Multifunctional role of Nobiletin in cancer chemoprevention.

The diversity of highly bioactive and pharmacologically active natural products which recognize essential biological targets having exquisite specificity, constitutes a massive pharmacological database for discovery of valuable drugs. The rapid accumulation of information has revealed chemopreventive role of nobiletin against wide variety of cancers. Recent efforts are now being expanded and new integrative omics technologies have illuminated continuously upgrading list of molecular mechanisms which underlie carcinogenesis and metastasis. In this mini-review, we explore the progress that has been made in the identification of promising molecular targets of nobiletin.

Regulation of cell signaling pathways by Wogonin in different cancers: Mechanistic review.

Natural products have historically been invaluable as a premium source of therapeutic agents. Recent advancements in genomics and structural biology have portrayed a high-resolution landscape of the diversity of proteins targeted by pharmacologically active products from natural sources. Natural product research has generated valuable wealth of information and cutting-edge research-works have leveraged our conceptual knowledge altogether to a new level. Wogonin (5,7-dihydroxy-8-methoxyflavone) is an O-methylated flavone and has attracted noteworthy appreciation because of its ability to pharmacologically target plethora of cell signaling pathways in different cancers. In this mini-review, we have gathered scattered pieces of available scientific evidence to summarize how wogonin pharmaceutically targeted Wnt/?-catenin, JAK/STAT, VEGF/VEGFR and TRAIL-driven apoptotic pathways in wide variety of cancers. We have also critically analyzed how wogonin prevented carcinogenesis and metastasis in tumor-bearing mice. Although researchers have uncovered pleiotropic role of wogonin in the regulation of different oncogenic signaling cascades but there are visible knowledge gaps in our understanding related to regulation of non-coding RNAs by wogonin. Future studies must converge on the unraveling of additional drug targets for wogonin to achieve a fuller and realistic understanding of the chemopreventive properties of wogonin.

TRAIL Mediated Signaling in Breast Cancer: Awakening Guardian Angel to Induce Apoptosis and Overcome Drug Resistance.

Sequencing technologies have allowed us to characterize highly heterogeneous molecular landscape of breast cancer with unprecedented details. Tremendous breakthroughs have been made in unraveling contributory role of signaling pathways in breast cancer development and progression. It is becoming progressively more understandable that deregulation of spatio-temporally controlled pathways underlie development of resistance against different drugs. TRAIL mediated signaling has attracted considerable appreciation because of its characteristically unique ability to target cancer cells while leaving normal cells intact. Discovery of TRAIL was considered as a paradigm shift in molecular oncology because of its conspicuous ability to selectively target cancer cells. There was an exponential growth in the number of high-quality reports which highlighted cancer targeting ability of TRAIL and scientists worked on the development of TRAIL-based therapeutics and death receptor targeting agonistic antibodies to treat cancer. However, later studies challenged simplistic view related to tumor targeting ability of TRAIL. Detailed mechanistic insights revealed that overexpression of anti-apoptotic proteins, inactivation of pro-apoptotic proteins and downregulation of death receptors were instrumental in impairing apoptosis in cancer cells. Therefore researchers started to give attention to identification of methodologies and strategies to overcome the stumbling blocks associated with TRAIL-based therapeutics. Subsequent studies gave us a clear picture of signaling cascade of TRAIL and how deregulation of different proteins abrogated apoptosis. In this chapter we have attempted to provide an overview of the TRAIL induced signaling, list of proteins frequently deregulated and modern approaches to strategically restore apoptosis in TRAIL-resistant breast cancers.

Regulation of signaling pathways by ß-elemene in cancer progression and metastasis.

Entry of ß-elemene into various phases of clinical trials advocates its significance as a premium candidate likely to gain access to mainstream medicine. Based on the insights gleaned from decades of research, it seems increasingly transparent that ß-elemene has shown significant ability to modulate multiple cell signaling pathways in different cancers. We partition this multicomponent review into how ß-elemene strategically modulates various signal transduction cascades. We have individually summarized regulation of tumor necrosis factor related apoptosis-inducing ligand, signal transducers and activators of transcription, transforming growth factor/SMAD, NOTCH, and mammalian target of rapamycin pathways by ß-elemene. Last, we will discuss the results of clinical trials of ß-elemene and how effectively we can use these findings to stratify patients who can benefit most from ß-elemene.

Apigenin as an effective anticancer natural product: Spotlight on TRAIL, WNT/ß-catenin, JAK-STAT pathways, and microRNAs.

Wealth of information gleaned from decades of high-impact research work; scientists have disentangled the complicated web of versatile regulators that underlie cancer development and progression. Use of structural biology approaches and functional genomics have helped us to gain new insights into complex nature of cancer, and it is now clear that genetic/epigenetic mutations, overexpression of oncogenes, inactivation of tumor suppressors, loss of apoptosis, and versatility of protein binding partners have contributory roles in carcinogenesis and metastatic spread. It is becoming progressively more understandable that reprogramming of gene expression during and nontranscriptional changes during cancer development and progression are initiated and controlled by deregulated signal transduction cascades, all of which collectively create an incalculable complexity. Data obtained through preclinical and clinical trials revealed that alterations in the targeted oncogenes and other downstream, and parallel pathways played a central role in the development of resistance against different therapeutics. Phytochemicals have regained limelight, and different natural products are currently being tested for efficacy in preclinical studies. Apigenin, a plant-derived flavonoid has considerable pharmacological value and is reportedly involved in the regulation of different signaling cascades. In this review, we have attempted to summarize rapidly evolving understanding of molecular biologists and pharmacologists about the potential of apigenin in the regulation of deregulated signaling pathways in different cancers. We have emphasized on the regulation of WNT/ß-catenin and janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways. We also comprehensively discuss how apigenin restored apoptosis in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant cancers. The review also gives a snapshot of microRNAs (miRNAs) that regulate wide-ranging biological processes, and it is now clear that each miRNA can control hundreds of gene targets. Apigenin was noted to upregulate miR-520b and miR-101 in different cancers to inhibit tumor growth. Moreover, apigenin-induced apoptotic rate was significantly higher when used in combination with miR-423-5p inhibitors or miR-138 mimics. Better comprehension of linear and integrated signaling pathways will be helpful in effective therapeutic targeting of deregulated signaling pathways to inhibit/prevent cancer.

Maslinic acid as an effective anticancer agent.

Maslinic acid (2α,3ß-dihydroxyolean-12-en-28-oic acid) is a naturally occurring pentacyclic triterpenic compound. Maslinic acid is gradually gaining attention as an excellent pharmacologically active product because of its premium biological properties. In this review we will focus on chemopreventive properties of Maslinic acid against different cancers. Seemingly, available data is limited and we have yet to unravel how Maslinic acid therapeutically targeted oncogenic cell signal transduction cascades in different cancers. Moreover, there are visible knowledge gaps about the ability of Maslinic acid to modulate oncogenic and tumor suppressor microRNAs in various cancers.

Regulation of signal transduction cascades by Pterostilbenes in different cancers: Is it a death knell for oncogenic pathways.

Interdisciplinary research has revolutionized the field of medicine and we have witnessed exponential increase in the high-impact research in past few decades. However, the road to this burgeoning research field is obstacle-ridden because of intratumor heterogeneity, loss of apoptosis and dysregulation of spatio-temporally controlled signaling pathways. Ground-breaking findings obtained through genetic, genomic and proteomic studies have considerably improved our concepts related to the complexity of protein network and excitingly, discovery of miRNAs has added another layer of intricacy to quantitatively regulated gene networks. In this review, we chronicle the milestone achievements and discuss how Pterostilbenes effectively regulated different cellular pathways. We have provided detailed mechanistic insights related to regulation of JAK-STAT signaling, Notch pathway, Wnt mediated intracellular signaling by pterostilbene. Underlying mechanisms about regulation of PI3K/AKT and MAPK pathways by pterostilbene in different cancers.  Regulation of Metastasis-associated protein 1 (MTA1) proteins and Human telomerase reverse transcriptase (hTERT) in cancer cells by pterostilbene. Pterostilbene has also been reported to modulate the expression of various oncogenic and tumor suppressor microRNAs in cancer cells. Better and sharper comprehension of the concepts associated with the modes of action of pterostilbene in different cancers will be useful in identification of cancers which can be efficiently targeted by pterostilbene.

Investigation of Differences in P53 Gene Polymorphisms between Schizophrenia and Lung Cancer Patients in the Turkish Population.

Objective. The reduced incidence of cancer observed in schizophrenia patients may be related to differences in genetic background. It has been suggested that genetic predisposition towards schizophrenia is associated with reduced vulnerability to lung cancer, and p53 gene is one of the candidate genes. In our study, we aimed to investigate polymorphisms in the BstUI in exon 4 and MspI in intron 6 restriction sites of the p53 gene in Turkish schizophrenia patients, lung cancer patients, and controls. Material and Methods. Allele and genotype incidence of these polymorphisms with their haplotype combinations were studied in 100 Turkish lung cancer and schizophrenia patients and 100 controls without malignant and schizophrenia diseases. The genotype characteristics were determined by PCR-based RFLP method using DNA extracted from peripheral blood. Results. For the BstUI and MspI polymorphism, there were found significant differences in the genotype and allele frequencies between schizophrenia and lung cancer patients with control groups (P < .01). The analysis based on haplotype frequencies showed the presence of BstUI-MspI 2-1 haplotype in cancer patients (12%) in contrast to the absence of this haplotype in schizophrenia and controls. Only in lung cancer patients we found both significant decrease of A1 allele of the p53 codon 72 (OR 0.23, 95% CI 0.9-0.58) and A1/A1 homozygous genotype (P < .0001, OR 0.19). Conclusion. The results of this study suggest a protective effect of A1 allele against lung cancer, and the p53 MspI polymorphism may modify the susceptibility to lung cancer as a single factor rather than in combination with BstUI polymorphism.

Interleukin-10 gene promoter polymorphism in patients with schizophrenia in a region of East Turkey.

Schizophrenia is one of the most severe psychiatric disorders, with a worldwide incidence of 1%. Immunological abnormalities have been found to be associated with schizophrenia for decades. Cytokines are key proteins involved in the immune system activation. Interleukin-10 (IL-10), an important immunoregulatory cytokine, is located on chromosome 1q31-32, a region previously reported to be linked to schizophrenia in genetic studies. In the present study it was aimed to examine the IL-10 gene promoter region's polymorphic variants in patients with schizophrenia in a population of the Elazig Region of East Anatolia, Turkey. Polymorphisms at position -1082, -819 and-592 in the IL-10 promoter region were determined in 171 Turkish patients who were diagnosed with schizophrenia, based on the DSM-IV, and 168 healthy controls, by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP). We analyzed allele, genotype, and haplotype distributions using a case-control association study. Genotyping was performed by RFLP. Statistically significant differences were observed in both allelic and genotypic frequencies of the-592A/C polymorphism (Allele, P=0.034, OR = 1.26, 95% CI 1.02-1.56; Genotype, P=0.048), while the other two polymorphisms in distribution of the alleles and genotypes in patients with schizophrenia were not significantly different from those of controls (P>0.05). Our results show a significant increase of GTA homozygotes (the high IL-10-producing haplotype) in schizophrenic patients compared to control subjects (P=0.0001). These data suggest that the IL-10 gene promoter polymorphism may be one of the susceptibility factors to develop schizophrenia in the Turkish population, and apparently in all humans.

The value of interleukin-12B (p40) gene promoter polymorphism in patients with schizophrenia in a region of East Turkey.

AIMS: It has been hypothesized that the activation of the immune system may be involved in the neuropathological changes occurring in the central nervous system of schizophrenic patients. Cytokines play a key role in the activation of the immune system. Moreover, they strongly influence the dopaminergic, noradrenergic and serotonergic neurotransmission. To the best of our knowledge, in schizophrenic patients, plasma levels of interleukin (IL)-12 were investigated only in one study, where deregulation of IL-12 was determined. However, genotypical variations of the IL-12B (p40) gene have not been investigated for schizophrenic patients yet. Therefore, in the present study, we aimed to examine polymorphic variants of IL-12B (p40) gene promoter region in patients with schizophrenia in a population of the Elazig Region of East Anatolia, Turkey. METHODS: One hundred Turkish patients diagnosed with schizophrenia based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), and 116 healthy control subjects participated in the present study. The genotype characteristics were determined by polymerase chain reaction-based restriction fragment length polymorphism method using DNA extracted from peripheral blood. RESULTS: Significant differences in both the genotype and allele frequencies were found between schizophrenia patients and control groups (P < 0.01). CONCLUSIONS: These findings may support the hypothesis that activation of the inflammatory response system and in particular, of Th-1 cells, is involved in the pathophysiology of schizophrenia. We think that this study is the first trial associated with IL-12 cytokine at the molecular genetic level on immune mechanisms for neuropsychiatric disorders including schizophrenia, and this perspective and the role of the cytokines in the pathogenesis of schizophrenia may constitute a reasonable target for the present and future treatment strategies and prognosis.