Despite advances in biology and treatment modalities, the prognosis of glioblastoma (GBM) remains poor. Serum reflects disease macroenvironment and thus provides a less invasive means to diagnose and monitor a diseased condition. By employing 4-plex iTRAQ methodology, we identified 40 proteins with differential abundance in GBM sera. The high abundance of serum S100A8/S100A9 was verified by multiple reaction monitoring (MRM). ELISA and MRM-based quantitation showed a significant positive correlation. Further, an integrated investigation using stromal, tumor purity and cell type scores demonstrated an enrichment of myeloid cell lineage in the GBM tumor microenvironment. Transcript levels of S100A8/S100A9 were found to be independent poor prognostic indicators in GBM. Medium levels of pre-operative and three-month post-operative follow-up serum S100A8 levels predicted poor prognosis in GBM patients who lived beyond median survival. In vitro experiments showed that recombinant S100A8/S100A9 proteins promoted integrin signalling dependent glioma cell migration and invasion up to a threshold level of concentrations. Thus, we have discovered GBM serum marker by iTRAQ and verified by MRM. We also demonstrate interplay between tumor micro and macroenvironment and identified S100A8 as a potential marker with diagnostic and prognostic value in GBM.

The ruthenium­(II) complexes [RuCl­(L1)­(L3)]Cl (1), [RuCl­(L1)­(L4)]­Cl (2), [RuCl­(L2)­(L4)]Cl (3), [RuCl­(L1)­(L5)]Cl (4), and [RuCl­(L2)­(L5)]Cl (5) of NNN-donor dipicolylamine (dpa) bases (L4, L5) having BODIPY (boron-dipyrromethene) moieties, NN-donor phenanthroline derivatives (L1, L2), and benzyldipicolylamine (bzdpa, L3) were prepared and characterized by spectroscopic techniques and their cellular localization/uptake and photocytotoxicity studied. Complex 1, as its PF6 salt (1a), has been structurally characterized with help of a single-crystal X-ray diffraction technique. It has a RuN5Cl core with the Cl bonded trans to the amine nitrogen atom of bzdpa. The complexes showed intense absorption spectral bands near 500 nm (ε ≈ 58000 M–1 cm–1) in 2 and 3 and 654 nm (ε ≈ 80000 M–1 cm–1) in 4 and 5 in 1/1 DMSO/DPBS (v/v). Complex 5 having biotin and PEGylated-disteryl BODIPY gave a singlet oxygen quantum yield (ΦΔ) of ∼0.65 in DMSO. Complex 5 exhibited remarkable PDT (photodynamic therapy) activity (IC50 ≈ 0.02 μM) with a photocytotoxicity index (PI) value of >5000 in red light of 600–720 nm in A549 cancer cells. The biotin-conjugated complexes showed better photocytotoxicity in comparison to nonbiotinylated analogues in A549 cells. The complexes displayed less toxicity in HPL1D normal cells in comparison to A549 cancer cells. The emissive BODIPY complexes 3 and 5 (ΦF ≈ 0.07 in DMSO) showed significant mitochondrial localization.

A series of multichromophoric ruthenium(II) complexes with the formulation [Ru(tpy-BODIPY)(tpy-R)]Cl 2 (1−4), having a heteroleptic Ru(II)-bis-tpy (tpy = 4′-phenyl-2,2′:6′,2″-terpyridine) moiety covalently linked to a boron-dipyrromethene (BODIPY) pendant, have been prepared and characterized and their application as a phototherapeutic and photodetection agent in cancer therapy has been explored. Ligand L 1 with a terpyridine-BODIPY moiety and complex 1 as its PF 6 salt (1a) have been structurally characterized by a single-crystal Xray diffraction study. Complex 1a has a distorted-octahedral RuN 6 core with a Ru(II)-bis-terpyridine unit that is covalently linked to one photoactive BODIPY unit. The complexes exhibit strong absorbance near 502 nm (ε ≈ (3.7−7.8) × 10 4 M −1 cm −1 ) and high singlet oxygen sensitization ability, giving singlet oxygen quantum yield (Φ Δ ) values ranging from 0.57 to 0.75 in DMSO. An emission-based study using complex 4 and Singlet Oxygen Sensor Green (SOSG) displays the formation of singlet oxygen inside the cells and also in the buffer medium upon light irradiation. DNA (pUC19) photocleavage experiments using ROS scavengers/stabilizers reveal photoinduced generation of singlet oxygen by a type-II process and of the superoxide anion radical by a type-I process. Complex 4 having a pendant biotin moiety as a cancer cell targeting group shows high photocytotoxicity with a remarkable phototherapeutic index (PI) value of >1400 in HeLa cancer cells with a low light dose activation (400−700 nm, 2.2 J cm −2 ). The complexes display reduced activity in noncancerous HPL1D cells. The emission property of the complexes is used for cellular imaging, thus making them suitable as next-generation theranostic PDT agents.

Cobalt­(III) complexes [Co­(TPA)­(L1)]­(ClO4)2 (1), [Co­(4-COOH-TPA)­(L1)]­(ClO4)2 (2), [Co­(TPA)­(L2)]­Cl2 (3), and [Co­(4-COOH-TPA)­(L2)]­Cl2 (4) having acetylacetonate-linked boron-dipyrromethene ligands (L 1 , acac-BODIPY; L 2 , acac-diiodo-BODIPY) were prepared and characterized, and their utility as bioimaging and phototherapeutic agents was evaluated (TPA, tris-(2-pyridylmethyl)­amine; 4-COOH-TPA, 2-((bis-(2-pyridylmethyl)­amino)­methyl)­isonicotinic acid). HL 1 , HL 2 , and complex 1 were structurally characterized by X-ray crystallography. Complexes 1 and 2 on photoactivation or in a reducing environment (excess GSH, ascorbic acid, and 3-mercaptopropionic acid) released the acac-BODIPY ligand. They exhibited strong absorbance near 501 nm (ε ∼ (5.2–5.8) × 104 M–1 cm–1) and emission bands near 513 nm (ΦF ∼ 0.13, λex = 490 nm) in dimethyl sulfoxide (DMSO). Complexes 3 and 4 with absorption maxima at ∼536 and ∼538 nm (ε ∼ (1.2–1.8) × 104 M–1 cm–1), respectively, afforded high singlet oxygen quantum yield (ΦΔ ∼ 0.79) in DMSO. Complexes 1–4 showed Co­(III)–Co­(II) redox responses near −0.2 V versus saturated calomel electrode (SCE) in dimethylformamide (DMF)–0.1 M tetrabutylammonium perchlorate (TBAP). The photocleavage of pUC19 DNA by complex 4 revealed the formation of both singlet oxygen and superoxide anion radicals as the reactive oxygen species (ROS). Confocal fluorescence microscopy showed the selective accumulation of complex 1 in the endoplasmic reticulum (ER) in A-549 cells. Complex 4 exhibited a high phototherapeutic index value (PI > 7000) in HeLa cancer cells (IC50 ∼ 0.007 μM in visible light of 400–700 nm, total dose ∼5 J cm–2). The ancillary ligands in the complexes demonstrated a structure–activity relationship and modulated the Co­(III)–Co­(II) redox potential, the complex solubility, acac-BODIPY ligand release kinetics, and phototherapeutic efficacy.

Maloplatin-B, a cisplatin-based complex, namely [Pt­(A-BOD)­(NH3)2]­(NO3) (Pt-A-BOD) with a pendant boron-dipyrromethene (BODIPY) moiety, where HA-BOD is a methyl malonyl chloride derived monostyryl BODIPY ligand, was designed and developed as near-IR light (600–720 nm) organelle-targeting photodynamic therapy agent. The complex [Pt­(acac)­(NH3)2]­(NO3) (Pt-Ac) was used as a control. Pt-A-BOD displayed an absorption band at 616 nm (ε = 2.9 × 104 M–1 cm–1) in 10% dimethyl sulfoxide/Dulbecco’s Modified Eagle’s Medium (DMSO/DMEM, pH 7.2). This complex displayed a broad emission band within 650–850 nm with a λem value of 720 nm in 10% DMSO–DMEM (pH 7.2) upon excitation (λex) at 615 nm with a large Stokes shift. The fluorescence quantum yield (ΦF) value for Pt-A-BOD is 0.032 and for the ligand HA-BOD is 0.24. The BODIPY complex and ligand showed the formation of singlet oxygen as the ROS (reactive oxygen species) on irradiation with near-IR red light of 660 nm, as evidenced from a 1,3-diphenylisobenzofuran (DPBF) assay. The complex displayed remarkable apoptotic NIR light-induced PDT activity with half-maximum inhibitory concentration values (IC50) of 1.6–2.4 μM in A549 lung and HeLa cervical cancer cells, while it was less active in the dark. The cellular ROS generation by the complex in red light was ascertained by a DCFDA (2′,7′-dichlorofluorescein diacetate) assay. Cellular imaging showed its localization primarily in the mitochondria of A549 cancer cells. The JC1 and Annexin-V FITC/PI assays carried out for A549 cancer cells treated with the BODIPY complex showed the alteration of mitochondrial membrane potential and apoptotic cell death on near-IR red light (600–720 nm) irradiation, respectively.

Metrics & More Article Recommendations * sı Supporting Information ABSTRACT: [Pt(RB)(Cur)]NO 3 (RBC), [Pt(IRB)(Cur)]NO 3 (IRBC), and [Pt(L)(Cur)]NO 3 (PBC), where HCur is curcumin, L is 1-benzyl-2-(2-pyridyl)benzimidazole, and RB and IRB are red-light-active non-iodo and diiodo-BODIPY tagged to L, respectively, were synthesized and characterized, and their anticancer activities were studied (BODIPY, boron-dipyrromethene). RBC and IRBC displayed BODIPY-centered absorption bands within 615−635 nm along with the respective curcumin bands at 445 and 492 nm in 10% dimethyl sulfoxide (DMSO)− Dulbecco's phosphate-buffered saline (DPBS). Emission bands were observed at 723 and 845 nm for RBC and IRBC, respectively, in 10% DMSO−DPBS. RBC (Φ Δ , 0.27) and IRBC (Φ Δ , 0.40) generated singlet oxygen in red light (λ = 642 nm) as evidenced from 1,3diphenylisobenzofuran (DPBF) titrations. The formation of 1 O 2 from BODIPY and HO • from the curcumin was evidenced from the mechanistic pUC19 DNA photocleavage studies. The BODIPY complexes showed photocytotoxicity in A549, HeLa, and MDA-MB-231 cells while being less toxic in the dark [IC 50 : 1.3−6.9 μM, red light; 7.2−12.8 μM, 400−700 nm visible light]. The emissive RBC displayed localization in the endoplasmic reticulum (ER).Apoptotic cell death was evidenced from the Annexin-V/fluorescein isothiocyanate (FITC)/propidium iodide (PI) assay and green fluorescence in red light in the Fluo-4 AM assay due to ER stress, and mitochondrial dysfunction was evidenced from the 5,5,6,6′tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) assay in A549 cells.

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Objective Oral submucous fibrosis (OSF) is a debilitating potentially malignant condition of the buccal cavity characterized by extensive extracellular matrix deposition resulting in stiffness and trismus. As OSF is a progressive disease, we hypothesized that there would be extensive epigenetic changes in OSF tissues. Materials and Methods Using the Infinium HumanMethylation450 BeadChip Array, we analyzed gross DNA methylation changes in seven OSF tissues compared to five controls. Comparison with transcriptomic data and pathway analyses was conducted to find commonly regulated genes. Results A total of 3,294 differentially methylated regions mapping to 857 genes were identified. Comparison with transcriptome data revealed 38 downregulated‐hypermethylated genes and 55 hypomethylated‐upregulated genes. Using methylation‐specific and qRT‐PCR, aberrant hypomethylation and increased expression of FGF13, RPS6KA3, and ACSL4 genes were confirmed. Pathways involved in insulin signaling, ubiquitin‐mediated proteolysis, nicotine addiction, and RAS/MAPK pathways were dysregulated, among others. Intriguingly, numerous genes located on the X chromosome were dysregulated in OSF tissues as the transcript for XIST gene was downregulated due to hypermethylation of the XIST promoter. Conclusions This study highlights global epigenetic dysregulation of tissues of the oral cavity in OSF patients and hints at possible X chromosomal dysregulation, previously not implicated in the pathogenesis of OSF.