Phytochemicals in Cancer Prevention and Therapy

Despite advances in modern medicine, cancer is still the major cause of mortality in both developing and developed countries. Search for safer and more effective chemoprevention and treatment strategy is a need for the improvement of patient care in the field. Prevention may be more effective and less costly because cancer is largely a preventable disease which could be attributed to a greater extent to lifestyle. Dietary phytochemicals have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Population based studies suggest that a reduced risk of cancer is associated with high consumption of vegetables and fruits. Promising phytochemicals not only disrupt aberrant signaling pathways leading to cancer but also synergize with chemotherapy and radiotherapy. Thus, the cancer chemoprevention and therapeutic potential of naturally occurring phytochemicals are of great interest. In this special issue we have collected many interesting original research articles and reviews that provide solid evidence to support the application of phytochemicals or dietary agents in prevention and treatment of cancer

Synthesis and biological evaluation of tetrahydropyridinepyrazoles ('PFPs') as inhibitors of STAT3 phosphorylation

The transcription factor STAT3 is constitutively overexpressed in many human tumors and hence represents a putative target for anticancer drug design. In this work, we describe the synthesis and biological evaluation of a novel chemotype, pyridine-fused pyrazoles ('PFPs') as inhibitors of STAT3 phosphorylation. The effect of the compounds synthesized was evaluated in cell proliferation assays of MCF-7 and HepG2 cancer cell lines and two of the compounds tested (12g and 12k) were found to show significant activity. Both compounds were also found to inhibit the proliferation of Hep3B, HUH-7 and PLC/PRF5 HCC cells in a dose-and time-dependent manner. Furthermore, we established in a DNA binding assay that one of the compounds (12g) was able to significantly inhibit the DNA binding ability of STAT3. Cytotoxicity of 12g against PC3 cells, which do not constitutively phosphorylate STAT3, was found to be minimal, hence lending further support for our mode-of-action hypothesis of this compound. We established for this structure a complete inhibition of CXCL12-induced cell invasion and associated wound healing in HCCLM3 cells, corroborating the proposed modulation of the STAT3 axis by 12g. Finally, molecular modeling was employed to evaluate the hypothesis of PFPs to bind to the SH2 domain of STAT3. Given the efficacy of PFPs in the biological systems studied here we propose their further evaluation in the context of STAT3-mediated cancer therapy

Synthesis, biological evaluation and in silico and in vitro mode-of-action analysis of novel dihydropyrimidones targeting PPAR-gamma

Hepatocellular carcinoma, a fatal liver cancer, affects 600 000 people annually and ranks third in cancer-related lethality. In this work we report the synthesis and related biological activity of novel dihydropyrimidones. Among the tested compounds, 5-acetyl-4-(1H-indol- 3-yl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (4g) was found to be most active towards the HepG2 cell line (IC50 = 17.9 mu M), being at the same time 7.6-fold selective over normal (LO2) liver cells (IC50 = 136.9 mu M). Subsequently, we identified peroxisome proliferator-activated receptor gamma as a target of compound 4g using an in silico approach, and confirmed this mode-of-action experimentally

Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects

Objective: Polycystic ovarian syndrome (PCOS) is a heterogeneous endocrine disorder associated with mitochondrial dysfunction and insulin resistance (IR). MOTS-c, a mitochondrial peptide, promotes insulin sensitivity (IS) through activating AKT and AMPK-dependent pathways. The current study was designed to examine the response of MOTS-c to lipids (intralipid) followed by insulin in PCOS and healthy subjects. Methods: All subjects underwent 5-hour intralipid/saline infusion with a hyperinsulinemic-euglycaemic clamp in the final 2 hours. Plasma samples were collected to measure circulating MOTS-c using a commercial ELISA kit. Subsequently, this was repeated following an eight-week exercise intervention. Results: Intralipid significantly increased plasma MOTS-c both in controls and PCOS subjects, whilst the insulin infusion blunted the intralipid-induced response seen for both lipids and MOT-c. Intralipid elevated plasma MOTS-c to 232±124% of basal in control (P < 0.01) and to 349 ± 206% of basal in PCOS (P < 0.001) subjects. Administration of insulin suppressed intralipid-induced MOTS-c from 232 ± 124% to 165 ± 97% (NS) in control and from 349 ± 206% to 183 ± 177% (P < 0.05) in PCOS subjects, respectively. Following exercise, intralipid elevated plasma MOTS-c to 305 ± 153% of basal in control (P < 0.01) and to 215 ± 103% of basal in PCOS (P < 0.01) subjects; insulin suppressed intralipid-induced MOTS-c only in controls.ConclusionsIn conclusion, this is the first study to show increased lipid enhanced circulating MOTS-c whilst insulin attenuated the MOTS-c response in human. Further, eight weeks of moderate exercise training did not show any changes in circulating MOTS-c levels in healthy controls and in women with PCOS

Dynamic Changes in Circulating Endocrine FGF19 Subfamily and Fetuin-A in Response to Intralipid and Insulin Infusions in Healthy and PCOS Women

© Copyright © 2020 Ramanjaneya, Bensila, Bettahi, Jerobin, Samra, Aye, Alkasem, Siveen, Sathyapalan, Skarulis, Atkin and Abou-Samra. Background: The fibroblast growth factors (FGF) 19 subfamily, also referred to as endocrine FGFs, includes FGF19, FGF21, and FGF23 are metabolic hormones involved in the regulation of glucose and lipid metabolism. Fetuin-A is a hepatokine involved in the regulation of beta-cell function and insulin resistance. Endocrine FGFs and fetuin-A are dysregulated in metabolic disorders including obesity, type 2 diabetes, non-alcoholic fatty liver disease and polycystic ovary syndrome (PCOS). Our study was designed to examine the response of endocrine FGFs and fetuin-A to an acute intralipid, insulin infusion and exercise in PCOS and healthy women. Subjects and Measurements: Ten healthy and 11 PCOS subjects underwent 5-h saline infusions with a hyperinsulinemic-euglycemic clamp (HIEC) performed during the final 2 h. One week later, intralipid infusions were undertaken with a HIEC performed during the final 2 h. After an 8 week of exercise intervention the saline, intralipid, and HIEC were repeated. Plasma levels of endocrine FGFs and fetuin-A were measured. Results: Baseline fetuin-A was higher in PCOS women but FGF19, FGF21, and FGF23 did not differ and were unaffected by exercise. Insulin administration elevated FGF21 in control and PCOS, suppressed FGF19 in controls, and had no effects on FGF23 and fetuin-A. Intralipid infusion suppressed FGF19 and increased FGF21. Insulin with intralipid synergistically increased FGF21 and did not have effects on lipid-mediated suppression of FGF19 in both groups. Conclusion: Our study provides evidence for insulin and lipid regulation of endocrine FGFs in healthy and PCOS women, suggesting that FGF family members play a role in lipid and glucose metabolism. Clinical Trial Registration: www.isrctn.org, Identifier: ISRCTN42448814

Cytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted therapy

Esophageal cancer (EC) is a disease often marked by aggressive growth and poor prognosis. Lack of targeted therapies, resistance to chemoradiation therapy, and distant metastases among patients with advanced disease account for the high mortality rate. The tumor microenvironment (TME) contains several cell types, including fibroblasts, immune cells, adipocytes, stromal proteins, and growth factors, which play a significant role in supporting the growth and aggressive behavior of cancer cells. The complex and dynamic interactions of the secreted cytokines, chemokines, growth factors, and their receptors mediate chronic inflammation and immunosuppressive TME favoring tumor progression, metastasis, and decreased response to therapy. The molecular changes in the TME are used as biological markers for diagnosis, prognosis, and response to treatment in patients. This review highlighted the novel insights into the understanding and functional impact of deregulated cytokines and chemokines in imparting aggressive EC, stressing the nature and therapeutic consequences of the cytokine-chemokine network. We also discuss cytokine-chemokine oncogenic potential by contributing to the Epithelial-Mesenchymal Transition (EMT), angiogenesis, immunosuppression, metastatic niche, and therapeutic resistance development. In addition, it discusses the wide range of changes and intracellular signaling pathways that occur in the TME. Overall, this is a relatively unexplored field that could provide crucial insights into tumor immunology and encourage the effective application of modulatory cytokine-chemokine therapy to EC.This study was supported by a PI grant from Sidra Medicine (5071012001) to Mohammad Haris. Ajaz A. Bhat is supported by Sidra Medicine internal grant (5011041002) and Ramalinga swami (Grant number: D.O.NO.BT/HRD/35/02/2006) Fellowship to Muzafar A. Macha and Nissar A. Wani by Department of Biotechnology (DBT), Govt. of India, New Delhi. Shahab Uddin is supported by Medical Research Centre grants (grant# 16102/6, #16354/16)

Emodin Suppresses Migration and Invasion through the Modulation of CXCR4 Expression in an Orthotopic Model of Human Hepatocellular Carcinoma

10.1371/journal.pone.0057015PLoS ONE83

Evaluation of the sensitivity of electro-acousic measurements for process monitoring and control of an atmospheric pressure plasma jet system

The development of non-invasive process diagnostic techniques for the control of atmospheric plasmas is a critical issue for the wider adoption of this technology. This paper evaluates the use of a frequency-domain deconvolution of an electro-acoustic emission as a means to monitor and control the plasma formed using an atmospheric pressure plasma jet (APPJ) system. The air plasma system investigated was formed using a PlasmaTreat™ OpenAir applicator. Change in the electro-acoustic signal with changes in substrate type (ceramic, steel, polymer). APPJ nozzle to substrate distance and substrate feature size were monitored. The decoding of the electro-acoustic emission yields three sub dataset that are described three separate emission mechanisms. The three emissions are associated with: the power supply fundamental drive frequency and its harmonics; the APPJ nozzle longitudinal mode acoustic emission and its odd overtones, and the acoustic surface reflection that is produced by the impedance mismatch between the discharge and the surface. Incorporating this knowledge into a LabVIEW a program facilitated the continuous deconvolution of the electro-acoustic data. This enabled the use of specific frequency band test limits to control the process the APPJ treatment process which is sensitive to both plasma processing conditions and substrate type and features. PAC Codes: 52.40.Hf, 52.70.-m, 52.77.Fv, 43.60.VxScience Foundation IrelandAuthor has checked copyrightAD 22/01/201