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Background: Oral submucous fibrosis (OSF) is a debilitating collagen-metabolic disorder leading to submucosal fibrosis and trismus. Lysyl oxidase (LOX), a critical collagen biosynthetic enzyme, is up-regulated in OSF. Polymorphisms in the Lysyl oxidase gene have been associated with increased risk of OSF and might affect normal collagen synthesis, accumulation, or degradation, crucial in determining fibrosis severity. Methods: One hundred OSF cases and 100 controls were genotyped for LOX G473A(Arg158Gln) polymorphism by polymerase chain reaction-restriction fragment length polymorphism. The expression of LOX was estimated both by quantitative mRNA analysis and western blot. Total soluble collagen was evaluated from mucosal tissue obtained from OSF cases. Immunohistochemical (IHC) localization of type 1 collagen was performed in mucosal tissue obtained from patients carrying various genotypes. Results: Heterozygous G473A genotype was significantly higher in OSF cases [2.063(95% CI =1.059-4.016)], among 26-40 years age-group [4.375(95% CI=1.323-14.267),p=0.029] and in male patients [2.38 (95% CI= 1.107-5.121), p= 0.042]. LOX expression was significantly higher in cases of the heterozygous or homozygous carrier (p

We report a novel phenazine-embedded fluorescent probe (2-[2-(pyridin-2-ylmethoxy)-phenyl]-1H-imidazo[4,5-b]phenazine, PIP), which upon complexation with Cu(II)-ion-forming [(PIP)CuII(Cl)] becomes ...

Human populations of Black African ancestry have a relatively high risk of aggressive cancer types, including keratinocyte‐derived squamous cell carcinomas (SCCs). We show that primary keratinocytes (HKCs) from Black African (Black) versus White Caucasian (White) individuals have on average higher oncogenic and self‐renewal potential, which are inversely related to mitochondrial electron transfer chain activity and ATP and ROS production. HSD17B7 is the top‐ranked differentially expressed gene in HKCs and Head/Neck SCCs from individuals of Black African versus Caucasian ancestries, with several ancestry‐specific eQTLs linked to its expression. Mirroring the differences between Black and White HKCs, modulation of the gene, coding for an enzyme involved in sex steroid and cholesterol biosynthesis, determines HKC and SCC cell proliferation and oncogenicity as well as mitochondrial OXPHOS activity. Overall, the findings point to a targetable determinant of cancer susceptibility among different human populations, amenable to prevention and management of the disease., Differences in individuals' cancer susceptibility can be attributed, in part, to specific genetic and epigenetic variations. Human populations of Black African ancestry have a higher risk of aggressive cancer of various types, including keratinocyte‐derived squamous cell carcinomas (SCCs).

Fluorescence spectroscopy is a significant bio-analytical technique for specific detection of nitric oxide (NO) and for broadcasting the in vitro and in vivo biological activities of this gasotransmitter. Herein, a benzo-coumarin embedded smart molecular probe (BCM) is employed for NO sensing through detailed fluorescence studies in purely aqueous medium. All the spectroscopic analysis and literature reports clearly validate the mechanistic insight of this sensing strategy i.e., the initial formation of 1,2,3,4-oxatriazole on treatment of the probe with NO which finally converted to its carboxylic acid derivative. This oxatriazole formation results in a drastic enhancement in fluoroscence intensity due to the photoinduced electron transfer (PET) effect. The kinetic investigation unveils the second and first-order dependency on [NO] and [BCM] respectively. The very low detection limit (16 nM), high fluorescence enhancement (123 fold) in aqueous medium and good formation constant (Kf = (4.33 ± 0.48) × 104 M−1) along with pH invariability, non-cytotoxicity, biocompatibility and cell permeability make this probe a very effective one for tracking NO intracellularly.

Ma et al. uncovers an essential role of AR signaling in melanoma cell expansion and tumorigenesis, with loss of AR activity inducing cellular senescence, genomic DNA breakage, a STING-dependent inflammatory cascade, and immune cell recruitment, providing an attractive venue for new combination approaches to disease management., Melanoma susceptibility differs significantly in male versus female populations. Low levels of androgen receptor (AR) in melanocytes of the two sexes are accompanied by heterogeneous expression at various stages of the disease. Irrespective of expression levels, genetic and pharmacological suppression of AR activity in melanoma cells blunts proliferation and induces senescence, while increased AR expression or activation exert opposite effects. AR down-modulation elicits a shared gene expression signature associated with better patient survival, related to interferon and cytokine signaling and DNA damage/repair. AR loss leads to dsDNA breakage, cytoplasmic leakage, and STING activation, with AR anchoring the DNA repair proteins Ku70/Ku80 to RNA Pol II and preventing RNA Pol II–associated DNA damage. AR down-modulation or pharmacological inhibition suppresses melanomagenesis, with increased intratumoral infiltration of macrophages and, in an immune-competent mouse model, cytotoxic T cells. AR provides an attractive target for improved management of melanoma independent of patient sex., Graphical Abstract

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-Jκ 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.

Oral submucous fibrosis (OSMF) is regarded as a collagen and collagenase metabolic disorder. Aberrant expression of matrix metalloproteinases (especially MMP-9) plays important role in remodeling of extracellular matrix (ECM) during development of OSMF. Single nucleotide polymorphisms (SNPs) in MMP-9 promoter and coding region have been demonstrated to be associated with several diseases. In this case-control study, 196 controls and 189 OSMF patients were genotyped at four MMP-9 polymorphic sites on −1562C>T, R279Q, P574R and R688Q loci by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) method to determine the susceptibility to OSMF. The functional effect of SNPs to the development of OSMF was analyzed by studying the expression of MMP-9, collagen type-I and IV in oral biopsy tissues. R279Q SNP was found to be associated with OSMF [OR 1.5, CI (1.04–2.43), p = 0.03]. The 574R and 668Q alleles were significantly associated with early age group at 2.08 (p = 0.007) and 2.12 (p = 0.011) fold risk to OSMF respectively. MDR analysis showed that -1562C>T and R688Q SNPs were in strong synergy (IG = 0.95%, p = 0.0032) with increased risk of OSMF. Genotypic and functional study revealed definitive role of MMP-9 coding SNPs R279Q, P574R and R668Q in the pathogenesis of OSMF with strong predictive and prognostic value to determine OSMF at early stages in the areca chewers. Pathologically, over-expression of MMP-9 leads to decrease in collagen type-IV and epithelial thinning which contribute to basement membrane degradation along with continuous accumulation of collagen type-I enhanced by MMP-9 −1562C>T, R279Q, P574R and R688Q SNPs, resulting into early onset of OSMF.

Methodological synthesis of a new biocompatible bi-compartmental rhodamine based probe (L3) provides a multi-inputs and multi-outputs molecular logic circuit based on simple chemosensing phenomena. Spectroscopic responses of Cu2+ and Hg2+ towards L3 together with reversible binding of S2- with L3-Cu2+ and L3-Hg2+ complexes help us to construct a thee-input molecular circuit on their control and sequential addition to a solution of L3 in a mixed organo-aqueous medium. We have further successfully encoded binary digits out of these inputs and outputs which may convert a three-digit input string into a two-digit output string resulting a simple monomolecular logic circuit. Such a molecular ‘Boolean’ logic operation may improve the complexity of logic gate circuitry and computational speed and may be useful to employ in potential biocompatible molecular logic platforms.

Developing simple probes to sense Al 3+ in vivo and in vitro in real time is highly desirable as Al 3+ imbalance has been linked to a variety of diseases in human being. Here, we introduce a new, highly selective and sensitive Schiff base chemosensor, H 2 bpet , based on benzophenone that can detect Al 3+ in a 0.01% ethanol in 50 mM HEPES buffer medium by fluorimetric sensing. The structure of the probe, H 2 bpet involves existence of keto−–enol tautomerism. Single crystal X-ray diffraction study reveals prevalence of keto form of H 2 bpet in the solid state. The binding properties of H 2 bpet with Al 3+ was thoroughly investigated by fluorescence spectroscopy and ESI–MS analyses. The binding of Al 3+ to the probe H 2 bpet , induces distinct 1 H and 13 C NMR shifts in favour of H 2 bpet (keto form):Al 3+ aggregate. The sensing mechanism of H 2 bpet toward Al 3+ and composition of H 2 bpet:Al 3+ aggregate was proposed and established by DFT/TDDFT calculations. Its application in fluorescent imaging in HepG2 cells was also tested. This report demonstrates an advancement in detection of Al 3+ with the introduction of a new benzophenone containing Schiff base chemosensor.

A sensor (HL5) based on rhodamine 6G–en and 3-(3,5-dimethyl-pyrazol-1-ylmethyl)-2-hydroxy-5-methyl-benzaldehyde (HL4) has been developed for a highly sensitive and selective CHEF based recognition of trivalent metal ions M3+ (M = Al, Fe and Cr) over mono- and di-valent and other biologically abundant trivalent metal ions with prominent enhancement in absorption and emission intensities. A large enhancement of fluorescence intensities for Fe3+ (21 fold), Al3+ (14 fold) and Cr3+ (10 fold) was observed upon addition of 1.8 equivalents of these metals into the probe in methanol/H2O (1 : 1, v/v, pH 7.2) with the possibility of naked eye detection. The corresponding Kf values were evaluated to be 6.7 × 104 M−1 (Fe3+); 8.2 × 104 M−1 (Al3+) and 6.0 × 104 M−1 (Cr3+). The quantum yields of HL5 and [HL5–Fe3+] and [HL5–Cr3+] and [HL5–Al3+] complexes in methanol/H2O (1 : 1, v/v, pH 7.2) are found to be 0.013, 0.290, 0.120, and 0.158, respectively, using rhodamine-6G as the standard. The LOD for Fe3+, Al3+ and Cr3+ were determined by 3σ methods with values 0.29, 0.34 and 0.31 μM, respectively. An arsenate ion snatches Al from the Al–HL5 complex and quenches its fluorescence via its ring closed spirolactam form. Advanced level molecular logic devices using the inputs 2 and 4 and memory devices, have been constructed. The low cytotoxicity and large enhancement in fluorescence intensity of HL5 upon complexation with M3+ metal ions make the probe suitable for bio-imaging of M3+ (M = Al, Fe and Cr) in living cells and native cellular iron pools.

A novel di-coordinating rhodamine-based chemosensor, HL with NO donor atoms, selectively and rapidly recognizes Fe3+ in the presence of all biologically relevant as well as toxic metal ions and numerous anions and also with other reactive oxygen and nitrogen species. It exhibits a lower detection limit (0.17 μM) and comparatively higher formation constant (Kf = 1.72 × 104 M−1). The DNA-binding properties of [LFe(NO3)2]+ complex have been comprehensively studied by using UV-Vis, fluorescence, and optical melting studies and circular dichroism, which clearly indicate that [LFe(NO3)2]+ interacts with DNA via a groove binding mode. In particular, competition experiments with Hoechst and DAPI constitute firm evidence for this binding mode, and clearly rule out intercalation. The negative ΔG0 and positive ΔS0 values obtained from a calorimetric technique confirm the spontaneity of the binding of [LFe(NO3)2]+ with DNA. The resulting [LFe(NO3)2]+/DNA composite material could be a valuable candidate for future photonics and/or biological applications.

Neo-tanshinlactone (NTL) a natural product is known for its specificity and selectivity towards the breast cancer cells. By NTL D-ring modification approach, 13 new analogues were synthesized (1A-1M). Among them 1J showed the best anticancer activity in MCF-7 (ER+, PR+/-, HER2-), SKBR3 (ER-, PR-, HER2+) and MDA-MB-231 (ER-, PR-, HER2-) cells lines with IC50 value 11.98nM, 23.71nM, and 62.91nM respectively. 1J showed minor grove binding interaction with DNA at AT-rich region and induced DNA double strand breaks (DDSBs). This had triggered several key molecular events involving, activation of ATM, Chk2 and p53, reduction in mitochondrial potential (Δψm) leading to caspase-3 and PARP cleavage mediated apoptosis. These results along with other biochemical studies strongly suggest that novel NTL analogue 1J caused DNA cleavage mediated apoptosis in the breast cancer cells and this may serve as potential lead for future breast cancer treatment.

Context The effect of 6-gingerol (6G), the bioactive component of Zingiber officinale Roscoe (Zingiberaceae), in the reduction of Vibrio cholerae (Vibrionaceae)-induced inflammation has not yet been reported. Materials and methods Cell viability assay was performed to determine the working concentration of 6G. Elisa and RT-PCR were performed with Int 407 cells treated with 50 μM 6G and 100 multiplicity of infection (MOI) V. cholerae for 0, 2, 3, 3.5, 6 and 8 h to determine the concentration of IL-8, IL-6, IL-1α and IL-1β in both protein and RNA levels. Furthermore, the effect of 50 μM 6G on upstream MAP-kinases and NF-κB signalling pathways was evaluated at 0, 10, 15, 30, 60 and 90 min. Results The effective dose (ED50) value of 6G was found to be 50 μM as determined by cell viability assay. Pre-treatment with 50 μM 6G reduced V. cholerae infection-triggered levels of IL-8, IL-6, IL-1α and IL-1β by 3.2-fold in the protein level and two-fold in the RNA level at 3.5 h. The levels of MAP-kinases signalling molecules like p38 and ERK1/2 were also reduced by two- and three-fold, respectively, after 30 min of treatment. Additionally, there was an increase in phosphorylated IκBα and down-regulation of p65 resulting in down-regulation of NF-κB pathway. Conclusion Our results showed that 6G could modulate the anti-inflammatory responses triggered by V. cholerae-induced infection in intestinal epithelial cells by modulating NF-κB pathway.

A new 8-hydroxyquinoline-pyrazole based highly sensitive and selective Al3+ sensor, 8Q-NH-Pyz (H2L3), was found to exhibit a turn-on fluorescence enhancement (FE) as high as 157 fold with Kd = (1.76 ± 0.06) × 10−5 M. The 1:1 binding stoichiometry was revealed from the linear fit of (Fmax − F0)/(F − F0) vs. 1/[Al3+] of the fluorescence titration data which was further substantiated by Job's method and HRMS studies. The LOD determined by 3σ methods was found to be 4.29 nM and quantum yields were determined to be 0.002 and 0.28 for the ligand and its Al3+ complex, respectively. The tentative coordination environment in the [Al(L3)(H2O)]+ complex was delineated by DFT calculations. TDDFT calculations reveal spectral features comparable to the experimental ones. This constitutes the first report on the fluorescence sensing of Al3+ and hence F− in a purely aqueous medium.

We report herein the development of a novel, diformyl-p-cresol (DFC)–thiosemicarbazide (TS) based sensor (DFC–TS) that selectively and sensitively recognizes Zn2+ by both UV-Vis and fluorescence methods. The gradual addition of Zn2+ to a solution of the ligand developed a new absorption band at 430 nm, while the bands at 370 and 316 nm gradually decrease generating one well defined isosbestic point at 390 nm exhibiting ∼17 fold turn-on fluorescent enhancement (FE). When we plot absorbance (at 430 nm) vs. [Zn2+] there is a gradual increase in absorption with [Zn2+], becoming saturated at ∼1 equivalent of Zn2+ and then again it increases with the increase in [Zn2+] and ultimately becomes saturated at ∼2 equivalents of added Zn2+. This clearly demonstrates that the Zn2+ binding event to the ligand occurs in two steps, one at a time. Non-linear least-squares computer-fitting of these data gives the parameters: K′f1 = (9.70 ± 5.51) × 105 M−1, n = (1.28 ± 0.05) for the first step and K′f2 = (1.11 ± 0.65) × 105 M−1 and n = (1.01 ± 0.06) for the second step. So far, this study provides the opportunity where we have successfully, for the first time, determined the stepwise formation constants; though they have values of the same order of magnitude. The ground state geometries of DFC–TS, both enol and keto forms and [Zn(DFC–TS)(OAc)], [Zn(DFC–TS)(OAc)]−, and [Zn2(DFC–TS)(OAc)2] were optimized using the Gaussian-03 suit program and bond distances of all species are in reasonable agreement with the reported values.

A novel 3-hydroxymethyl-5-methylsalicylaldehydenaphthyl-hydrazone (H3SAL-NH) exhibits ESIPT behaviour due to proton transfer from the phenolic OH group to the azomethine N atom in the excited state. Through this ESIPT behaviour together with cis–trans isomerization of the azomethine group, the free ligand becomes very weakly fluorescent. However, in the presence of Zn2+ and Al3+ the ESIPT and isomerization are blocked due to coordination to the metal ions thereby causing turn on fluorescence for Al3+ and Zn2+. Moreover, Zn2+ can easily be displaced from the [H2SAL-NH–Zn2+] complex by Al3+ thereby enhancing the differential selectivity for Al3+ over Zn2+. This probe was found to be selective for Al3+ over Zn2+ in the presence of Na2H2EDTA, under both intra- and extracellular conditions. The LODs for Zn2+ and Al3+ were determined by 3σ methods and were found to be 3.1 nM and 0.92 nM, respectively. Thus, the differentially selective turn-on fluorescence behaviour of H3SAL-NH for Zn2+ and Al3+ is based on the combined blocking of ESIPT and CN isomerization, and a chelation-enhanced fluorescence (CHEF) effect. The coordination modes of the complexes were investigated through spectroscopic and computational studies. H3SAL-NH also exhibits good photostability and very low cytotoxicity and is useful for fluorescence imaging of Zn2+ and Al3+ ions in live HepG2 cells.

Organic molecules with the possibility of logic operations are highly useful building blocks for the development of molecule-based “intelligent” devices for information processing applications. We have designed herein a very simple bio-friendly chemosensor (LC) equipped with a rhodamine fluorophore moiety. This probe showed a chromo-fluorescence response profile for Al3+ but a colorimetric response for Cu2+ metal. The absorption responses of LC caused by these metal ions along with the “OFF–ON–OFF” fluorescence behavior of an LC–Al3+ complex towards EDTA were employed for the development of a three-input and one output combinatorial molecular system. Interactions of the mentioned metal ions with LC in controlled sequential experiments gave fluorescence responses, enabling us to fabricate a ‘key-pad-logic’ function. So, a single molecular system performing such multiple ‘Boolean’ operations not only simplifies the complexity of a chemical driven ‘Intelligence’ device but also enriches the security of such a device against information invasion due to the sequence controlled sensor–analyte interactions and may find potential applications in biocompatible molecular logic platforms.

A new rhodamine 6G-benzylamine-based sensor (L1), having only hydrocarbon skeletons in the extended part, was synthesized and characterized by single-crystal X-ray crystallographic study. It exhibited excellent selective and sensitive recognition of trivalent metal ions M3+ (M = Fe, Al and Cr) over mono- and di-valent and other trivalent metal ions. A large enhancement of the fluorescence intensity for Fe3+ (41-fold), Al3+ (31-fold) and Cr3+ (26-fold) was observed upon the addition of 3.0 equivalent of these metal ions into the probe in H2O/CH3CN (4 : 1, v/v, pH 7.2) with naked eye detection. The corresponding Kf values were evaluated to be 9.4 × 103 M−1 (Fe3+), 1.34 × 104 M−1 (Al3+) and 8.7 × 103 M−1 (Cr3+). Quantum yields of the L1, [L1–Fe3+], [L1–Al3+] and [L1–Cr3+] complexes in H2O/CH3CN (4 : 1, v/v, pH 7.2) were found to be 0.012, 0.489, 0.376 and 0.310, respectively, using rhodamine-6G as standard. LODs for Fe3+, Al3+ and Cr3+ were determined by 3σ methods and found to be 1.28, 1.34 and 2.28 μM, respectively. Cyanide ion scavenged Fe3+ from the [Fe3+–L1] complex and quenched its fluorescence via its ring-closed spirolactam form. Advanced level molecular logic devices using different inputs (2 and 4 inputs) as advanced level logic gates and memory devices were constructed. The large enhancement in fluorescence emission of L1 upon complexation with M3+ metal ions makes the probe suitable for the bio-imaging of M3+ (M = Fe, Al and Cr) in living cells.

A simple molecular probe displays highly selective turn-on response toward NO by the unprecedented NO-induced formation of a 1,2,3,4-oxatriazole ring exhibiting no interference from various endogenous biomolecules including DHA, AA, etc. Kinetics of the reactions between NO and the probe provide a mechanistic insight into the formation of 1,2,3,4-oxatriazole which showed that, though initially 1,2,3,4-oxatriazole is formed and extractable in solid form, it exists in equilibrium with the ring opened azide form which ultimately hydrolyzed and converted to carboxylic acid and nitrate. The reaction displays second-order dependence on [NO] and first-order on [Probe]. The probe is water-soluble, cell permeable, and noncytotoxic and appropriates for live cell imaging. This constitutes the first report where there is a direct evidence of NO-induced ring closing reaction of an acyl hydrazide moiety leading to the formation of 1,2,3,4-oxatriazole.

A new sensor (L3) based on Rhodamine-B-en (2) and 2-(pyridin-2-ylmethoxy)benzaldehyde (1) has been developed for highly sensitive and selective recognition of NO in purely aqueous medium where the reaction of NO with the fluorophore leads to an unusual formation of nitrosohydroxylamine with the selective opening of the spirolactam ring over different cations, anions, amino-acids and other biological species with prominent enhancement in absorption and emission intensities. A large enhancement of fluorescence intensity for NO (11 fold) was observed upon addition of 3 equivalents of NO into the sensor in aqueous HEPES buffer (20 mM) at pH 7.20, μ = 0.05 M NaCl with naked eye detection. The corresponding Kf value was evaluated to be (7.55 ± 2.04) × 104 M-1 from the fluorescence titration plot. Quantum yields of L3 and the [L3 + NO] compound are found to be 0.07 and 0.77, respectively, using Rhodamine-6G as the standard. The LOD for NO was determined by the 3σ method and found to be 83.4 nM. The L3 sensor has low cytotoxicity, and is cell permeable and suitable for in vitro NO sensing. The in vivo compatibility of the sensor was also checked on zebrafish.