Repression of resistance mechanisms of Pseudomonas aeruginosa: implications of the combination of antibiotics and phytoconstituents.

Antimicrobial resistance is a prevalent problem witnessed globally and creating an alarming situation for the treatment of infections caused by resistant pathogens. Available armaments such as antibiotics often fail to exhibit the intended action against resistant pathogens, leading to failure in the treatments that are causing mortality. New antibiotics or a new treatment approach is necessary to combat this situation. P. aeruginosa is an opportunistic drug resistant pathogen and is the sixth most common cause of nosocomial infections. P. aeruginosa due to its genome organization and other factors are exhibiting resistance against drugs. Bacterial biofilm formation, low permeability of outer membrane, the production of the beta-lactamase, and the production of several efflux systems limits the antibacterial potential of several classes of antibiotics. Combination of phytoconstituents with antibiotics is a promising strategy to combat multidrug resistant P. aeruginosa. Phytoconstituents such as flavonoids, terpenoids, alkaloids, polypeptides, phenolics, and essential oils are well known antibacterial agents. In this review, the activity of combination of the phytoconstituents and antibiotics, and their corresponding mechanism of action was discussed elaborately. The combination of antibiotics and plant-derived compounds exhibited better efficacy compared to antibiotics alone against the antibiotic resistance P. aeruginosa infections.

Non-Canonical Targets of MicroRNAs: Role in Transcriptional Regulation, Disease Pathogenesis and Potential for Therapeutic Targets.

MicroRNAs are a class of regulatory, non-coding small ribonucleic acid (RNA) molecules found in eukaryotes. Dysregulated expression of microRNAs can lead to downregulation or upregulation of their target gene. In general, microRNAs bind with the Argonaute protein and its interacting partners to form a silencing complex. This silencing complex binds with fully or partial complementary sequences in the 3'-UTR of their cognate target mRNAs and leads to degradation of the transcripts or translational inhibition, respectively. However, recent developments point towards the ability of these microRNAs to bind to the promoters, enhancers or coding sequences, leading to upregulation of their target genes. This review briefly summarizes the various non-canonical binding sites of microRNA and their regulatory roles in various diseased conditions.

Multi-dimensional role of gangliosides in modulating cancer hallmarks and their prospects in targeted cancer therapy.

Gangliosides are glycosphingolipids with prevalence in nervous tissue and their involvement in certain neuronal diseases have been widely known. Interestingly, many recent studies highlighted their importance in the development and progression of various cancers through orchestration of multiple attributes of tumorigenesis, i.e., promoting migration, invasion, escaping the host immune system, and influencing other cancer hallmarks. Therefore, the multidimensional role of gangliosides in different cancers has established them as potential cancer targets. However, the tremendous structural complexity and functional heterogeneity are the major challenges in ganglioside research. Moreover, despite numerous immunotherapeutic attempts to target different gangliosides, it has failed to yield consistent results in clinical trials owing to their poor immunogenicity, a broad range of cross-reactivity, severe side effects, lack of uniform expression as well as heterogeneity. The recent identification of selective O-acetylated ganglioside expression in cancer tissues, but not in normal tissues, has strengthened their potential as a better and specific target for treating cancer patients. It was further supported by reduced cross-reactivity and side effects in clinical trials, although poor immunogenicity remains a major concern. Therefore, in addition to characterization and identification of the biological importance of O-acetylated gangliosides, their specific and efficient targeting in cancer through engineered antibodies is an emerging area of glycobiology research. This review highlights the modulatory effect of select gangliosides on different hallmarks of cancer and presents the overall development of ganglioside targeted immunotherapies along with recent progress. Here, we have also discussed its potential for future modifications aimed towards improvement in ganglioside-based cancer therapies.

Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.

OBJECTIVES: 46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of underandrogenization of male genitalia. Such patients should be approached systematically to reach an aetiological diagnosis. However, we lack, at present, a clinical practice guideline on diagnostic approach in 46, XY DSD from this part of the globe. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests, performed in these cases. The consensus committee consisting of 34 highly experienced endocrinologists with interest and experience in managing DSD discussed and drafted a consensus statement on the diagnostic approach to 46, XY DSD focussing on relevant history, clinical examination, biochemical evaluation, imaging and genetic analysis. CONTENT: The consensus was guided by systematic reviews of existing literature followed by discussion. An initial draft was prepared and distributed among the members. The members provided their scientific inputs, and all the relevant suggestions were incorporated. The final draft was approved by the committee members. SUMMARY: The diagnostic approach in 46, XY DSD should be multidisciplinary although coordinated by an experienced endocrinologist. We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods. Meticulous history taking and thorough head-to-toe examination should initially be performed with focus on external genitalia, including location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to the age and interpreted according to age-appropriate norms Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, are acceptable alternatives. All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may be used to demonstrate the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings. OUTLOOK: The members of the committee believe that patients with 46, XY DSD need to be approached systematically. The proposed diagnostic algorithm, provided in the consensus statement, is cost effective and when supplemented with appropriate genetic studies, may help to reach an aetiological diagnosis in majority of such cases.

Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis.

While the anti-inflammatory activities of Eriodictyol, a plant-derived flavonoid is well-known, reports on its anti-cancer efficacy and selective cytotoxicity in cancer cells are still emerging. However, little is known regarding its mechanism of selective anti-cancer activities. Here, we show the mechanism of selective cytotoxicity of Eriodictyol towards cancer cells compared to normal cells. Investigation reveals that Eriodictyol significantly upregulates TNFR1 expression in tumor cells (HeLa and SK-RC-45) while sparing the normal cells (HEK, NKE and WI-38), which display negligible TNFR1 expression, irrespective of the absence or presence of Eriodictyol. Further investigation of the molecular events reveal that Eriodictyol induces apoptosis through expression of the pro-apoptotic DISC components leading to activation of the caspase cascade. In addition, CRISPR-Cas9 mediated knockout of TNFR1 completely blocks apoptosis in HeLa cells in response to Eriodictyol, confirming that Eriodictyol induced cancer cell apoptosis is indeed TNFR1-dependent. Finally, in vivo data demonstrates that Eriodictyol not only impedes tumor growth and progression, but also inhibits metastasis in mice implanted with 4T1 breast cancer cells. Thus, our study has identified Eriodictyol as a compound with high selectivity towards cancer cells through TNFR1 and suggests that it can be further explored for its prospect in cancer therapeutics.

Evaluation of antimicrobial activity of the extract of Streptomyces euryhalinus isolated from the Indian Sundarbans.

The discovery of new antimicrobials is the prime target in the fight against antimicrobial resistance. The continuous search for new lead compounds from bacteria of untapped and extreme ecosystems such as mangroves is currently being undertaken. This study describes the metabolite profiling of the Streptomyces euryhalinus culture extract. Previously, Streptomyces euryhalinus was isolated from the mangrove forest of Indian Sundarbans as a novel microorganism. The antimicrobial mechanism of action of Streptomyces euryhalinus culture extract against bacteria and fungi has been analyzed in this study. The gas chromatography-mass spectrometry profile of the ethyl acetate extract bacterial culture displayed the presence of several bioactive compounds with antibacterial, antifungal and antioxidant properties. The bacterial extract showed significant antimicrobial activity in terms of zone of inhibition, minimum inhibitory concentration, minimum bactericidal concentration, and minimum fungicidal concentration. Moreover, substantial capacity to alter or damage the inner membrane as well as the outer membrane of the gram-positive and gram-negative bacteria was exhibited by the bacterial extract. This membrane alteration or damaging potential of the extract is the mechanism of action. Biofilm formation inhibition property of the extract also signified its antimicrobial action, and possible use against resistant bacteria. The extract has shown notable activity against the virulence factors like prevention of hemolysis in bacteria and inhibition of secreted aspartyl proteinase in fungi. These functions of the bacterial extract have revealed the extent of its action in the prevention of infection by terminating the secretory virulence factors and by damaging the tissue.

A study on normal reference values of echocardiographic chamber dimensions in young eastern Indian adults.

OBJECTIVE: Various studies have shown racial differences in adult cardiac chamber measurements by echocardiography. There is lack of any large scale data from India regarding the echocardiographic chamber measurements in cardiologically healthy individuals. In this study we present the normal reference values of echocardiographic chamber dimensions in young eastern Indian adults and compare it with the data in present guidelines and recent studies involving Indian subjects. METHODS: This study was performed on 1377 healthy adults aged 18-35 years. Standard transthoracic echocardiographies were performed to obtain basic measurements. All measurements were indexed to body surface area. RESULTS: The mean maximal aortic valve cusp separation (ACS) and indexed ACS were significantly more in females (p = 0.002, p = 0.03). Mean left ventricular (LV) ejection fraction (LVEF) and LV fractional shortening were marginally higher in females. Upper normal reference limit of LV end diastolic dimension (LVEdD) is slightly more for males. Comparing to ASE data, LVEdD, LV end systolic dimension, LV end diastolic volume, indexed LV end systolic volume, left atrial anteroposterior dimension, aortic root dimension and right ventricle outflow diameter were significantly lower in study population while LVEF was significantly higher (p < 0.0001). CONCLUSION: The study reconfirms that Indian subjects have smaller cardiac chamber measurements compared to western population where as LVEF is higher in the Indian population and also demonstrates the wide variation of normal echocardiographic measurements within Indian subcontinent. No previous data from eastern India makes this research a singular experience.

Two Decades of Gla-100-Reflections from the Pivotal Clinical Trials.

The progressive nature of type 2 diabetes mellitus (T2DM) renders the shifting of patients from oral drugs to insulin therapy an inevitability in most patients especially in those with long duration of diabetes. At the turn of the last millennium, neutral protamine Hagedorn (NPH) insulin was still the only long-acting insulin available for people with diabetes. The advent of the first truly long-acting basal insulin, i.e. insulin glargine 100 U/mL (Gla-100) brought to the table a remarkably long duration of action and a very minimal risk of hypoglycemia by due to less pronounced peaks in their action profile. Further, in trying to achieve fasting normoglycemia, Gla-100 has demonstrated remarkably more holistic glucose-lowering efficacy in several pivotal trials compared to other insulin formulations, such as premixed insulin and coformulations-apart from NPH insulin. This article delineates clinical data on the effectiveness of Gla-100 vs. other insulin formulations in the context of T2DM.

Utility of global longitudinal strain to detect significant coronary artery disease, its extent and severity in patients with stable ischemic heart disease.

BACKGROUND: Early changes in cardiac function due to ischemia may be detected by global longitudinal peak systolic strain (GLS). Till date, no Indian data exist regarding role of GLS in stable ischemic heart disease (SIHD) and data showing correlation of GLS and SYNTAX score (SS) is meager in world literature. Our aim was to ascertain the role of GLS in SIHD. METHODS: One hundred and seventeen subjects with angina and normal transthoracic echocardiogram (TTE) underwent strain echocardiography and coronary angiography (CAG). RESULTS: There was significant correlation between GLS and SS values (R2  = .686, P < .0001). The correlation was weaker yet significant in the low SS (<22) group (R2  = .491, P < .0001) and high SS (≥22) group (R2  = .602, P < .0001). The cutoff value of GLS to detect significant CAD was -16.5 (87.6% sensitivity, 85.7% specificity, P < .0001), to predict high SS was -13.5% (sensitivity 78.3%, specificity 87.9%, P < .0001) and to predict triple vessel disease (TVD) was -14.5 (95.7% sensitivity, 73.4% specificity, P < .0001). The agreement between GLS and CAG for detection of significant CAD was substantial (κ = 0. 676, P < .0001), similar to that between territorial strain and CAG in detecting LAD disease (κ = 0.688, P < .0001) while agreement between strain imaging and CAG for detecting number of vessels diseased was moderate (κ = 0.406, P < .0001). CONCLUSION: Global longitudinal peak systolic strain must be conducted on subjects with angina and inconclusive electrocardiogram (ECG) findings to rule out significant CAD even if conventional TTE was normal. This may facilitate early diagnosis of CAD or sub-clinical left ventricular systolic dysfunction (LVSD), preventive or treatment measures, and overall cost savings.

Association of severity of coronary artery disease by SYNTAX score (SS) and lower extremity arterial disease by duplex ultrasound (DUS) study-an Indian perspective.

BACKGROUND: Coronary artery disease (CAD) and lower extremity artery disease (LEAD) often coexist. Ankle brachial index (ABI) has been shown to be an independent predictor of CAD. Studies have reported correlation of CAD and LEAD on the basis of ABI and also invasive angiography. But rigorous searching did not reveal any similar research where severity of LEAD was assessed by duplex ultrasound (DUS). In this study, we assessed the association of severity and localisation of LEAD by DUS with SYNTAX score (SS). RESULTS: A total of 637 subjects above 45 years of age with coronary angiographic confirmation of CAD were studied in this single centre cross-sectional, descriptive and analytical research. High SS was significantly more common in subjects with LEAD (p = 0.04). In the femoro-popliteal segment, total occlusion of arteries was found in significantly more proportion of subjects with high SS. A progressive increase in mean SS was noted across the grades of arterial disease in the femoro-popliteal segment (p = 0.007). 85.2% of the LEAD was in the femoro-popliteal segment, while below-knee arterial disease was present in 98.5% of subjects with LEAD. Hypertension, smoking, history of CVE and presentation with ACS independently increased the risk of LEAD. CONCLUSION: High prevalence of asymptomatic LEAD and association of high SS with LEAD as a whole as well as femoro-popliteal involvement suggests the need for a point of care DUS study (POCUS) since treatment varies with location and extent of disease which cannot be fathomed by ABI alone. Being the largest study on association of CAD and LEAD from Indian subcontinent till date and also the first study to use non-invasive tool as DUS for LEAD assessment while studying its association with CAD makes this a landmark experience.

Levothyroxine Absorption Test to Differentiate Pseudomalabsorption from True Malabsorption.

BACKGROUND: The levothyroxine absorption test for evaluation of pseudomalabsorption in patients with primary hypothyroid is not standardised. An individual in whom a workup for malabsorption is warranted remains undefined. METHODS: Twenty-five euthyroid, 25 newly diagnosed hypothyroid, 25 treated hypothyroid with normalised TSH, and 25 hypothyroid subjects with elevated TSH despite adequate dose of levothyroxine for more than 6 months, and 10 euthyroid subjects with true malabsorption were administered levothyroxine (10 µg/kg or maximum 600 µg) to study its absorption profile by measuring free T4 level at hourly intervals for 5 h. Results : Free T4 peaked at 3 h with marginal insignificant decline at 4 h in all groups. The increments of free T4 (between baseline and 3 h) of the four groups (except malabsorption) were not statistically different. The mean increment of free T4 in true malabsorption was 0.39 ng/dL (95% CI: 0.29-0.52) and it was 0.78 ng/dL (95% CI: 0.73-0.85) (10.4 pmol/L) for other groups combined together. The cut off of free T4 increment at 3 h from baseline above 0.40 ng/dL had a sensitivity of 97% and specificity of 80% (AUC 0.904, p < 0.001) to exclude true malabsorption. CONCLUSION: Subjects with elevated TSH on adequate dose of LT4 can be reliably diagnosed to be non-adherent to treatment with levothyroxine absorption test. The incremental value above 0.40 ng/dL (5.14 pmol/L) at 3 h may be useful to identify individuals where workup of malabsorption is unwarranted.

A Cross-sectional Study of Stretched Penile Length in Boys from West Bengal, India.

INTRODUCTION: Short penile length is a commonly encountered problem in clinical practice. Detection of abnormal stretched penile length (SPL) warrants appropriate endocrine evaluation. Ethnicity-specific SPL data are required to detect these abnormalities. There is a dearth of such data in India. This study aims to establish normative values of SPL in boys from West Bengal. MATERIALS AND METHODS: This is a cross-sectional study. SPL, testicular volume (TV), height/length, and weight were measured in 460 boys aged 1 to 13 years from the schools located at urban, suburban, and rural areas in the state of West Bengal, India. Similar data were collected from 36 healthy neonates within 1-3 days of full-term delivery at IPGME and R and SSKM Hospital, Kolkata, West Bengal, India. RESULTS: The 5th percentile, median, and 95th percentile of SPL were 1.7, 2.0, and 2.7 cm for neonates; 3.5, 4.4, and 6.4 cm for the children aged 1 Y-2 Y 11 M; 4.0, 5.5, and 7.0 cm for the age group 3 Y-4 Y 11 M; 4.2, 6.0, and 7.2 cm for the age group 5 Y-6 Y 11 M; 4.3, 6.0, and 7.6 cm for the age group 7 Y-8 Y 11 M; 4.4, 6.5, and 9.0 cm for the age group 9 Y-10 Y 11 M; and 4.8, 7.0, and 11.0 cm for the age group 11 Y-12 Y 11 M, respectively. SPL showed significant positive correlation with TV [r = 0.365, P < 0.0005] and height of the children [r = 0.516, P < 0.0005], but not with BMI. CONCLUSION: Our study provides normative data of SPL in neonate and children aged 1 to 13 years from the eastern part of India. SPL value correlated positively with TV and height of children.

Ricinus communis L. fruit extract inhibits migration/invasion, induces apoptosis in breast cancer cells and arrests tumor progression in vivo.

Medicinal plant-based therapies can be important for treatment of cancer owing to high efficiency, low cost and minimal side effects. Here, we report the anti-cancer efficacy of Ricinus communis L. fruit extract (RCFE) using estrogen positive MCF-7 and highly aggressive, triple negative MDA-MB-231 breast cancer cells. RCFE induced cytotoxicity in these cells in dose and time-dependent manner. It also demonstrated robust anti-metastatic activity as it significantly inhibited migration, adhesion, invasion and expression of matrix metalloproteinases (MMPs) 2 and 9 in both cell lines. Further, flow cytometry analysis suggested RCFE-mediated induction of apoptosis in these cells. This was supported by attenuation of anti-apoptotic Bcl-2, induction of pro-apoptotic Bax and caspase-7 expressions as well as PARP cleavage upon RCFE treatment. RCFE (0.5 mg/Kg body weight) treatment led to significant reduction in tumor volume in 4T1 syngeneic mouse model. HPLC and ESI-MS analysis of active ethyl acetate fraction of RCFE detected four compounds, Ricinine, p-Coumaric acid, Epigallocatechin and Ricinoleic acid. Individually these compounds showed cytotoxic and migration-inhibitory activities. Overall, this study for the first time demonstrates the anti-cancer efficacy of the fruit extract of common castor plant which can be proposed as a potent candidate for the treatment of breast cancer.

Structure and Stability of High CaO- and P2O5-Containing Silicate and Borosilicate Bioactive Glasses.

The present work elucidates about the structure of bioactive glasses having chemical compositions expressed as (mol %) (50.0 - x)SiO2-xB2O3-9.3Na2O-37CaO-3.7P2O5, where x = 0.0, 12.5, 25, and 37.5, and establishes a correlation between the structure and thermal stability. The structural modifications in the parent boron-free glass (B0) with the gradual substitutions of B2O3 for SiO2 are assessed by Raman and 29Si, 31P, 11B, and 23Na magic angle spinning (MAS)-nuclear magnetic resonance (NMR) spectroscopies. The structural studies reveal the presence of QSi2 and QSi3 structural units in both silicate and borosilicate glasses. However, QSi4(3B) units additionally form upon incorporating B2O3 in B0 glass. B-containing silicate glasses exhibit both three-coordinated boron (BIII) and four-coordinated boron (BIV) units. The 31P MAS-NMR studies reveal that the majority of phosphate species exist as isolated orthophosphate (QP0) units. The incorporation of B2O3 in B0 glass increases the cross-linking between the SiO4 and BO4 structural units. However, incorporation of B2O3 lowers the glass thermal stability (ΔT), as shown by differential scanning calorimetry. Although both silicate and borosilicate glasses exhibit good in vitro apatite-forming ability and cell compatibility, the bactericidal action against Escherichia coli bacteria is more evident in borosilicate glass in comparison to silicate base glass. The controlled release of (BO3)3- ions from boron-modified bioactive glasses improves both the cell proliferation and the antibacterial properties, making them promising for hard tissue engineering applications.

Application of tungsten disulfide quantum dot-conjugated antimicrobial peptides in bio-imaging and antimicrobial therapy.

Two-dimensional (2D) tungsten disulfide (WS2) quantum dots offer numerous promising applications in materials and optoelectronic sciences. Additionally, the catalytic and photoluminescence properties of ultra-small WS2 nanoparticles are of potential interest in biomedical sciences. Addressing the use of WS2 in the context of infection, the present study describes the conjugation of two potent antimicrobial peptides with WS2 quantum dots, as well as the application of the resulting conjugates in antimicrobial therapy and bioimaging. In doing so, we determined the three-dimensional solution structure of the quantum dot-conjugated antimicrobial peptide by a series of high-resolution nuclear magnetic resonance (NMR) techniques, correlating this to the disruption of both model lipid and bacterial membranes, and to several key biological performances, including antimicrobial and anti-biofilm effects, as well as cell toxicity. The results demonstrate that particle conjugation enhances the antimicrobial and anti-biofilm potency of these peptides, effects inferred to be due to multi-dendate interactions for the conjugated peptides. As such, our study provides information on the mode-of-action of such conjugates, laying the foundation for their potential use in treatment and monitoring of infections.

Elevated histone H3 acetylation and loss of the Sp1-HDAC1 complex de-repress the GM2-synthase gene in renal cell carcinoma.

GM2-synthase produces sialic acid-containing glycosphingolipids called gangliosides, and its mRNA overexpression and the gangliosides it generates are linked to tumor progression, migration, and suppression of tumor-specific host immune responses. However, the mechanism underlying GM2-synthase de-repression in renal cell carcinoma (RCC) is poorly understood. Here, we demonstrate that higher GM2-synthase mRNA expression levels in various cancer cells and in human RCC tumors correlate with higher histone acetylation levels (H3K9, H3K14, or both) at region +38/+187 relative to the transcription start site (TSS) of the GM2-synthase gene than in normal kidney epithelial (NKE) cells or healthy adjacent tissues. An increase in GM2-synthase mRNA expression in cells treated with a histone deacetylase (HDAC) inhibitor was accompanied by increased histone acetylation levels at this promoter region. DNA methylation around the TSS was absent in both RCC cell lines and NKE cells. Of note, both the transcription factor Sp1 and corepressor HDAC1 associated with the +38/+187 region when the GM2-synthase gene was repressed in NKE and tumor-adjacent tissues, indicating plausible site-specific repressive roles of HDAC1 and Sp1 in GM2-synthase mRNA expression. Site-directed mutagenesis of the Sp1-binding site within the +38/+187 region relieved repressed luciferase activity of this region by limiting HDAC1 recruitment. Moreover, Sp1 or HDAC1 knock down increased GM2-synthase transcription, and butyrate-mediated activation of GM2-synthase mRNA expression in SK-RC-45 cells was accompanied by Sp1 and HDAC1 loss from the +38/+187 region. Taken together, we have identified an epigenetic mechanism for the de-repression of the GM2-synthase gene in RCC.

Regulation of monoamine oxidase A (MAO-A) expression, activity, and function in IL-13-stimulated monocytes and A549 lung carcinoma cells.

Monoamine oxidase A (MAO-A) is a mitochondrial flavoenzyme implicated in the pathogenesis of atherosclerosis and inflammation and also in many neurological disorders. MAO-A also has been reported as a potential therapeutic target in prostate cancer. However, the regulatory mechanisms controlling cytokine-induced MAO-A expression in immune or cancer cells remain to be identified. Here, we show that MAO-A expression is co-induced with 15-lipoxygenase (15-LO) in interleukin 13 (IL-13)-activated primary human monocytes and A549 non-small cell lung carcinoma cells. We present evidence that MAO-A gene expression and activity are regulated by signal transducer and activator of transcription 1, 3, and 6 (STAT1, STAT3, and STAT6), early growth response 1 (EGR1), and cAMP-responsive element-binding protein (CREB), the same transcription factors that control IL-13-dependent 15-LO expression. We further established that in both primary monocytes and in A549 cells, IL-13-stimulated MAO-A expression, activity, and function are directly governed by 15-LO. In contrast, IL-13-driven expression and activity of MAO-A was 15-LO-independent in U937 promonocytic cells. Furthermore, we demonstrate that the 15-LO-dependent transcriptional regulation of MAO-A in response to IL-13 stimulation in monocytes and in A549 cells is mediated by peroxisome proliferator-activated receptor γ (PPARγ) and that signal transducer and activator of transcription 6 (STAT6) plays a crucial role in facilitating the transcriptional activity of PPARγ. We further report that the IL-13-STAT6-15-LO-PPARγ axis is critical for MAO-A expression, activity, and function, including migration and reactive oxygen species generation. Altogether, these results have major implications for the resolution of inflammation and indicate that MAO-A may promote metastatic potential in lung cancer cells.

Inhibition of cancer progression by a novel trans-stilbene derivative through disruption of microtubule dynamics, driving G2/M arrest, and p53-dependent apoptosis.

Resveratrol, a trans-stilbene polyphenolic compound and its synthetic analogs are widely used bioactive molecules due to their remarkable chemo-preventive potential. Here, we have identified a novel synthetic trans-stilbene compound, Z-DAN-11 ((Z)-3-(3, 4-dimethoxyphenyl)-2-(3, 4, 5-trimethoxyphenyl) acrylonitrile) which shows remarkable efficacy in blocking tumor growth and progression both in vitro and in vivo. Z-DAN-11 inhibits proliferation of cancer cells in vitro through microtubule depolymerization that induced G2/M arrest and consequently leads to apoptotic cell death. More importantly, Z-DAN-11 shows limited cytotoxicity to normal cells as compared to cancer cells. Quite interestingly, we have found that Z-DAN-11-mediated ROS production helps in dramatic alteration in the mitochondrial redox status which critically contributes to the apoptosis. Mechanistic studies reveal that Z-DAN-11 induces the expression of pro-apoptotic proteins and decreases anti-apoptotic protein expression that decisively helps in the activation of caspase 8, caspase 9, and caspase 3, leading to cleavage of PARP1 and cell death via intrinsic and extrinsic pathways of apoptosis. Moreover, Z-DAN-11-mediated apoptosis of cancer cells is through a partial p53-dependent pathway, since both HCT116 p53-/- cells as well as p53-silenced cells (siRNA) were able to block apoptosis partially but significantly. Importantly, Z-DAN-11 also imparts its anti-tumorigenic effect by inhibiting clonogenic property and anchorage-independent growth potential of cancer cells at concentrations at least 10 times lower than that required for inducing apoptosis. Finally, in vivo study with immuno-competent syngeneic mice shows Z-DAN-11 to be able to impede tumor progression without any adverse side-effects. Hence, we identified a novel, synthetic trans-stilbene derivative with anti-tumorigenic potential which might tremendously help in devising potential therapeutic strategy against cancer.