Integration of metabolites from meta-analysis with transcriptome reveals enhanced SPHK1 in PDAC with a background of pancreatitis.

BACKGROUND: Pathophysiology of transformation of inflammatory lesions in chronic pancreatitis (CP) to pancreatic ductal adenocarcinoma (PDAC) is not clear. METHODS: We conducted a systematic review, meta-analysis of circulating metabolites, integrated this data with transcriptome analysis of human pancreatic tissues and validated using immunohistochemistry. Our aim was to establish biomarker signatures for early malignant transformation in patients with underlying CP and identify therapeutic targets. RESULTS: Analysis of 19 studies revealed AUC of 0.86 (95% CI 0.81-0.91, P < 0.0001) for all the altered metabolites (n = 88). Among them, lipids showed higher differentiating efficacy between PDAC and CP; P-value (< 0.0001). Pathway enrichment analysis identified sphingomyelin metabolism (impact value-0.29, FDR of 0.45) and TCA cycle (impact value-0.18, FDR of 0.06) to be prominent pathways in differentiating PDAC from CP. Mapping circulating metabolites to corresponding genes revealed 517 altered genes. Integration of these genes with transcriptome data of CP and PDAC with a background of CP (PDAC-CP) identified three upregulated genes; PIGC, PPIB, PKM and three downregulated genes; AZGP1, EGLN1, GNMT. Comparison of CP to PDAC-CP and PDAC-CP to PDAC identified upregulation of SPHK1, a known oncogene. CONCLUSIONS: Our analysis suggests plausible role for SPHK1 in development of pancreatic adenocarcinoma in long standing CP patients. SPHK1 could be further explored as diagnostic and potential therapeutic target.

Biogenesis of silver nanoparticles using leaf extract of Indigofera hirsuta L. and their potential biomedical applications (3-in-1 system).

The present study reports the biosynthesis of silver nanoparticles (IH-AgNPs) using aqueous leaf extract of Indigofera hisruta L. The biosynthesized IH-AgNPs were found to be FCC crystals, 5-10 nm in size, spherical in shape and stable. The biosynthesized IH-AgNPs showed dose-dependant cytotoxicity against prostate cancer (PC3) (IC50 = 68.5 µg/mL), colon cancer (COLO205) (IC50 = 85.2 µg/mL), and mouse melanoma (B16F10) (IC50 = 80.9 µg/mL). IH-AgNPs were found to be nontoxic towards normal CHO (Chinese hamster ovary) cells. The biosynthesized IH-AgNPs showed effective in vitro antioxidant activity against DPPH (IC50 = 63.43 µg/mL) and H2O2 (IC50 = 89.93 µg/mL) radicals. IH-AgNPs exhibited effective antibacterial activity against both Gram+ve and Gram-ve bacteria. MIC values of IH-AgNPs against S. aureus, B. subtilis, P. aeruginosa and E. coli were found to be 7.8 µg/mL, 3.9 µg/mL, 15.6 µg/mL and 15.6 µg/mL respectively. IH-AgNPs also showed inhibitory activity against fungal pathogens including C. albicans, C. nonalbicans and C. tropicalis. Considering the results together, we demonstrate that IH-AgNPs exhibits three different bioactivities (3-in-1 system) and they could be employed as future antimicrobial, antioxidant and anticancer agents/drug delivery vehicles in the field of biomedicine.

Potential anticancer activity of biogenic silver nanoparticles using leaf extract of Rhynchosia suaveolens: an insight into the mechanism.

The present study reports a simple and eco-friendly synthesis of silver nanoparticles (AgNPs) using leaf extract of Rhynchosia suaveolens. UV-Vis analysis of R. suaveolens synthesized AgNPs (RS-AgNPs) showed surface plasmon resonance (SPR) peak at 426 nm. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analysis revealed that RS-AgNPs were 10-30 nm in size with spherical shape. X-ray diffraction (XRD) analysis of RS-AgNPs confirmed the crystalline nature with face-centered cubic (FCC) lattice. Fourier transform infrared (FTIR) interprets that polyphenols and proteins take part in bioreduction and capping of RS-AgNPs. RS-AgNPs exhibited dose-dependent inhibition of proliferation of different cancer cells including DU145 and PC-3(human prostate carcinoma cell lines), SKOV3 (human ovarian carcinoma) and A549 (human lung adenocarcinoma)with IC50 values of 4.35, 7.72, 4.2 and 24.7 µg/mL, respectively. The plausible reasons behind anticancer activity of RS-AgNPs were explained using different assays on the most susceptible SKOV3 cells. RS-AgNPs induced oxidative stress in SKOV3 cells by generating reactive oxygen species (ROS), enhancing lipid peroxidation (LPO) levels and decreasing glutathione (GSH) levels. RS-AgNPs induced the apoptosis of SKOV3 cells by up regulating the caspase-3, caspase -8, caspase -9, p53 and BAX and down regulating the antiapoptotic protein Bcl-2. Further, RS-AgNPs showed elevation of caspase 3/7 activity and also exhibited antimigratory effect by inhibiting the migration of SKOV3 cells into the wounded area. The findings suggested that biogenic RS-AgNPs provide an alternative approach to overcome several limitations of chemotherapy.

Synthesis and biological evaluation of novel quinazoline-sulfonamides as anti-cancer agents.

A robust economic approach to N-(quinazoline-4-yl)sulfonamides was developed and synthesized different aryl, hetero aryl, alkyl and cyclopropyl sulfonamides in excellent yields. All the compounds were evaluated for cytotoxic affinity to SKOV3, DU145, THP1, U937, and COLO205 cell lines. Interesting to find that the bulkiness of substituent at C-2 position of quinazoline forces the molecule to flip around in order to bind in the active site, when compared to the binding preference of previously known quinazoline compounds. Among the 21 compounds synthesized 2b, 2d, 2e, 2h, 2i, 3c, 3d, 3f, 3g and 3h found to be active on all the cell lines tested with IC50 values <10µg/mL. Performed docking simulations to understand the binding preference of various C-2 substituted quinazoline sulfonamides.

Biogenesis of silver nanoparticles using endophytic fungus Pestalotiopsis microspora and evaluation of their antioxidant and anticancer activities.

An endophytic fungal strain isolated from the leaves of Gymnema sylvestre was identified as Pestalotiopsis microspora VJ1/VS1 based on nucleotide sequencing of internal transcribed spacer region (ITS 1-5.8S-ITS 2) of 18S rRNA gene (NCBI accession number KX213894). In this study, an efficient and ecofriendly approach has been reported for the synthesis of silver nanoparticles (AgNPs) using aqueous culture filtrate of P. microspora. Ultraviolet-visible analysis confirmed the synthesis of AgNPs by showing characteristic absorption peak at 435 nm. Fourier transform infrared spectroscopy analysis revealed the presence of phenolic compounds and proteins in the fungal filtrate, which are plausibly involved in the biosynthesis and capping of AgNPs. Transmission electron microscopy (TEM) showed that the AgNPs were spherical in shape of 2-10 nm in size. Selected area electron diffraction and X-ray diffraction studies determined the crystalline nature of AgNPs with face-centered cubic (FCC) lattice phase. Dynamic light scattering analysis showed that the biosynthesized AgNPs possess high negative zeta potential value of -35.7 mV. Biosynthesized AgNPs were proved to be potential antioxidants by showing effective radical scavenging activity against 2,2'-diphenyl-1-picrylhydrazyl and H2O2 radicals with IC50 values of 76.95±2.96 and 94.95±2.18 µg/mL, respectively. The biosynthesized AgNPs exhibited significant cytotoxic effects against B16F10 (mouse melanoma, IC50 =26.43±3.41 µg/mL), SKOV3 (human ovarian carcinoma, IC50 =16.24±2.48 µg/mL), A549 (human lung adenocarcinoma, IC50 =39.83±3.74 µg/mL), and PC3 (human prostate carcinoma, IC50 =27.71±2.89 µg/mL) cells. The biosynthesized AgNPs were found to be biocompatible toward normal cells (Chinese hamster ovary cell line, IC50 =438.53±4.2 µg/mL). Cytological observations on most susceptible SKOV3 cells revealed concentration-dependent apoptotic changes that include cell membrane blebbing, cell shrinkage, pyknotic nuclei, karyorrhexis followed by destructive fragmentation of nuclei. The results together in this study strongly provided a base for the development of potential and versatile biomedical applications of biosynthesized AgNPs in the near future.