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A covalently bonded hexanuclear neutral complex, [Mn6(μ3-O)2(3-MeO-salox)6(OAc)2(H2O)4] (1), has been synthesized and characterized by single crystal X-ray diffraction analysis along with IR and HRMS studies. Complex 1 has been found to selectively interact with human serum albumin (HSA), a model transport protein. The interaction of 1 with HSA was investigated by monitoring the change in the absorbance value of HSA at λ = 280 nm with increasing concentration of 1. Likewise, fluorescence titrations were carried out under two conditions: (i) titration of a 5 μM solution of complex 1 with the gradual addition of HSA, showing a ∼9-fold fluorescence intensity enhancement at 424 nm, upon excitation at 300 nm; and (ii) upon excitation at 295 nm, titration of 5 μM HSA solution with the incremental addition of complex 1, showing a quenching of fluorescence intensity at 334 nm, with simultaneous development of a new emission band at 424 nm. A linear form of the Stern–Volmer equation gives KSV = 9.77 × 104 M−1 and the Benesi–Hildebrand plot yields the binding constant as KBH = 1.98 × 105 M−1 at 298 K. The thermodynamic parameters, ΔS°, ΔH°, and ΔG°, were estimated by using the van't Hoff relationship which infer the major contribution of hydrophobic interactions between HSA and 1. It was observed that quenching of HSA emission arises mainly through a dynamic quenching mechanism as indicated by the dependence of average lifetime 〈τ〉 on the concentration of 1. The changes in the CD (circular dichroism) spectral pattern of HSA in the presence of 1 clearly establish the variation of HSA secondary structure on interaction with 1. The most probable interaction region in HSA for 1 was determined from molecular docking studies which establish the preferential trapping of 1 in the subdomain IIA of site I in HSA and substantiated by the results of site-specific marker studies. Complex 1 was further evaluated for its antiproliferative effects in lung cancer A549 cells, which strictly inhibits the growth of the cells in both 2D and 3D mammospheres, indicating its potential application as an anticancer drug. [ABSTRACT FROM AUTHOR]

Here, we report the design and synthesis of a D⋯π⋯A-based fluorescent probe, (E)-4-(4-(dibutylamine)-2-hydroxystyryl)-1-methylquinolin-1-ium (DHMQ), which is nonfluorescent in ∼100% PBS buffer medium due to a twisted intra molecular charge transfer (TICT) phenomenon and it becomes highly fluorescent (∼149 fold) in the presence of human serum albumin (HSA), owing to the restriction of its intramolecular free rotation inside the hydrophobic binding cavity of HSA. The site-selective fluorescence displacement assay and molecular docking studies clearly reveal that DHMQ selectively binds at subdomain IB of HSA. The 3σ/slope method was adopted to determine the limit of detection (LOD) value, which was as low as 2.39 nM in ∼100% PBS medium, indicating its high sensitivity towards HSA. The low dissociation constant value [Kd = (1.066 ± 0.017) μM] suggests a strong complexation between the DHMQ and HSA. Importantly, it has been demonstrated that DHMQ is capable of detecting HSA in real human serum and urine samples and was found to be suitable for live cell imaging of HSA. [ABSTRACT FROM AUTHOR]

Human serum albumin (HSA) is regarded as a useful biomarker for rapid medical diagnosis of various disorders mainly related to the kidneys and liver. Hence, it is crucial to identify and monitor the HSA level in complex biofluids (urine and blood samples) using a simple approach. Herein, we have designed and synthesized an intramolecular charge transfer (ICT) based environment-sensitive fluorescent molecular probe, (E)-2-(3-(2-(5-methoxy-1H-indol-3-yl)vinyl)-5,5-dimethylcyclohex-2-en-1-ylidene)malononitrile (DCI-MIN), that can selectively interact with HSA in PBS buffer solution and exhibit a ~78-fold enhancement in fluorescence intensity with a significant Stokes shift (~126 nm), which is important to avoid interference from the excitation light. The significant red fluorescence response can be attributed to the suppression of free intramolecular rotation of the DCI-MIN probe inside the hydrophobic binding cavity of HSA and the low polar microenvironment present within HSA. According to the 3σ/slope method, the detection limit was found to be 1.01 nM (0.0671 mg L-1) in aqueous solutions, which is significantly lower than the normal level of HSA in healthy urine and blood serum, indicating its high sensitivity. DCI-MIN has the ability to exhibit useful applications, including the detection and quantification of HSA concentration in complex biofluids (human urine and blood samples) as well as the imaging of serum albumin in living cells. [ABSTRACT FROM AUTHOR]

The aging-associated increase of cancer risk is linked with stromal fibroblast senescence and concomitant cancer- associated fibroblast (CAF) activation. Surprisingly little is known about the role of androgen receptor (AR) signaling in this context.We have found downmodulated AR expression in dermal fibroblasts underlying premalignant skin cancer lesions (actinic keratoses and dysplastic nevi) as well as in CAFs from the 3 major skin cancer types, squamous cell carcinomas (SCCs), basal cell carcinomas, and melanomas. Functionally, decreased AR expression in primary human dermal fibroblasts (HDFs) from multiple individuals induced early steps of CAF activation, and in an orthotopic skin cancer model, AR loss in HDFs enhanced tumorigenicity of SCC and melanoma cells. Forming a complex, AR converged with CSL/RBP-J[kappa] in transcriptional repression of key CAF effector genes. AR and CSL were positive determinants of each other's expression, with BET inhibitors, which counteract the effects of decreased CSL, restoring AR expression and activity in CAFs. Increased AR expression in these cells overcame the consequences of CSL loss and was by itself sufficient to block the growth and tumor-enhancing effects of CAFs on neighboring cancer cells. As such, the findings establish AR as a target for stroma-focused cancer chemoprevention and treatment., IntroductionThe aging-associated increase of many cancer types has been linked with stromal fibroblast senescence and concomitant production of diffusible growth factors, cytokines, and extracellular matrix/ remodeling proteins (1) that are [...]

Here, we report the design and synthesis of a Schiff base probe, DBNHC ((E)-2-(2,4-dihydroxybenzylidene)-N-(naphthalen-1-yl)hydrazine-1-carbothioamide), and its interaction with bovine serum albumin (BSA). In ∼100% PBS buffer, the probe DBNHC can self-assemble into nonfluorescent nanoaggregates due to the aggregation caused quenching (ACQ) effect. However, it becomes highly fluorescent (∼14 fold) in the presence of BSA which facilitates the disassembly of nanoaggregates into its monomer. The site-selective fluorescence displacement assay and molecular docking simulations reveal that mainly hydrogen bonding, π⋯sulphur and π⋯alkyl interactions are responsible for the disassembly of nanoaggregates leading to encapsulation of DBNHC monomer at site II in BSA, resulting in a cyan green emission. The detection limit determined by the 3σ/slope method was found to be 58 nM, and the lower dissociation constant [Kd = (1.506 ± 0.196) μM] value suggests strong binding between the probe and BSA. Further, DBNHC was used for cell incubation and in vitro fluorescence imaging of BSA. [ABSTRACT FROM AUTHOR]

Oral submucous fibrosis (OSMF) is a chronic inflammatory disease of the oral cavity but the pathogenesis of the disease is still uncertain among the areca nut chewers. Every chewer does not show up with fibrotic changes that further extend to genetic basis of OSMF pathogenesis. Genetic predisposition has been now identified as a major risk factor for increasing the susceptibility toward the disease among these chewers. In this study, two single nucleotide polymorphism (SNP) of COL1A2 rs42542 (Exon 28, G1645C) and rs421587 (Intron 28, 665+15A>G) showing mRNA splice variant trait with exon 28 skipping, extended exon 28 and intron 28 retention. The polymorphisms of the COL1A2 gene was identified by polymerase chain reaction‐direct genomic DNA sequencing from 187 patients with OSMF and 188 control participants matched on age, gender, and ethnicity. COL1A2 alternative splice variants from mRNA in human oral biopsy tissues obtained from OSMF patient and controls were confirmed by using reverse transcription PCRs (RT‐PCRs). Significant genotypic associations were observed for an exon 28 SNP (GC; P < [OR‐2.35; CI {1.44‐3.83}; P <.001] and CC [OR‐6.99; CI {1.83‐31.24}; P =.001) induces Ala to Pro substitution at amino acid 459 of COL1A2 in OSMF patients. Exon skipping is significantly associated with both the SNPs. Our results confirm the role of rs42542 and rs421587 in COL1A2 alternative splicing and support a strong role in susceptibility to OSMF, and could have served as surrogate markers. [ABSTRACT FROM AUTHOR]

A new, highly sensitive probe L2 for the selective detection of Hg2+ in organo-aqueous (H2O:CH3CN, 1:1, v/v, HEPES buffer, pH 7.2) medium has been synthesized from rhodamine 6G-hydrazide and 4-nitroindole-3-carboxaldehyde. It was thoroughly characterized by physicochemical techniques including single crystal X-ray diffraction studies. The reaction of L2 with Hg2+ gives a 1:1 stoichiometry resulting in a 146 fold fluorescence enhancement and a binding constant (Kf) of 3 × 104 M−1. The spirolactam form of the probe is non-fluorescent; however, it shows dual channel (absorbance and fluorescence) recognition of Hg2+ via CHEF effect through the opening of the spirolactam ring. The quantum yields of L2 (0.00045) and L2-Hg2+ (0.29) show the higher stability of complex in the excited state over the free ligand. The 44.5 nM LOD value demonstrates the detection of Hg2+ at a very low concentration range. Cell imaging studies show the cytoplasmic recognition of Hg2+ by L2. Experimental results are comparable with theoretical values obtained by DFT studies. The fluorescence emission of the complex was completely quenched by I- and from the reversibility studies an advance level INHIBIT logic gate and memory device can be framed. [ABSTRACT FROM AUTHOR]