Natural compounds targeting YAP/TAZ axis in cancer: Current state of art and challenges.

Cancer has become a burgeoning global healthcare concern marked by its exponential growth and significant economic ramifications. Though advancements in the treatment modalities have increased the overall survival and quality of life, there are no definite treatments for the advanced stages of this malady. Hence, understanding the diseases etiologies and the underlying molecular complexities, will usher in the development of innovative therapeutics. Recently, YAP/TAZ transcriptional regulation has been of immense interest due to their role in development, tissue homeostasis and oncogenic transformations. YAP/TAZ axis functions as coactivators within the Hippo signaling cascade, exerting pivotal influence on processes such as proliferation, regeneration, development, and tissue renewal. In cancer, YAP is overexpressed in multiple tumor types and is associated with cancer stem cell attributes, chemoresistance, and metastasis. Activation of YAP/TAZ mirrors the cellular "social" behavior, encompassing factors such as cell adhesion and the mechanical signals transmitted to the cell from tissue structure and the surrounding extracellular matrix. Therefore, it presents a significant vulnerability in the clogs of tumors that could provide a wide window of therapeutic effectiveness. Natural compounds have been utilized extensively as successful interventions in the management of diverse chronic illnesses, including cancer. Owing to their capacity to influence multiple genes and pathways, natural compounds exhibit significant potential either as adjuvant therapy or in combination with conventional treatment options. In this review, we delineate the signaling nexus of YAP/TAZ axis, and present natural compounds as an alternate strategy to target cancer.

Canonical DDR activation by EMT inducing agent 5-Fluorouracil is modulated by a cannabinoid based combinatorial approach via inducing autophagy and suppression of vimentin expression.

Anastasis cascade including induction of Epithelial to Mesenchymal Transition (EMT), DNA repair, and stimulation of pro-survival mediators collectively exaggerate therapy resistance in cancer prognosis. The extensive implications of DNA-damaging agents are clinically proven futile for the rapid development of disease recurrence during treatment regime. Herein we report a glycosidic derivative of Δ9-tetrahydrocannabinol (THC-9-OG) abrogates sub-toxic doses of 5-Fluorouracil (5FU) induced EMT in colon cancer cells nullifying DNA repairing mechanism. Our in vitro and in vivo data strongly proclaims that THC-9-OG could not only abrogate 5FU mediated background EMT activation through stalling matrix degradation as well as murine 4T1 lung metastasis but also vigorously diminished Rad-51 repairing mediator along with stimulation of γ-H2AX foci formation. The combinatorial treatment (5FU + THC-9-OG) in Apc knockout colorectal carcinoma model conferred remission of the crypt progenitor phenotype which was prominently identified in 5FU treatment. Mechanistically, we demonstrated that 5FU plus THC-9-OG significantly attenuated major EMT inducer Vimentin via extensive ROS generation along with autophagy induction via LC3B I-II conversion and p62 degradation in a p-ATM dependent manner. Additionally, Cannabinoid receptor CB1 was responsible for abrogation of Vimentin since we found increase in the expression of γH2AX and decrease in vimentin expression in CB1 agonist (ACEA) plus 5FU treated cells. Nutshell, our results unveil a new direction of Cannabinoid based combinatorial approach to control background EMT along with robust enhancing of DNA damage potential of sub-toxic concentration of 5FU resulting immense inhibition of distant metastasis coupled with triggering cell death in vitro and in vivo.

MicroRNA signatures differentiate types, grades, and stages of breast invasive ductal carcinoma (IDC): miRNA-target interacting signaling pathways.

BACKGROUND: Invasive ductal carcinoma (IDC) is the most common form of breast cancer which accounts for 85% of all breast cancer diagnoses. Non-invasive and early stages have a better prognosis than late-stage invasive cancer that has spread to lymph nodes. The involvement of microRNAs (miRNAs) in the initiation and progression of breast cancer holds great promise for the development of molecular tools for early diagnosis and prognosis. Therefore, developing a cost effective, quick and robust early detection protocol using miRNAs for breast cancer diagnosis is an imminent need that could strengthen the health care system to tackle this disease around the world. METHODS: We have analyzed putative miRNAs signatures in 100 breast cancer samples using two independent high fidelity array systems. Unique and common miRNA signatures from both array systems were validated using stringent double-blind individual TaqMan assays and their expression pattern was confirmed with tissue microarrays and northern analysis. In silico analysis were carried out to find miRNA targets and were validated with q-PCR and immunoblotting. In addition, functional validation using antibody arrays was also carried out to confirm the oncotargets and their networking in different pathways. Similar profiling was carried out in Brca2/p53 double knock out mice models using rodent miRNA microarrays that revealed common signatures with human arrays which could be used for future in vivo functional validation. RESULTS: Expression profile revealed 85% downregulated and 15% upregulated microRNAs in the patient samples of IDC. Among them, 439 miRNAs were associated with breast cancer, out of which 107 miRNAs qualified to be potential biomarkers for the stratification of different types, grades and stages of IDC after stringent validation. Functional validation of their putative targets revealed extensive miRNA network in different oncogenic pathways thus contributing to epithelial-mesenchymal transition (EMT) and cellular plasticity. CONCLUSION: This study revealed potential biomarkers for the robust classification as well as rapid, cost effective and early detection of IDC of breast cancer. It not only confirmed the role of these miRNAs in cancer development but also revealed the oncogenic pathways involved in different progressive grades and stages thus suggesting a role in EMT and cellular plasticity during breast tumorigenesis per se and IDC in particular. Thus, our findings have provided newer insights into the miRNA signatures for the classification and early detection of IDC.

Delineating the role of nuclear receptors in colorectal cancer, a focused review.

Colorectal cancer (CRC) stands as one of the most prevalent form of cancer globally, causing a significant number of deaths, surpassing 0.9 million in the year 2020. According to GLOBOCAN 2020, CRC ranks third in incidence and second in mortality in both males and females. Despite extensive studies over the years, there is still a need to establish novel therapeutic targets to enhance the patients' survival rate in CRC. Nuclear receptors (NRs) are ligand-activated transcription factors (TFs) that regulate numerous essential biological processes such as differentiation, development, physiology, reproduction, and cellular metabolism. Dysregulation and anomalous expression of different NRs has led to multiple alterations, such as impaired signaling cascades, mutations, and epigenetic changes, leading to various diseases, including cancer. It has been observed that differential expression of various NRs might lead to the initiation and progression of CRC, and are correlated with poor survival outcomes in CRC patients. Despite numerous studies on the mechanism and role of NRs in this cancer, it remains of significant scientific interest primarily due to the diverse functions that various NRs exhibit in regulating key hallmarks of this cancer. Thus, modulating the expression of NRs with their agonists and antagonists, based on their expression levels, holds an immense prospect in the diagnosis, prognosis, and therapeutical modalities of CRC. In this review, we primarily focus on the role and mechanism of NRs in the pathogenesis of CRC and emphasized the significance of targeting these NRs using a variety of agents, which may represent a novel and effective strategy for the prevention and treatment of this cancer.

Exosomal noncoding RNA-mediated spatiotemporal regulation of lipid metabolism: Implications in immune evasion and chronic inflammation.

The hallmark of chronic inflammatory diseases is immune evasion. Successful immune evasion involves numerous mechanisms to suppress both adaptive and innate immune responses. Either direct contact between cells or paracrine signaling triggers these responses. Exosomes are critical drivers of these interactions and exhibit both immunogenic and immune evasion properties during the development and progression of various chronic inflammatory diseases. Exosomes carry diverse molecular cargo, including lipids, proteins, and RNAs that are crucial for immunomodulation. Moreover, recent studies have revealed that exosomes and their cargo-loaded molecules are extensively involved in lipid remodeling and metabolism during immune surveillance and disease. Many studies have also shown the involvement of lipids in controlling immune cell activities and their crucial upstream functions in regulating inflammasome activation, suggesting that any perturbation in lipid metabolism results in abnormal immune responses. Strikingly, the expanded immunometabolic reprogramming capacities of exosomes and their contents provided insights into the novel mechanisms behind the prophylaxis of inflammatory diseases. By summarizing the tremendous therapeutic potential of exosomes, this review emphasizes the role of exosome-derived noncoding RNAs in regulating immune responses through the modulation of lipid metabolism and their promising therapeutic applications.

Role of Turmeric and Curcumin in Prevention and Treatment of Chronic Diseases: Lessons Learned from Clinical Trials.

Turmeric (Curcuma longa) has been used for thousands of years for the prevention and treatment of various chronic diseases. Curcumin is just one of >200 ingredients in turmeric. Almost 7000 scientific papers on turmeric and almost 20,000 on curcumin have been published in PubMed. Scientific reports based on cell culture or animal studies are often not reproducible in humans. Therefore, human clinical trials are the best indicators for the prevention and treatment of a disease using a given agent/drug. Herein, we conducted an extensive literature survey on PubMed and Scopus following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The keywords "turmeric and clinical trials" and "curcumin and clinical trials" were considered for data mining. A total of 148 references were found to be relevant for the key term "turmeric and clinical trials", of which 70 were common in both PubMed and Scopus, 44 were unique to PubMed, and 34 were unique to Scopus. Similarly, for the search term "curcumin and clinical trials", 440 references were found to be relevant, of which 70 were unique to PubMed, 110 were unique to Scopus, and 260 were common to both databases. These studies show that the golden spice has enormous health and medicinal benefits for humans. This Review will extract and summarize the lessons learned about turmeric and curcumin in the prevention and treatment of chronic diseases based on clinical trials.

Pretraining strategies for effective promoter-driven gene expression prediction.

Advances in gene delivery technologies are enabling rapid progress in molecular medicine, but require precise expression of genetic cargo in desired cell types, which is predominantly achieved via a regulatory DNA sequence called a promoter; however, only a handful of cell type-specific promoters are known. Efficiently designing compact promoter sequences with a high density of regulatory information by leveraging machine learning models would therefore be broadly impactful for fundamental research and direct therapeutic applications. However, models of expression from such compact promoter sequences are lacking, despite the recent success of deep learning in modelling expression from endogenous regulatory sequences. Despite the lack of large datasets measuring promoter-driven expression in many cell types, data from a few well-studied cell types or from endogenous gene expression may provide relevant information for transfer learning, which has not yet been explored in this setting. Here, we evaluate a variety of pretraining tasks and transfer strategies for modelling cell type-specific expression from compact promoters and demonstrate the effectiveness of pretraining on existing promoter-driven expression datasets from other cell types. Our approach is broadly applicable for modelling promoter-driven expression in any data-limited cell type of interest, and will enable the use of model-based optimization techniques for promoter design for gene delivery applications. Our code and data are available at https://github.com/anikethjr/promoter_models.

Targeting Autophagy Using Long Non-Coding RNAs (LncRNAs): New Landscapes in the Arena of Cancer Therapeutics.

Cancer has become a global health hazard accounting for 10 million deaths in the year 2020. Although different treatment approaches have increased patient overall survival, treatment for advanced stages still suffers from poor clinical outcomes. The ever-increasing prevalence of cancer has led to a reanalysis of cellular and molecular events in the hope to identify and develop a cure for this multigenic disease. Autophagy, an evolutionary conserved catabolic process, eliminates protein aggregates and damaged organelles to maintain cellular homeostasis. Accumulating evidence has implicated the deregulation of autophagic pathways to be associated with various hallmarks of cancer. Autophagy exhibits both tumor-promoting and suppressive effects based on the tumor stage and grades. Majorly, it maintains the cancer microenvironment homeostasis by promoting viability and nutrient recycling under hypoxic and nutrient-deprived conditions. Recent investigations have discovered long non-coding RNAs (lncRNAs) as master regulators of autophagic gene expression. lncRNAs, by sequestering autophagy-related microRNAs, have been known to modulate various hallmarks of cancer, such as survival, proliferation, EMT, migration, invasion, angiogenesis, and metastasis. This review delineates the mechanistic role of various lncRNAs involved in modulating autophagy and their related proteins in different cancers.

Coordinated anatomical and functional variability in the human brain during adolescence.

Adolescence represents a time of unparalleled brain development. In particular, developmental changes in morphometric and cytoarchitectural features are accompanied by maturation in the functional connectivity (FC). Here, we examined how three facets of the brain, including myelination, cortical thickness (CT), and resting-state FC, interact in children between the ages of 10 and 15. We investigated the pattern of coordination in these measures by computing correlation matrices for each measure as well as meta-correlations among them both at the regional and network levels. The results revealed consistently higher meta-correlations among myelin, CT, and FC in the sensory-motor cortical areas than in the association cortical areas. We also found that these meta-correlations were stable and little affected by age-related changes in each measure. In addition, regional variations in the meta-correlations were consistent with the previously identified gradient in the FC and therefore reflected the hierarchy of cortical information processing, and this relationship persists in the adult brain. These results demonstrate that heterogeneity in FC among multiple cortical areas are closely coordinated with the development of cortical myelination and thickness during adolescence.

Natural compounds targeting nuclear receptors for effective cancer therapy.

Human nuclear receptors (NRs) are a family of forty-eight transcription factors that modulate gene expression both spatially and temporally. Numerous biochemical, physiological, and pathological processes including cell survival, proliferation, differentiation, metabolism, immune modulation, development, reproduction, and aging are extensively orchestrated by different NRs. The involvement of dysregulated NRs and NR-mediated signaling pathways in driving cancer cell hallmarks has been thoroughly investigated. Targeting NRs has been one of the major focuses of drug development strategies for cancer interventions. Interestingly, rapid progress in molecular biology and drug screening reveals that the naturally occurring compounds are promising modern oncology drugs which are free of potentially inevitable repercussions that are associated with synthetic compounds. Therefore, the purpose of this review is to draw our attention to the potential therapeutic effects of various classes of natural compounds that target NRs such as phytochemicals, dietary components, venom constituents, royal jelly-derived compounds, and microbial derivatives in the establishment of novel and safe medications for cancer treatment. This review also emphasizes molecular mechanisms and signaling pathways that are leveraged to promote the anti-cancer effects of these natural compounds. We have also critically reviewed and assessed the advantages and limitations of current preclinical and clinical studies on this subject for cancer prophylaxis. This might subsequently pave the way for new paradigms in the discovery of drugs that target specific cancer types.

The Journey of Resveratrol from Vineyards to Clinics.

With rising technological advancements, several factors influence the lifestyle of people and stimulate chronic inflammation that severely affects the human body. Chronic inflammation leads to a broad range of physical and pathophysiological distress. For many years, non-steroidal drugs and corticosteroids were most frequently used in treating inflammation and related ailments. However, long-term usage of these drugs aggravates the conditions of chronic diseases and is presented with morbid side effects, especially in old age. Hence, the quest for safe and less toxic anti-inflammatory compounds of high therapeutic potential with least adverse side effects has shifted researchers' attention to ancient medicinal system. Resveratrol (RSV) - 3,4,5' trihydroxystilbene is one such naturally available polyphenolic stilbene derivative obtained from various plant sources. For over 2000 years, these plants have been used in Asian medicinal system for curing inflammation-associated disorders. There is a wealth of in vitro, in vivo and clinical evidence that shows RSV could induce anti-aging health benefits including, anti-cancer, anti-inflammatory, anti-oxidant, phytoesterogenic, and cardio protective properties. However, the issue of rapid elimination of RSV through the metabolic system and its low bio-availability is of paramount importance which is being studied extensively. Therefore, in this article, we scientifically reviewed the molecular targets, biological activities, beneficial and contradicting effects of RSV as evinced by clinical studies for the prevention and treatment of inflammation-mediated chronic disorders.

Modulation of diverse oncogenic signaling pathways by oroxylin A: An important strategy for both cancer prevention and treatment.

BACKGROUND: Regardless of major advances in diagnosis, prevention and treatment strategies, cancer is still a foreboding cause due to factors like chemoresistance, radioresistance, adverse side effects and cancer recurrence. Therefore, continuous development of unconventional approaches is a prerequisite to overcome foregoing glitches. Natural products have found their way into treatment of serious health conditions, including cancer since ancient times. The compound oroxylin A (OA) is one among those with enormous potential against different malignancies. It is a flavonoid obtained from the several plants such as Oroxylum indicum, Scutellaria baicalensis and S. lateriflora, Anchietea pyrifolia, and Aster himalaicus. PURPOSE: The main purpose of this study is to comprehensively elucidate the anticancerous effects of OA against various malignancies and unravel their chemosensitization and radiosensitization potential. Pharmacokinetic and pharmacodynamic studies of OA have also been investigated. METHOD: The literature on antineoplastic effects of OA was searched in PubMed and Scopus, including in vitro and in vivo studies and is summarized based on a systematic review protocol prepared according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The term "oroxylin A" was used in combination with "cancer" and all the title, abstracts and keywords appeared were considered. RESULTS: In Scopus, a total of 157 articles appeared out of which 103 articles that did not meet the eligibility criteria were eliminated and 54 were critically evaluated. In PubMed, from the 85 results obtained, 26 articles were eliminated and 59 were included in the preparation of this review. Mounting number of studies have illustrated the anticancer effects of OA, and its mechanism of action. CONCLUSION: OA is a promising natural flavonoid possessing wide range of pleiotropic properties and is a potential anticancer agent. It has a great potential in the treatment of multiple cancers including brain, breast, cervical, colon, esophageal, gall bladder, gastric, hematological, liver, lung, oral, ovarian, pancreatic and skin. However, lack of pharmacokinetic studies, toxicity assessments, and dose standardization studies and adverse effects limit the optimization of this compound as a therapeutic agent.

The multifaceted role of STAT3 pathway and its implication as a potential therapeutic target in oral cancer.

Oral cancer is one of the leading causes of cancer-related deaths, and it has become a matter of serious concern due to the alarming rise in its incidence rate worldwide. Despite recent advancements in oral cancer treatment strategies, there are no significant improvements in patient's survival rate. Among the numerous cell signaling pathways involved in oral cancer development and progression, STAT3 is known to play a multifaceted oncogenic role in shaping the tumor pathophysiology. STAT3 hyperactivation in oral cancer contributes to survival, proliferation, invasion, epithelial to mesenchymal transition, metastasis, immunosuppression, chemoresistance, and poor prognosis. A plethora of pre-clinical and clinical studies have documented the role of STAT3 in the initiation and development of oral cancer and showed that STAT3 inhibition holds significant potential in the prevention and treatment of this cancer. However, to date, targeting STAT3 activation mainly involves inhibiting the upstream signaling molecules such as JAK and IL-6 receptors. The major challenge in targeting STAT3 lies in the complexity of its phosphorylation- and dimerization-independent functions, which are not affected by disrupting the upstream regulators. The present review delineates the significance of the STAT3 pathway in regulating various hallmarks of oral cancer. In addition, it highlights the STAT3 inhibitors identified to date through various preclinical and clinical studies that can be employed for the therapeutic intervention in oral cancer treatment.

Targeting PD-1/PD-L1 axis as new horizon for ovarian cancer therapy.

Ovarian cancer is one of the deadliest gynecological cancers and the 7th most commonly occurring cancer in women globally. The 5 year survival rate is estimated to be less than 25 %, as in most cases, diagnosis occurs at an advanced stage. Despite recent advancements in treatment, clinical outcomes still remain poor, thus implicating the need for urgent identification of novel therapeutics for the treatment of this cancer. Ovarian cancer is considered a low immune reactive cancer as the tumor cells express insufficient neoantigens to be recognized by the immune cells and thus tend to escape from immune surveillance. Thus, in the recent decade, immunotherapy has gained significant attention and has rejuvenated the understanding of immune regulation in tumor biology. One of the critical immune checkpoints is programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis. Engagement of PD-1 to PD-L1 promotes immunologic tolerance and suppresses the effector T cells and maintains tumor Tregs, thus playing a crucial role in enhancing tumor survival. Recent studies are targeted to develop inhibitors that block this signal to augment the anti-tumor activity of immune cells. Also, compared to monotherapy, the combinatorial treatment of immune checkpoint inhibitors with small molecule inhibitors have shown promising results with improved efficacy and acceptable adverse events. The present review provides an overview of the PD-1/PD-L1 axis and role of non-coding RNAs in regulating this axis. Moreover, we have highlighted the various preclinical and clinical investigations on PD-1/PD-L1 immune checkpoint inhibitors and have discussed the limitations of immunotherapies in ovarian cancer.

Targeting Nuclear Receptors in Lung Cancer-Novel Therapeutic Prospects.

Lung cancer, the second most commonly diagnosed cancer, is the major cause of fatalities worldwide for both men and women, with an estimated 2.2 million new incidences and 1.8 million deaths, according to GLOBOCAN 2020. Although various risk factors for lung cancer pathogenesis have been reported, controlling smoking alone has a significant value as a preventive measure. In spite of decades of extensive research, mechanistic cues and targets need to be profoundly explored to develop potential diagnostics, treatments, and reliable therapies for this disease. Nuclear receptors (NRs) function as transcription factors that control diverse biological processes such as cell growth, differentiation, development, and metabolism. The aberrant expression of NRs has been involved in a variety of disorders, including cancer. Deregulation of distinct NRs in lung cancer has been associated with numerous events, including mutations, epigenetic modifications, and different signaling cascades. Substantial efforts have been made to develop several small molecules as agonists or antagonists directed to target specific NRs for inhibiting tumor cell growth, migration, and invasion and inducing apoptosis in lung cancer, which makes NRs promising candidates for reliable lung cancer therapeutics. The current work focuses on the importance of various NRs in the development and progression of lung cancer and highlights the different small molecules (e.g., agonist or antagonist) that influence NR expression, with the goal of establishing them as viable therapeutics to combat lung cancer.

Tumor cell anabolism and host tissue catabolism-energetic inefficiency during cancer cachexia.

Cancer-associated cachexia (CC) is a pathological condition characterized by sarcopenia, adipose tissue depletion, and progressive weight loss. CC is driven by multiple factors such as anorexia, excessive catabolism, elevated energy expenditure by growing tumor mass, and inflammatory mediators released by cancer cells and surrounding tissues. In addition, endocrine system, systemic metabolism, and central nervous system (CNS) perturbations in combination with cachexia mediators elicit exponential elevation in catabolism and reduced anabolism in skeletal muscle, adipose tissue, and cardiac muscle. At the molecular level, mechanisms of CC include inflammation, reduced protein synthesis, and lipogenesis, elevated proteolysis and lipolysis along with aggravated toxicity and complications of chemotherapy. Furthermore, CC is remarkably associated with intolerance to anti-neoplastic therapy, poor prognosis, and increased mortality with no established standard therapy. In this context, we discuss the spatio-temporal changes occurring in the various stages of CC and highlight the imbalance of host metabolism. We provide how multiple factors such as proteasomal pathways, inflammatory mediators, lipid and protein catabolism, glucocorticoids, and in-depth mechanisms of interplay between inflammatory molecules and CNS can trigger and amplify the cachectic processes. Finally, we highlight current diagnostic approaches and promising therapeutic interventions for CC.

Nuclear receptors in oral cancer-Emerging players in tumorigenesis.

Oral cancer has been a global concern for decades, with an estimated 377,713 new cases and 177,757 deaths worldwide, according to the GLOBOCAN 2020. Despite extensive research over the years, there is still a need to establish therapeutic targets to improve patient survival in oral tumorigenesis. Nuclear receptors (NRs) are transcription factors that regulate various biological processes such as growth, differentiation, development, and metabolism, and their aberrant expression has been reported in many diseases, including cancers. Deregulation of different NRs has been linked to various alterations such as mutations, epigenetic changes, and impaired signaling cascades by other proteins and molecules. Very few studies have shown the diagnostic and prognostic potential of NRs in oral cancer. These receptors have been targeted using a plethora of agonists and antagonists, leading to inhibition of tumor proliferation, migration and invasion, and inducing apoptosis, suggesting that NRs could serve as plausible targets for treating oral malignancies. In this review, we focus on the involvement of NRs in oral tumor pathogenesis and highlight the importance of targeting NRs using various agonists and antagonists that could serve as a potential strategy for the prevention and treatment of oral malignancies.

An overview of the pharmacological activities of scopoletin against different chronic diseases.

Chronic diseases are considered a major public health concern worldwide, and most of these diseases like cancer, cardiovascular, metabolic, and neurological disorders occur due to atypical regulation of multiple signaling pathways. It has also been observed that most of the currently approved therapies for these diseases fail to show prolonged efficacy due to their mono-targeted nature and are associated with the development of chemoresistance, thus restricting their utility. The plant-derived compounds, on the other hand, show multi-targeted nature, and thus these phytochemicals have gained wide attention as they offer negligible side effects. The present review aims to recapitulate the potential effects of one such phytochemical, Scopoletin, which was found to have a diverse range of pharmacological activities such as anti-cancer, anti-diabetic, anti-inflammatory, cardioprotective, hepatoprotective, etc. Scopoletin modulated multiple molecular signatures in cancer, including AMPK, EGFR, MAPK/ ERK, NF-κB, PI3K/Akt/ mTOR, and STAT3; regulated the levels of critical markers of metabolic diseases such as ALT, AST, TG, and TC; inflammatory diseases such as ILs and TNFs; neurological diseases such as AChE, etc. thus relieving the symptoms and severity associated with these diseases. Further, this compound has a non-toxic nature and possesses an excellent pharmacokinetic property, which warrants further investigation in clinical settings for developing it as a potential drug.

STAT3/HIF1A and EMT specific transcription factors regulated genes: Novel predictors of breast cancer metastasis.

Metastasis, the fatal hallmark of breast cancer (BC), is a serious hurdle for therapy. Current prognostic approaches are not sufficient to predict the metastasis risk for BC patients. Therefore, in the present study, we analyzed gene expression data from GSE139038 and TCGA database to develop predictive markers for BC metastasis. Initially, the data from GSE139038 which contained 65 samples consisting of 41 breast tumor tissues, 18 paired morphologically normal tissues and 6 from non-malignant breast tissues were analyzed for differentially expressed genes (DEGs). DEGs were obtained from three different comparisons: paired morphologically normal (MN) versus tumor samples (C), apparently normal (AN) versus tumor samples (C), and paired morphologically normal (MN) versus apparently normal samples (AN). Multiple bioinformatic methods were employed to evaluate metastasis, EMT and triple negative breast cancer (TNBC) specific genes. Further, regulation of gene expression, clinicopathological factors and DNA methylation patterns of DEGs in BC were validated with TCGA datasets. Our bioinformatic analysis showed that 40 genes were upregulated and 294 were found to be downregulated between AN vs C; 124 were upregulated and 760 genes were downregulated between MN vs C; 4 were upregulated and 13 were downregulated between MN vs AN. Analysis using TCGA dataset revealed 18 genes were significantly altered in nodal positive BC patients compared to nodal negative BC patients. Our study showed novel candidate genes as predictive markers for BC metastasis which can also be used for therapeutic targets for BC treatment.