Engineering linker defects in functionalized UiO-66 MOF nanoparticles for oil-in-water Pickering emulsion stabilization.

Designing metal-organic framework (MOF)-based solid nanoparticles to stabilize Pickering emulsions by fine-tuning their hydrophobicity and lipophobicity is vital for essential applications and fundamental understanding. We demonstrate in situ grafting of palmitic acid in UiO-66 MOF through its linker defects. Our designed and activated nanoparticles (denoted as UP') stabilized the Pickering emulsions of n-heptane-in-water. Furthermore, we showed how UP' stabilized emulsion droplets disperse in media by covering each tiny droplet with a nanoscale layer made of UP'. To support our claim, we carried out the freeze-drying process to remove the liquid part from the emulsion, leaving behind the solid shell-like microstructures that we further characterized through several microscopic techniques. The stable n-heptane-in-water emulsion was confirmed by dilution (drop test), conductivity, zeta potential, and theoretical surface electrostatic potential measurements. Rheological studies indicate that the Pickering emulsions of n-heptane-in-water stabilized by UP' are much more resistant to deformation and flow imparting higher (mechanical) stability and shelf-life. Pickering emulsions stabilized by UP' emerged as a versatile way to design smart functional materials of UiO-66 through engineering linker defects that may have potential applications in interfacial catalysis, dye or contaminant separation, etc.

Scaling mechanical instabilities in drying micellar droplets.

Drying-induced mechanical instabilities in aqueous solution droplets occur primarily because, during evaporation, the central liquid minimizes the surface tension by pulling the packed gel-like region, leading to a stretching effect of the liquid region at the receding wet front. Under an appropriate scenario, it finally perturbs the gel-like zone at the droplet periphery, generating cracks, wrinkles, folds, cavities, buckles, etc. Here we report unique wrinkling patterns from evaporating sessile micellar aqueous droplets on rigid and soft substrates kept at temperatures well above the ambient. The wrinkling patterns remarkably vary depending on the material's elastic modulus and substrate, the concentration of the micellar solution (CCTAB), and the substrate temperature (TS). In the low concentration regime (CCTAB ≤ 0.0364 wt%), coffee-ring-like morphologies are observed devoid of any wrinkling morphology irrespective of TS and the substrate's elastic modulus. In the high initial concentration regime (CCTAB ≥ 0.0364 wt%), for droplets deposited at TS ≥ 85 °C, wrinkle formation starts at the droplet peripheral zone, radial on the stiff glass substrate, and annular on the soft cross-linked PDMS substrate. At CCTAB ≥ 2.73 wt%, radial wrinkles on the glass substrate and annular wrinkles on the cross-linked PDMS substrate nucleate from the edges connecting to the central region of the deposit. The ratio between the width of the gel-like deposit (or wrinkle length) and the droplet's radius scales with the initial concentration of the surfactant and depends on the initial equilibrium contact angle of the micellar droplets. Our results support existing understandings of mechanical instabilities of dried deposits, which satisfies interdependent scaling relationships among their number, lengthscale (dried deposit radius, the wavelength of the wrinkles, and peripheral undulations from Rayleigh-Bénard instability), thickness, and elastic modulus. Interestingly, we found substrate-dependent antagonistic interdependence of the elastic modulus of the dried deposit with the initial surfactant concentration.

Cationic surfactant-directed structural control of NaCl crystals from evaporating sessile droplets.

We report morphological regulation of NaCl (sodium chloride) crystals through the evaporative crystallisation process of microdroplets containing a cationic surfactant CTAB (cetyltrimethylammonium bromide). Various fascinating evaporative salt morphologies are observed using different combinations of salt (CNaCl) and surfactant (CCTAB) concentrations. Each observed morphology is carefully explained by the interplaying physical phenomena, such as crystallisation, micellisation, evaporative dewetting, and surface adsorption of anionic couneterions. Salt morphologies are investigated for low (CNaCl = 0.1 (M)), intermediate (CNaCl = 0.5 (M)) and high (CNaCl = 2 (M)) concentrations, whereas surfactant concentrations are varied four orders of magnitudes (from 0.0001 (M) to 0.1 (M)). Interestingly, we observe a threshold in CCTAB at 0.001 (M), beyond which the peripheral rings of dried deposits are found to be composed of CTAB for CNaCl = 0.1 (M), while the same is seen to be made up of NaCl for CNaCl = 2 (M). We have explained the morphological evolution by the process of competitive surface adsorption phenomenon between Cl- and Br- counter ions. Such a detailed study of saline droplet crystallisation in the presence of a cationic surfactant underpins the fundamental understanding of the crystallisation process. In addition, it may further impact application sectors where crystallisation of saline solution plays an important role, especially in the presence of additives.

Piperine and Celecoxib synergistically inhibit colon cancer cell proliferation via modulating Wnt/ß-catenin signaling pathway.

BACKGROUND: Celecoxib (CXB), a selective COX-2 inhibitor NSAID, has exhibited prominent anti-proliferative potential against numerous cancers. However, its low bioavailability and long term exposure related cardiovascular side effects, limit its clinical application. In order to overcome these limitations, natural bioactive compounds with lower toxicity profile are used in combination with therapeutic drugs. Therfore, in this study Piperine (PIP), a natural chemo-preventive agent possessing drug bioavailability enhancing properties, was considered to be used in combination with low doses of CXB. PURPOSE: We hypothesized that the combination of PIP with CXB will have a synergistic anti-proliferative effect on colon cancer cells. STUDY DESIGN: The potency of PIP and CXB alone and in combination was evaluated in HT-29 human colon adenocarcinoma cells and mechanism of growth inhibition was investigated by analyzing the players in apoptotic and Wnt/ß-catenin signaling pathways. METHODS: The effect of PIP on the oral bioavailability of CXB in mice was investigated using HPLC analysis. The study investigated the synergistic anti-proliferative effect of CXB and PIP on HT-29 cells and IEC-6 non-tumorigenic rat intestinal epithelial cells by SRB cell viability assay. Further, the cellular and molecular mechanism(s) involved in the anti-proliferative combinatorial effect was extensively explored in HT-29 cells by flow cytometry and western blotting. The in vivo efficacy of this combination was studied in CT26.WT tumor syngeneic Balb/c mice model. RESULTS: PIP as a bioenhancer increased the oral bioavailability of CXB (129%). The IC50 of CXB and PIP were evaluated to select doses for combination treatment of HT-29 cells. The drug combinations having combination index (CI) less than 1 were screened using CompuSyn software. These combinations were significantly cytotoxic to HT-29 cells but IEC-6 were least effected. Further, the mechanism behind CXB and PIP mediated cell death was explored. The co-treatment led to reactive oxygen species generation, mitochondrial dysfunction, caspase activation and enhanced apoptosis in HT-29 cells. Additionally, the combination treatment synergistically modulated Wnt/ß-catenin pathway, downregulated the stemness markers and boosted therapeutic response in CT26 syngeneic Balb/c mice. CONCLUSION: The outcomes of the study suggests that combining CXB and PIP offers a novel approach for the treatment of colon cancer.

N-acetyl-cysteine in combination with celecoxib inhibits Deoxynivalenol induced skin tumor initiation via induction of autophagic pathways in swiss mice.

Deoxynivalenol is a trichothecene mycotoxin which naturally contaminates small grain, cereals intended for human and animal consumption. Investigations for dermal toxicity of DON has been needed and highlighted by WHO. Previous studies on dermal toxicity suggest that DON has DNA damaging potential leading to skin tumor initiation in mice skin. However, considering its toxicological manifestations arising after dermal exposure, strategies for its prevention/protection are barely available in literatute. Collectively, our study demonstrated that N-acetylcysteine (NAC), precursor of glutathione, significantly alters the genotoxic potential of DON. Further NAC in combination with Celecoxib (CXB) inhibits tumor growth by altering antioxidant status and increasing autophagy in DON initiated Swiss mice. Despite the broad spectrum use of CXB, its use is limited by the concerns about its adverse effects on the cardiovascular system. Serum parameters and histology analysis revealed that CXB (2 mg) when applied topically for 24 weeks did not impart any cardiovascular toxicity which could be because skin permeation potential of CXB was quite low when analyzed through HPLC analysis. Although the anticancer effects of CXB and NAC have been studied, however, the combination of NAC and CXB has yet not been explored for any cancer treatment. Therefore our observations provide additional insights into the therapeutic effects of combinatorial treatment of CXB and NAC against skin tumor prevention. This approach might form a novel alternative strategy for skin cancer treatment as well as skin associated toxicities caused by mycotoxins such as DON. This combinatorial approach can overcome the limitations associated with the use of CXB for long term as topical application of the same seems to be safe in comparison to the oral mode of administration.

Celecoxib reduces Deoxynivalenol induced proliferation, inflammation and protein kinase C translocation via modulating downstream targets in mouse skin.

Exposure to mycotoxins is mostly by ingestion but also occurs by the dermal and inhalation routes. The present study for the first time demonstrated that mycotoxin Deoxynivalenol (DON), permeates through Swiss albino mice skin, which demands awareness of health risks in people who are dermally exposed to mycotoxins especially agricultural farmers. Despite the widespread contamination of DON in food commodities studies to alleviate DON's toxicity are sparsely reported. Thus effective measures to combat mycotoxins associated toxicity remains an imperative aspect to be considered from the angle of dermal exposure. Topical application of Celecoxib (1-2 mg), followed by DON (100 µg) application on the dorsal side of mice, resulted in substantial decrease in DON-induced (i) edema, hyperplasia, cell proliferation (ii) inhibition of cytokine and prostaglandin-E2 levels (iii) phosphorylation of ERK1/2, JNK, p38, MAPKKs, CREB, P90-RSK (iv) downregulation of c-Jun, c- Fos, phospho-NF-kB and their downstream target proteins cyclin D1 and COX-2. Using Ro-31-8220 (Protein-Kinase-C inhibitor), it was observed PKC was responsible for DON induced upregulation of COX-2 and iNOS proteins. Treatment of Celecoxib decreased DON-induced translocation of Protein Kinase C isozymes (α,ε,γ), demonstrating the role of PKC in DON-mediated biochemical and molecular alterations responsible for its dermal toxicity. The present findings indicate that topical application of celecoxib is effective in the management of inflammatory skin disorders induced by foodborne fungal toxin DON. The skin permeation potential of Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor NSAID, was also assessed, and the results indicated that the permeation was relatively lower as compared to the oral mode of administration. Hence topical use of celecoxib may be preferred over oral dosing because of lower systemic absorption and to avoid the unwanted side effects. This study provides a prospect for exploring the clinical efficacy of topically applied COX-2 inhibitors for the management of inflammatory skin disorders induced by foodborne fungal toxins.

Multifunctional hybrid nanoconstructs facilitate intracellular localization of doxorubicin and genistein to enhance apoptotic and anti-angiogenic efficacy in breast adenocarcinoma.

The progressive development of tumors leading to angiogenesis marks the advancement of cancer which requires specific targeted treatment preferably with combination chemotherapy. However, there is still a long way to go to develop an efficient delivery system that could overcome the tumor microenvironment to achieve efficient delivery. Therefore, we have developed spermine (SPM) tethered lipo-polymeric hybrid nanoconstructs with cell surface heparan sulfate proteoglycan (HSPG) specificity for higher intracellular localization and pH dependent charge reversal in the tumor microenvironment (below pH 5.8) to facilitate Doxorubicin (Dox) and Genistein (Gen) release in a synergistic combination. We have observed the specific uptake of SPM anchored hybrid nanoconstructs by receptor-mediated endocytosis in human breast cancer cells (MDA-MB-231) through the HSPG receptor. The SPM-D + G/NPs induced a higher rate of apoptosis in MDA-MB-231 cells via disruption of the mitochondrial membrane potential and also exhibited a stronger anti-angiogenic effect governing the inhibition of VEGF pathway modulation, proliferation, invasion and migration of HUVECs in in vitro and in vivo Balb/c mouse models. The involvement of Akt/Hif1α/VEGF dependent signal cascading and its down-regulation with a pro-apoptotic drug Dox and an anti-angiogenic agent Gen was evident as demonstrated by an in silico docking study and subsequently proven by RT-PCR and western blotting. Altogether this study highlights the potential role of SPM in targeting HSPG receptors and synergistic delivery of Dox and Gen as a promising strategy to effectively inhibit BAC progression and these findings could open a new window to deliver combinations of chemotherapeutic agents along with anti-angiogenic ligands using hybrid nanoparticles.

Global occurrence of deoxynivalenol in food commodities and exposure risk assessment in humans in the last decade: a survey.

Preventing food from fungal infestation has become a cause of great concern as food safety is of particular importance to public health globally. Recently International Agency for Research on Cancer (IARC) and the World Health Organization (WHO) in its 2016 press release has urged to take action against widespread mycotoxin contamination in developing countries. Deoxynivalenol (DON) is a group B trichothecene mycotoxin, produced by common field pathogens such as Fusarium graminearum and Fusarium culmorum, and reported to be the predominant contaminant of food commodities. At present, no detailed/systematic review regarding the global occurrence of DON in various food and grain samples is available in the literature. Considering DON's cosmopolitan behavior and toxicological manifestations, the present review summarizes the region-wise reports and surveys conducted across the globe during the last decade, on the occurrence of DON in the food commodities intended for human consumption. Studies conducted on DON metabolites either in food, urine or blood samples from humans have also been reviewed. The present review indicates that the current exposure levels of DON might pose a health risk for the consumers, especially in growing children, necessitating to take vigilant steps to guarantee food safety.

Induction of Mitochondrial Cell Death and Reversal of Anticancer Drug Resistance via Nanocarriers Composed of a Triphenylphosphonium Derivative of Tocopheryl Polyethylene Glycol Succinate.

We have devised a nanocarrier using "tocopheryl polyethylene glycol succinate (TPGS) conjugated to triphenylphosphonium cation" (TPP-TPGS) for improving the efficacy of doxorubicin hydrochloride (DOX). Triphenylphosphonium cation (TPP) has affinity for an elevated transmembrane potential gradient (mitochondrial), which is usually high in cancer cells. Consequently, when tested in molecular docking and cytotoxicity assays, TPP-TPGS, owing to its structural similarity to mitochondrially directed anticancer compounds of the "tocopheryl succinate" family, interferes specifically in mitochondrial CII enzyme activity, increases intracellular oxidative stress, and induces apoptosis in breast cancer cells. DOX loaded nanocarrier (DTPP-TPGS) constructed using TPP-TPGS was positively charged, spherical in shape, sized below 100 nm, and had its drug content distributed evenly. DTPP-TPGS offers greater intracellular drug delivery due to its rapid endocytosis and subsequent endosomal escape. DTPP-TPGS also efficiently inhibits efflux transporter P glycoprotein (PgP), which, along with greater cell uptake and inherent cytotoxic activity of the construction material (TPP-TPGS), cumulatively results in 3-fold increment in anticancer activity of DOX in resistant breast cancer cells as well as greater induction of necroapoptosis and arrest in all phases of the cell cycle. DTPP-TPGS after intravenous administration in Balb/C mice with breast cancer accumulates preferentially in tumor tissue, which produces significantly greater antitumor activity when compared to DOX solution. Toxicity evaluation was also performed to confirm the safety of this formulation. Overall TPP-TPGS is a promising candidate for delivery of DOX.

Plasminogen activator inhibitor-1 polymorphisms as a risk factor for chronic periodontitis in North Indian population.

OBJECTIVES: Impaired plasminogen activator inhibitor-1 (PAI-1), controlling coagulation and the fibrinolytic system is supposed to be involved in the pathogenesis of periodontitis. This study was performed to examine the association of PAI-1 gene polymorphisms with Chronic Periodontitis (CP) and alveolar bone loss severity involved with the disease and for understanding the role of genetic contributions in disease progression. METHODS: 87 volunteers were included in the study. Genomic DNA was isolated from peripheral blood, subsequently, DNA samples were subjected to polymerase chain reaction and endonuclease digestion. Direct gene sequencing were performed for all the samples to identify genotype polymorphisms (rs 11560324) in the 3' untranslated region of PAI-1 gene. For bone loss assessment full mouth IOPA was taken. RESULTS: Statistical analysis showed that for SNP PAI-I in 3' UTR, genotype CC (homozygous mutant) and allele C (mutant) has a risk associated with CP, although statistically significant association was not found. An increased risk of association of disease severity with CG (heterozygous mutant) and CC (homozygous mutant) genotypes, i.e., an increased carriage rate of genotype CG and CC (homozygous mutant) was evident with the increase in the severity of CP, highlighting an increased susceptibility to CP due to this gene polymorphisms. CONCLUSION: PAI-1 genotype has a risk association with CP and alveolar bone loss severity in North-Indian population.

Safety assessment of the pharmacological excipient, diethylene glycol monoethyl ether (DEGEE), using in vitro and in vivo systems.

BACKGROUND: Diethylene glycol monoethyl ether (DEGEE) is widely used as a solubilizer in cosmetics as well as in oral, topical, transdermal and injectable pharmaceutical formulations. Due to the unavailability of detailed toxicological studies on DEGEE, the Scientific Committee on Consumer Products (SCCP) found its toxicological reports to be unsatisfactory, comprising only summaries. Also, a few reports have raised concern on the use of DEGEE as it might cause damage to the kidneys. OBJECTIVE: Safety assessment of DEGEE using in vitro and in vivo models. METHODS: In vitro effects of DEGEE (0.5-25 mg/ml) were assessed in the HEK293 human embryonic kidney cells. In vivo effects were evaluated after single acute exposure of DEGEE via intraperitoneal route in Swiss albino mice and further, a 28 days subchronic exposure study was conducted where DEGEE was administered orally, once daily. RESULTS: DEGEE was cytotoxic to HEK293 cells, and an IC50 of 15 mg/ml was established. An increase in the intracellular levels of ROS and alteration in the mitochondrial membrane potential led to nuclear fragmentation and induction of apoptosis in these cells. Survival rate of animals administered intraperitoneally with a single acute dose of 1000 mg/kg DEGEE was 100% with no significant changes in the behavioural and histological parameters. However, the dose of 3000 mg/kg and above led to total mortality within 14 days of acute exposure. Subchronic oral exposure of 500-2000 mg/kg DEGEE showed no significant changes in the hematological, biochemical and histopathological parameters. CONCLUSIONS: The in vitro findings indicate that the nephrotoxic potential of DEGEE cannot be ruled out. The results of the in vivo studies reveal that the degree of toxic effects shown by DEGEE varies, depending on the dose, duration of exposure and routes of administration. Therefore, the present findings are of relevance and thorough studies should be conducted before using this substance in clinical formulations. Graphical abstract Evaluation of the toxic potential of Diethylene glycol monoethyl ether.

Salinomycin inhibits breast cancer progression via targeting HIF-1α/VEGF mediated tumor angiogenesis in vitro and in vivo.

Cancer is a complex disease wherein cells begin to divideabnormally and spread into surrounding tissues. Angiogenesis plays a crucial role in tumor progression as it is required for sustained growth and metastasis, therefore targeting angiogenesis is a promising therapeutic approach for breast cancer management. Salinomycin (SAL) has been reported to exhibit anticancer response on various types of cancer. In the present study, we explored the antiangiogenic and anticancer efficacy of the polyether ionophore SAL in the breast cancer model. It effectively inhibited cell proliferation, invasion, and migration. It also inhibited the expression of pro-angiogenic cell surface marker CD31 in HUVEC, thereby interrupting the endothelial tubulogenesis. It decreased the HIF-1α transcription factor DNA binding activity to HRE sequence in HUVEC and human breast cancer cells. Further, corresponding to our in vitro findings, SAL suppressed neovascularization in the chick chorioallantoic membrane and the Matrigel plug implanted mice model. Bioluminescence and immunofluorescence imaging revealed that SAL treatment in mice inhibits breast cancer growth and tumor angiogenesis. SAL also suppressed the serum VEGFA level in tumor-bearing mice and induced caspase-dependent apoptosis in breast cancer cells. Taken together our findings suggested that SAL inhibits VEGF induced angiogenesis and breast cancer growth via interrupting HIF-1α/VEGF signalling and could be used as a promising antiangiogenic agent for breast cancer treatment.

Sneaky Entry of IFNγ Through Arsenic-Induced Leaky Blood-Brain Barrier Reduces CD200 Expression by Microglial pro-Inflammatory Cytokine.

Recent studies showed that neuronal surface protein CD200 plays a key role in the regulation of neuroinflammation. Previously, we showed that arsenic (0.38 mg/kg body weight) exposure induces microglial activation and consequently IL-6/TNF-α secretion. This result indicated the possibility of alteration in the expression of CD200. Therefore, the present study was focused on checking arsenic-induced alteration in CD200 expression and revealing the underlying mechanism. Male BALB/c mice were exposed to arsenic (vehicle, 0.038 and 0.38 mg/kg body weight) for 60 days, and the expression level of CD200 was found to be decreased which was rescued by minocycline (33 mg/kg body weight) co-administration. Higher CD68 staining, increased level of IL-6/TNF-α, as well as higher level of IFNγ, were observed in in vivo arsenic-exposed groups. Interestingly, in vitro arsenic exposure could not increase IL-6/TNF-α level in the culture supernatant, whereas, supplementation of IFNγ could mimic the in vivo results. However, arsenic could not induce IFNγ production from brain endothelial cells, microglia, and astrocytes, thereby suggesting the entry of IFNγ through the impaired blood-brain barrier. Evans blue fluorescence in the brain confirms altered blood-brain barrier permeability although no changes were observed in the expression level of tight junction proteins (claudin-5 and occludin). Finally, intracerebral injection of anti-IFNγ neutralizing antibody in arsenic-exposed brain reduced microglia activation (IL-6 and TNF-α and CD68 expression) and subsequently rescued CD200 level. Taken together, the study showed that arsenic-mediated compromised blood-brain barrier is a major driving force to induce microglial IL-6 and TNF-α production through serum IFNγ leading to CD200 downregulation.

Correction to: Sneaky Entry of IFNγ Through Arsenic-Induced Leaky Blood-Brain Barrier Reduces CD200 Expression by Microglial pro-Inflammatory Cytokine.

The original version of this article unfortunately contained mistake on Fig. 3A.

Chetomin induces apoptosis in human triple-negative breast cancer cells by promoting calcium overload and mitochondrial dysfunction.

Human triple-negative breast cancer (TNBC) is poorly diagnosed and unresponsive to conventional hormone therapy. Chetomin (CHET), a fungal metabolite synthesized by Chaetomium cochliodes, has been reported as a promising anticancer and antiangiogenic agent but the complete molecular mechanism of its anticancer potential remains to be elucidated. In our study, we explored the anti-neoplastic action of CHET on TNBC cells. Cytotoxicity studies were performed in human TNBC cells viz. MDA-MB-231 and MDA-MB-468 cells by Sulforhodamine B assay. It exhibited antiproliferative response and induced apoptosis in both the cell types. Cell cycle analysis revealed that it increases the sub G0/G1 phase cell population. Modulation of mitochondrial membrane potential, activation of caspase 3/7 and a remarkable increase in the expression of cleaved PARP and increased chromatin condensation was observed after CHET treatment in MDA-MB-231 and MDA-MB-468 cells. Additionally, an elevated level of intracellular Ca2+ played an important role in CHET mediated cell death response. Calcium overload in mitochondria led to release of cytochrome c which in turn triggered caspase-3 mediated cell death. Inhibition of calcium signalling using BAPTA-AM reduced apoptosis confirming the involvement of calcium signalling in CHET induced cell death. Chetomin also inhibited PI3K/mTOR cell survival pathway in human TNBC cells. The overall findings suggest that Chetomin inhibited the growth of human TNBC cells by caspase-dependent apoptosis and modulation of PI3K/mTOR signalling and could be used as a novel chemotherapeutic agent for the treatment of human TNBC in future.

Centchroman regulates breast cancer angiogenesis via inhibition of HIF-1α/VEGFR2 signalling axis.

AIMS: Angiogenesis is a recognized hallmark of cancer which promotes cancer cell progression and metastasis. Inhibition of angiogenesis to attenuate cancer growth is becoming desirable strategy for breast cancer management. The present study is aimed to investigate the antiangiogenic efficacy of a novel selective estrogen receptor modulator Centchroman (CC) on human breast cancer cells. MAIN METHODS: Effect of CC on cell viability was evaluated using Sulforhodamine B assay. Endothelial cell proliferation, wound healing, Boyden chamber cell invasion, tube formation and chorioallantoic membrane (CAM) assays were performed to assess the effect of CC on migration, invasion and angiogenesis. Apoptosis, reactive oxygen species generation, caspase-3/7 and intracellular calcium ion level were measured through flow cytometry. Expression levels of HIF-1α, VEGF, VEGFR2, AKT and ERK were assessed by western blot analysis. KEY FINDINGS: CC selectively induces apoptosis in human breast cancer cells without affecting non-tumorigenic breast epithelial cells MCF-10A. Moreover, it inhibits migratory, invasive and mammosphere forming potential of breast cancer. Furthermore, CC also inhibited VEGF-induced migration, invasion and tube formation of HUVECs in vitro. CC effectively inhibited neovasculature formation in chicken CAM. Western blot analysis demonstrated that CC inhibited expression of HIF-1α and its downstream target VEGF. Interestingly, CC also suppressed VEGFR2 phosphorylation and consequently attenuated AKT and ERK phosphorylation. SIGNIFICANCE: Our findings suggest that CC downregulates VEGF-induced angiogenesis by modulating HIF-1α/VEGFR2 pathway and recommend it (CC) as a potential therapeutic drug for breast cancer treatment.

miRNA genetic variants: As potential diagnostic biomarkers for oral cancer.

MicroRNAs (miRNAs) comprise a novel class of small, non-coding endogenous RNAs that have a role in the plethora of regulatory activities by directing their target mRNAs for degradation or translational repression. Single nucleotide polymorphisms (SNPs) in miRNA genes can lead to alteration in mRNA expression, resulting in serious consequences. Detection of miRNA-polymorphisms can potentially improve diagnosis, treatment, prognosis in patients and has extreme implications in the fields of pharmacogenomics and personalization of medicine. The aim of this study is to investigate the association between miR-499 A/G and miR-149 C/T polymorphisms with susceptibility to development of Oral Squamous Cell Carcinoma (OSCC). 200 histopathologically diagnosed and confirmed samples from OSCC patients and 200 control samples from the general population were recruited for the study. All OSCC patients were graded based on their differentiation, and genetic analysis was performed by PCR-RFLP and sequencing. qRT-PCR was carried out to compare the expression of miR-499 and miR-149 in different grades of various stages of OSCC patients concerning to the controls. Further Immunohistochemistry (IHC) was performed to study the target gene of miR-499. The study shows a probable association of miR-499 A/G and miR-149 C/T with susceptibility of OSCC. Random sequencing analysis and Immunohistochemistry contribute to the result that miR-499 A/G increases the susceptibility of OSCC by targeting SOX-6. PCR- Restriction Fragment Length Polymorphism (RFLP) and multivariable logistic analysis revealed that there is a significant association between miR-149 CT+TT and CT and susceptibility of OSCC. Our study suggests that miR-499 A/G and miR-149 C/T polymorphisms may play crucial roles in susceptibility and development of OSCC in Indian population.

Renal Clearable New NIR Probe: Precise Quantification of Albumin in Biofluids and Fatty Liver Disease State Identification through Tissue Specific High Contrast Imaging in Vivo.

Development of a highly photostable, renal clearable, and nontoxic new NIR probe (CyG) for precise quantification of albumin in different biofluids and liver targeted in vivo albumin visualization is demonstrated. CyG's inherent property to interact selectively with albumin among different biomolecules in intracellular environment with high degree of sensitivity helps CyG in targeted liver imaging. In addition to its long excitation/emission wavelengths (λex = 740 nm, λem = 804 nm), which are much above the biological tissue opaque window (400-700 nm) ensuring better photon penetration, diminished tissue autofluorescence and high contrasts, its molecular mass and size are far below the renal cutoff and hence, CyG qualifies as imaging material for clinical studies. We anticipate that CyG will provide new strategies to overcome the pitfall of present day albumin detection methods as well as accelerate the detection process at relatively lower costs without compromising the accuracy of detection. Moreover, the renal excretion kinetic and intrahepatic albumin binding affinity of CyG can further be used to differentiate between fatty liver from healthy liver in an experimentally arrived mouse model using noninvasive technique.

Novel combination of salinomycin and resveratrol synergistically enhances the anti-proliferative and pro-apoptotic effects on human breast cancer cells.

Resveratrol (RES) is a natural polyphenol having anti-proliferative activity against breast cancer cells. RES in combination with other chemo modulatory agents, minimizes toxicity and increases efficacy of the treatment. Salinomycin (SAL), a monocarboxylic polyether ionophore is known for selectively targeting breast cancer stem cells. Purpose of the present study was to investigate whether RES in combination with SAL exerts synergistic anti-proliferative activity on breast cancer cells. We further evaluated the molecular mechanism behind SAL and RES mediated cell death. Cytotoxicity assay was performed to determine 50% inhibitory concentration (IC50) of SAL and RES in different human breast cancer cells (HBCCs). Drug synergism and combination index (CI) were calculated using CompuSyn software and effects of synergistic combinations (CI < 1) involving lower doses of SAL and RES were selected for further studies. This combination significantly induced apoptosis in HBCCs without affecting non tumorigenic human breast epithelial cells MCF-10A. Co-treatment enhanced apoptosis in MCF-7 cells via reactive oxygen species (ROS) mediated mitochondrial dysfunction. Oxidative stress disrupt redox homeostasis which altered antioxidant enzymes viz. CuZn Superoxide dismutase (SOD), MnSOD and catalase. Additionally, combination altered nuclear morphology, enhanced PARP cleavage and led to caspase activation. SAL and RES also synergistically modulated MAPK pathway. Study suggests that SAL and RES offer a novel combination approach for the treatment of breast cancer.