, we have utilized an integrated transcriptomic-computational approach to identify alternate treatments to the NMIBC. In this study, we have performed the comprehensive comparative analysis between three groups of 36 patients with non-relapsed (NR), recurrence and progressive symptoms. Differentially expressed genes involved in the pathways associated with the NMIBC were identified. In silico protein-protein interaction (PPI) network was performed to create the network of the hub genes associated with NMIBC. Further, we compared NR individuals with two cohorts of patients with recurrent and progressive symptoms that lead to the identification of three major biomarkers CD34, FLT1 and WHSC1 genes. Concurrently, PPI also suggests that they are significant hub genes responsible for disease recurrence and progression. Furthermore, targeted genes WHSC-1 and FLT-1 were subjected to virtual screening for identification phytochemical inhibitors. Docking and molecular dynamics simulations concluded that the phytochemicals anonymously named 'UNK' and '6-hydroxycyanidin' are suitable for the inhibition of the proteins causing the NMIBC. In the future, this study will help for strengthening the strategies development at the molecular level for the control of carcinomas at early as well as detection of active and binding site, receptor-ligand interaction and also make drug designing for the early treatment of the carcinomas.Communicated by Ramaswamy H. Sarma.

Exosomal miR-30a-5p promoted intrahepatic cholangiocarcinoma progression by increasing angiogenesis and vascular permeability in PDCD10 dependent manner.

Tumor-associated angiogenesis positively associates with malignant metastasis of intrahepatic cholangiocarcinoma (ICCA). Cancer cell-derived exosomes carrying microRNAs involves in tumor microenvironment (TME) regulation. We aimed to evaluate exosomal miR-30a-5p in ICCA development. Our data showed that increased miR-30a-5p level was correlated with higher microvascular density (MVD) and worse prognosis. Augmented miR-30a-5p expression was induced by hypoxia induced factor 1α (HIF-1α) in ICCA cell. Further exploration revealed that ICCA-derived miR-30a-5p could be transferred to endothelial and increased endothelial cells recruitment and proliferation, induced angiogenesis and vascular permeability in exosome dependent manner. In addition, circulating exosomal miR-30a-5p was higher in ICCA patients, and correlated with ICCA tissues-expressing miR-30a-5p. Hypoxic stress enhanced the effects of exosomal miR-30a-5p on endothelial-associated phenotypes. Rescued experiments showed that exosomal miR-30a-5p modulated endothelial-associated phenotypes in a way relied on programmed cell death 10 (PDCD10). Moreover, we revealed that the packing of miR-30a-5p into ICCA cells-derived exosomes was mediated by eukaryotic translation initiation factor 4B (EIF4B). More importantly, the combined application of targeting miR-30a-5p and apatinib could synergistically improve antiangiogenic efficacy in ICCA. Combined, ICCA-derived exosomal miR-30a-5p could be an excellent therapeutic and monitoring indicator for ICCA patients.

Unravelling the Link between Psychological Distress and Liver Disease: Insights from an Anxiety-like Rat Model and Metabolomics Analysis.

Psychological distress is associated with an increase in liver disease mortality. This association highlights the close relationship between psychological and physical health. The underlying mechanism of this association needs to be elucidated. In this study, a rat model of anxiety was developed via compound stress. Changes in the HPA axis and inflammatory factors in the brains of the rats were evaluated for behavioral tests and liver function, respectively. The liver metabolic profiles of the rats were characterized through liquid chromatography-mass spectrometry (LC-MS). Differential metabolites were screened based on the conditions of p < 0.05 and VIP > 1. A pathway enrichment analysis was performed on the metabolomics data using the Ingenuity Pathway Analysis (IPA). Immunofluorescence (IF), immunohistochemistry (IHC), and Western blotting assays were performed to examine the expression of the screened target epidermal growth factor receptor (EGFR) and to elucidate the pathway associated with the mechanism. The results showed the impairment of liver function among the rats in an anxiety-like state. Additionally, 61 differential metabolites in the control and anxiety groups were screened using metabolomics (p < 0.05, VIP > 1). The results of the IPA analysis showed that the key target was EGFR. We also found that an anxiety-like state in rats may cause liver injury through the EFGR/PI3K/AKT/NF-κB pathway, which can lead to the production of inflammatory factors in the liver. Our results revealed a mechanism by which anxiety-like behavior leads to liver damage in rats. The findings of this study provided new insights into the deleterious effects of psychological problems on physical health.

Vitexin suppresses the proliferation, angiogenesis and stemness of endometrial cancer through the PI3K/AKT pathway.

CONTEXT: Endometrial cancer is a common gynecologic malignancy. Vitexin is an active flavonoid compound with an antitumor function. OBJECTIVE: This study elucidated the role of vitexin in endometrial cancer development and clarified the potential mechanism. MATERIALS AND METHODS: The toxicity of vitexin (0-80 µM) treatment for 24 h on HEC-1B and Ishikawa cells was tested utilizing the CCK-8 assay. Endometrial cancer cells were divided into vitexin 0, 5, 10, and 20 µM groups. Cell proliferation, angiogenesis and stemness in vitro after treatment with vitexin (0, 5, 10, 20 µM) for 24 h were evaluated using the EdU staining assay, tube formation assay and sphere formation assay, respectively. Twelve BALB/c mice were grouped into control and vitexin (80 mg/kg) groups to monitor tumour growth for 30 days. RESULTS: Vitexin suppressed cell viability of HEC-1B (IC50 = 9.89 µM) and Ishikawa (IC50 = 12.35 µM) cells. The proliferation (55.3% and 80% for HEC-1B; 44.7% and 75% for Ishikawa), angiogenesis (54.3% and 78.4% for HEC-1B; 47.1% and 68.2% for Ishikawa) and stemness capacity (57.2% and 87.3% for HEC-1B; 53.4% and 78.4% for Ishikawa) of endometrial cancer cells were inhibited by 10 and 20 µM vitexin. Furthermore, the inhibitory effects of vitexin on endometrial cancer were reversed by PI3K/AKT agonist 740Y-P (20 µM). Moreover, the xenograft tumour experiment lasting for 30 days proved that vitexin (80 mg/kg) blocked tumour growth of endometrial cancer in vivo. DISCUSSION AND CONCLUSIONS: Vitexin has therapeutic potential on endometrial cancer, which supports further clinical trials.

Kaempferol suppression of acute colitis is regulated by the efflux transporters BCRP and MRP2.

The bioavailability of most flavonoids is low but effective in vivo; however, the mechanism of the efficacy of flavonoids has not been elucidated. Kaempferol is typical flavonoids., preliminary research indicates that kaempferol has a significant anti-colon cancer and anti-inflammatory effect. We reported previously that the triple recycling pathways significantly increase the local bioavailability of flavonoids and prolong the residence time of flavonoids in the liver and intestines, which is likely the mode by which flavonoids exert local efficacy. Notably, Efflux transporters (ETs), such as Breast cancer resistance protein (BCRP) and Multi drug resistance-associated protein 2 (MRP2), are the main regulatory molecules of the enterohepatic triple recycling pathways. Thus, our current study explored the regulation of kaempferol by BCRP and MRP2 and the role of BCRP and MRP2 in the suppression of Dextran sulfate sodium (DSS)-induced colitis by kaempferol. Herein, four mouse model was constructed, and the Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was established to simultaneously quantify kaempferol and its 3 metabolites and investigate the oral pharmacokinetic characteristics and tissue distribution of these compounds. In Bcrp-/--Mrp2-/- mice, the movement of kaempferol via the enterohepatic triple recycling was blocked, and the preventative and therapeutic effects of this compound on acute colitis were inhibited. BCRP and MRP2 defects hindered the efflux of kaempferol and its phase II metabolites and increased the plasma levels. Our study revealed that the disposal of kaempferol was regulated by the ETs BCRP and MRP2, and most importantly, the results will help elucidate the mechanism by which kaempferol suppresses the transformation of colitis into colon cancer.

CRISPLD2 attenuates pro-inflammatory cytokines production in HMGB1-stimulated monocytes and septic mice.

HMGB1 has been identified as a pro-inflammatory mediator which leads to sepsis lethality. Previous studies suggested that CRISPLD2 had anti-inflammatory property and might severe as a therapeutic agent in sepsis. In the present study, we first conducted bioinformatic analysis to explore the expression profile of HMGB1 in septic survivors and non-survivors. We found that the serum HMGB1 level of septic non-survivors was significantly higher than that of septic survivors, and there was a positive correlation between CRISPLD2 and HMGB1 in mRNA expression in most of the cancer and normal tissue types, revealing a co-expression or dependency relationship between the two genes. In vitro, using cultured THP-1 cells, we confirmed that HMGB1 can induce the expression of CRISPLD2 in a time dependent manner through TLR4-dependent pathway. Given that CRISPLD2 and HMGB1 shared a wide range of time scales in gene expression and the anti-inflammatory property of CRISPLD2, we further verified that HMGB1 induced cytokines production might be partially reversed by CRISPLD2. In vivo, intravenously treatment of CRISPLD2 failed to rescue septic mice, although the serum levels of inflammatory cytokines were decreased. In conclusion, our study demonstrated that HMGB1 can act as stimuli to up-regulate the expression of CRISPLD2 in THP-1 cells, and in turn, increased CRISPLD2 can curtail HMGB1 induced pro-inflammatory cytokines production. Unfortunately, the anti-inflammatory effects of CRISPLD2 did not translate into survival benefit in mice with sepsis.

Information Needs of Breast Cancer Patients: Theory-Generating Meta-Synthesis.

BACKGROUND: Breast cancer has become one of the most frequently diagnosed carcinomas and the leading cause of cancer deaths. The substantial growth in the number of breast cancer patients has put great pressure on health services. Meanwhile, the information patients need has increased and become more complicated. Therefore, a comprehensive and in-depth understanding of their information needs is urgently needed to improve the quality of health care. However, previous studies related to the information needs of breast cancer patients have focused on different perspectives and have only contributed to individual results. A systematic review and synthesis of breast cancer patients' information needs is critical. OBJECTIVE: This paper aims to systematically identify, evaluate, and synthesize existing primary qualitative research on the information needs of breast cancer patients. METHODS: Web of Science, EBSCO, Scopus, ProQuest, PubMed, PsycINFO, The Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature were searched on February 12 and July 9, 2019, to collect relevant studies. A Google Scholar search, interpersonal network recommendations, and reference chaining were also conducted. Eligible studies included qualitative or mixed-methods studies focusing on the information needs (across the cancer continuum) of breast cancer patients or their social networks. Subsequently, a Critical Appraisals Skills Programme checklist was used to assess the quality of included research. The results, findings, and discussions were extracted. Data analysis was guided by the theory-generating meta-synthesis and grounded theory approach. RESULTS: Three themes, 19 categories, and 55 concepts emerged: (1) incentives (physical abnormality, inquiry from others, subjective norm, and problems during appointments); (2) types of information needs (prevention, etiology, diagnosis, clinical manifestation, treatment, prognosis, impact and resumption of normal life, scientific research, and social assistance); (3) moderating variables (attitudes, health literacy, demographic characteristics, disease status, as well as political and cultural environment). The studies revealed that the information needs of breast cancer patients were triggered by different incentives. Subsequently, the patients sought a variety of information among different stages of the cancer journey. Five types of variables were also found to moderate the formation of information needs. CONCLUSIONS: This study contributes to a thorough model of information needs among breast cancer patients and provides practical suggestions for health and information professionals.

Dual pH/ROS-Responsive Nanoplatform with Deep Tumor Penetration and Self-Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy.

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA-NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active-targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self-amplified drug release for effective drug delivery. The RLPA-NPs are constructed by encapsulation of a pH-sensitive polymer octadecylamine-poly(aspartate-1-(3-aminopropyl) imidazole) (OA-P(Asp-API)) and a ROS-generation agent, ß-Lapachone (Lap), in micelles assembled by the tumor-penetration peptide internalizing RGD (iRGD)-modified ROS-responsive paclitaxel (PTX)-prodrug. iRGD could promote RLPA-NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor-mediated endocytosis, OA-P(Asp-API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA-NPs escape from the endosome through the "proton sponge effect". At the same time, the RLPA-NPs micelle disassembles, releasing Lap and PTX-prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA-NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA-NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.

Hyaluronic acid reduction-sensitive polymeric micelles achieving co-delivery of tumor-targeting paclitaxel/apatinib effectively reverse cancer multidrug resistance.

Multidrug resistance (MDR) of cancer cells is a significant challenge in chemotherapy, highlighting the urgent medical need for simple and reproducible strategies to reverse this process. Here, we report the development of an active tumor-targeting and redox-responsive nanoplatform (PA-ss-NP) using hyaluronic acid-g-cystamine dihydrochloride-poly-ε-(benzyloxycarbonyl)-L-lysine (HA-ss-PLLZ) to co-deliver paclitaxel (PTX) and apatinib (APA) for effective reversal of MDR. This smart nanoplatform specifically bound to CD44 receptors, leading to selective accumulation at the tumor site and uptake by MCF-7/ADR cells. Under high concentrations of cellular glutathione (GSH), the nanocarrier was degraded rapidly with complete release of its encapsulated drugs. Released APA effectively inhibited the function of the P-glycoprotein (P-gp) drug pump and improved the sensitivity of MDR cells to chemotherapeutic agents, leading to the recovery of PTX chemosensitivity in MDR cells. As expected, this newly developed intelligent drug delivery system could effectively control MDR, both in vitro and in vivo.

A ROS-responsive polymeric prodrug nanosystem with self-amplified drug release for PSMA (-) prostate cancer specific therapy.

BACKGROUND: The selectively accumulate in tumor site and completely release drug within cancer cells great limit the therapeutic effect of nano-drug delivery system. Moreover, absence of appropriate biomarker is one of the major challenges for prostate specific membrane antigen negative (PSMA (-)) prostate cancer therapy. RESULTS: Herein, a PSMA (-) prostate cancer specific targeted and intracellular reactive oxygen species (ROS) amplification for ROS-responsive self-accelerating drug release nanoplatform (ATD-NPs) was developed. ATD-NPs was formed by three parts, including PSMA (-) prostate cancer specifically targeted part (DUP-PEG-DSPE), ROS-sensitive doxorubicin (DOX) polymeric prodrug (P(L-TK-DOX)), and the ROS generation agent (α-tocopheryl succinate, α-TOS); and this delivery system is expected to enhance PSMA (-) prostate cancer therapeutic effect, increase selective accumulation at tumor site and overcome intracellular incomplete drug release. After administration i.v injection, ATD-NPs could specifically accumulate in tumor site and markedly be internalized by cancer cells based on the DUP-1 (a PSMA (-) cancer cells specific target peptide). Subsequently, ATD-NPs could be dissociated under the high concentration reactive oxygen species (ROS) condition, resulting in DOX and α-TOS release. Then, the released α-TOS could be reacted with mitochondria to produce ROS, which in turn accelerating the release of drugs. Finally achieved the purpose of enhancing therapeutic efficacy and reducing side effect. Both in vitro and in vivo experiments demonstrated that the combination of tumor actively-targeted and self-amplifying ROS-responsive drug release showed more significant antitumor activity in the human PSMA (-) prostate cancer. CONCLUSION: The described technology unifies the tumor actively targets, self-amplified drug release, and excellent biocompatibility into one formulation, are promising for cancer treatment.

Treatment of murine lupus with TIGIT-Ig.

The TIGIT (T cell immunoreceptor with Ig and ITIM domains) protein is a co-inhibitory receptor that has been reported to suppress autoreactive T and B cells to trigger immunological tolerance. We generated a new recombinant protein by connecting the extracellular domain of murine TIGIT to the Fc region of the mouse immunoglobulin IgG2a. The fusion protein was then characterized. The results suggested that among mice with lupus that were treated with the TIGIT-Ig fusion protein, the onset of proteinuria was delayed, serum concentrations of autoantibodies, such as antinuclear antibodies, were reduced without a decrease in the total IgG concentrations, and the survival rate was significantly increased compared to those of the controls. In conclusion, TIGIT-Ig administration showed promising results for both the prevention and treatment of autoimmune diseases in mice. This indicates that treatment with recombinant human TIGIT-Ig shows promise as an effective way to treat human autoimmune diseases.

pH and redox dual-responsive copolymer micelles with surface charge reversal for co-delivery of all-trans-retinoic acid and paclitaxel for cancer combination chemotherapy.

BACKGROUND: Co-delivery all-trans-retinoic acid (ATRA) and paclitaxel (PTX) is an effective strategy for cancer therapy. However, in many previous reported ATRA conjugated co-delivery systems, the ATRA was released slower than PTX, and the total drug release of ATRA far lower than that of PTX. PURPOSE: We designed and prepared a pH and redox dual responsive drug delivery system (DA-ss-NPs) co-delivery ATRA and PTX for cancer therapy. The surface charge of DA-ss-NPs could change from negative to positive under tumor slightly acidic microenvironment, and both drugs could be quickly released from DA-ss-NPs under intracellular high concentration of glutathione (GSH). METHODS: The DA-ss-NPs were constructed by encapsulating PTX into the hydrophobic core of the polymer micelles, in which the polymer was synthesized by conjugating ATRA and 2,3-Dimethylmalefic anhydride (DMA) on side chains of Cystamine dihydrochloride (Cys) modified PEG-b-PAsp (named DA-ss-NPs). The surface charge of DA-ss-NPs under different pH conditions were detected. And the drug release was also measured under different concentration of GSH. The therapeutic effect of DA-ss-NPs were investigated in Human lung cancer A549 cells and A549 tumor-bearing mice. RESULTS: The zeta potential of DA-ss-NPs was -16.3 mV at pH 7.4, and which changed to 16 mV at pH 6.5. Cell uptake experiment showed that more DA-ss-NPs were internalized by A549 cells at pH 6.5 than that at pH 7.4. In addition, in presence of 10 mM GSH at pH 7.4, about 75%-85% ATRA was released from DA-ss-NPs within 48 h; but less than 20% ATRA was released without GSH. In vivo antitumor efficiency showed that the DA-ss-NPs could affectively inhibite the tumor in compared with control groups. CONCLUSION: The charge-reversal and GSH-responsive DA-ss-NPs provide an excellent platform for potential tumor therapy.

Sphingobacterium alkalisoli sp. nov., isolated from a saline-alkaline soil.

A Gram-staining-negative, non-motile, non-spore-forming bacterium designated Y3L14T was isolated from the saline-alkaline soil of a farmland, Inner Mongolia, northern China. Strain Y3L14T could grow at 10-40 °C (optimally at 30 °C), pH 6.0-10.0 (optimally at pH 8.0), and in the presence of 0-6.0 % (w/v) NaCl (optimally with 0-2.0 %). Phylogenetic analysis based on the 16S rRNA gene and DNA gyrase subunit B (gyrB) gene sequences revealed that strain Y3L14T clustered with strains belonging to the genus Sphingobacterium, sharing the highest 16S rRNA gene sequence similarity with Sphingobacterium lactis WCC 4512T (94.99 %). Its major cellular fatty acids contained iso-C15 : 0, C16 : 0, iso-C17 : 0 3-OH and summed feature 3 (iso-C15 : 0 2-OH and/or C16 : 1ω7c). Menaquinone-7 (MK-7) was the only isoprenoid quinone. Strain Y3L14T contained phosphatidylethanolamine, sphingophospholipid, two unknown phospholipids and three unknown lipids as the major polar lipids. The genomic DNA G+C content of strain Y3L14T was 36.0 mol%. Based on the phenotypic, phylogenetic and genotypic characteristics, strain Y3L14T represents a novel species within the genus Sphingobacterium, for which Sphingobacterium alkalisoli sp. nov. is proposed; the type strain is Y3L14T (=CGMCC 1.15782T=KCTC 52379T).

Diverse Bacteria with Lignin Degrading Potentials Isolated from Two Ranks of Coal.

Taking natural coal as a "seed bank" of bacterial strains able to degrade lignin that is with molecular structure similar to coal components, we isolated 393 and 483 bacterial strains from a meager lean coal sample from Hancheng coalbed and a brown coal sample from Bayannaoer coalbed, respectively, by using different media. Statistical analysis showed that isolates were significantly more site-specific than medium-specific. Of the 876 strains belonging to 27 genera in Actinobacteria, Firmicutes, and Proteobacteria, 612 were positive for lignin degradation function, including 218 strains belonging to 35 species in Hancheng and 394 strains belonging to 19 species in Zhongqi. Among them, the dominant lignin-degrading strains were Thauera (Hancheng), Arthrobacter (Zhongqi) and Rhizobium (both). The genes encoding the laccases- or laccase-like multicopper oxidases, key enzymes in lignin production and degradation, were detected in three genera including Massila for the first time, which was in high expression by real time PCR (qRT-PCR) detection, confirming coal as a good seed bank.