Regulation of Cell Signaling Pathways and Non-Coding RNAs by Baicalein in Different Cancers.

Landmark discoveries in molecular oncology have provided a wide-angle overview of the heterogenous and therapeutically challenging nature of cancer. The power of modern 'omics' technologies has enabled researchers to deeply and comprehensively characterize molecular mechanisms underlying cellular functions. Interestingly, high-throughput technologies have opened new horizons for the design and scientific fool-proof evaluation of the pharmacological properties of targeted chemical compounds to tactfully control the activities of the oncogenic protein networks. Groundbreaking discoveries have galvanized the expansion of the repertoire of available pharmacopoeia to therapeutically target a myriad of deregulated oncogenic pathways. Natural product research has undergone substantial broadening, and many of the drugs which constitute the backbone of modern pharmaceuticals have been derived from the natural cornucopia. Baicalein has gradually gained attention because of its unique ability to target different oncogenic signal transduction cascades in various cancers. We have partitioned this review into different sub-sections to provide a broader snapshot of the oncogenic pathways regulated by baicalein. In this review, we summarize baicalein-mediated targeting of WNT/ß-catenin, AKT/mTOR, JAK/STAT, MAPK, and NOTCH pathways. We also critically analyze how baicalein regulates non-coding RNAs (microRNAs and long non-coding RNAs) in different cancers. Finally, we conceptually interpret baicalein-mediated inhibition of primary and secondary growths in xenografted mice.

A rare case of deep vein and right atrial thrombosis in a patient with chronic heart failure and pulmonary embolism.

Deep vein thrombosis (DVT) is frequently observed in patients with chronic heart failure (CHF), increasing the risk of pulmonary embolism (PE). Clinical evaluation of CHF patients with suspected acute PE is challenging since these diseases share several symptoms and signs such as dyspnea. Thus, it is intuitive that correct and fast diagnosis of PE in these patients might be able to significantly change their clinical outcome. In the present report, we describe a rare case of a patient with CHF and PE due to a huge thrombosis of deep veins and of right atrium in whom echo evaluation permitted the correct diagnosis and therapy.

Nanotechnology-based cancer chemoprevention in glioblastoma.

Brain tumours are heterogeneous and are classified comprehensively into molecular subtypes based on genetic alterations. Glioblastoma rapid progression, drug resistance, and recurrence have been scientifically linked to several factors, including its rapid growth rate, loss of apoptosis, pro-survival signalling, molecular heterogeneities and hallmark features to infiltrate vital brain structures. Because of the growing demand for design and development of delivery systems to overcome the existing limitations with the current therapeutic strategies, researchers are exploiting multifaceted aspects of nanotechnology to improve delivery of the drug payload. Firstly, nanotechnology procedures can improve the drug delivery methods with the help of nanoparticles (NPs) based nanovectors that can efficiently cross blood-brain barrier. Secondly, NPs also improve the cellular uptake of the drug as they can efficiently bind with the cell surface. Thirdly, NPs make the delivery of siRNAs and peptides possible, which can suppress the resistance of glioblastoma against TMZ or other chemo-preventive drugs. Fourthly, the use of metal NPs increases the efficiency of scanning or magnetic resonance imaging (MRI) procedures as they can produce contrasts in it. Lastly, NPs make it possible to use highly targeted co-administered strategies like chemoprevention and near infrared (NIR) or radiotherapy (RT). Hence, nanotechnology offers several promising solutions against glioblastoma by countering it on many fronts.

Role of Ubiquitination and Epigenetics in the Regulation of AhR Signaling in Carcinogenesis and Metastasis: "Albatross around the Neck" or "Blessing in Disguise".

The molecular mechanisms and signal transduction cascades evoked by the activation of aryl hydrocarbon receptor (AhR) are becoming increasingly understandable. AhR is a ligand-activated transcriptional factor that integrates environmental, dietary and metabolic cues for the pleiotropic regulation of a wide variety of mechanisms. AhR mediates transcriptional programming in a ligand-specific, context-specific and cell-type-specific manner. Pioneering cutting-edge research works have provided fascinating new insights into the mechanistic role of AhR-driven downstream signaling in a wide variety of cancers. AhR ligands derived from food, environmental contaminants and intestinal microbiota strategically activated AhR signaling and regulated multiple stages of cancer. Although AhR has classically been viewed and characterized as a ligand-regulated transcriptional factor, its role as a ubiquitin ligase is fascinating. Accordingly, recent evidence has paradigmatically shifted our understanding and urged researchers to drill down deep into these novel and clinically valuable facets of AhR biology. Our rapidly increasing realization related to AhR-mediated regulation of the ubiquitination and proteasomal degradation of different proteins has started to scratch the surface of intriguing mechanisms. Furthermore, AhR and epigenome dynamics have shown previously unprecedented complexity during multiple stages of cancer progression. AhR not only transcriptionally regulated epigenetic-associated molecules, but also worked with epigenetic-modifying enzymes during cancer progression. In this review, we have summarized the findings obtained not only from cell-culture studies, but also from animal models. Different clinical trials are currently being conducted using AhR inhibitors and PD-1 inhibitors (Pembrolizumab and nivolumab), which confirm the linchpin role of AhR-related mechanistic details in cancer progression. Therefore, further studies are required to develop a better comprehension of the many-sided and "diametrically opposed" roles of AhR in the regulation of carcinogenesis and metastatic spread of cancer cells to the secondary organs.

TRAIL-mediated signaling in bladder cancer: realization of clinical efficacy of TRAIL-based therapeutics in medical oncology.

Bladder cancer is a therapeutically challenging disease and wealth of knowledge has enabled researchers to develop a clear understanding of mechanisms which underlie carcinogenesis and metastasis. Excitingly, research over decades has unveiled wide-ranging mechanisms which serve as central engine in progression of bladder cancer. Loss of apoptosis, drug resistance, and pro-survival signaling are some of the highly studied cellular mechanisms. Therefore, restoration of apoptosis in resistant cancers is a valuable and attractive strategy. Discovery of TRAIL-mediated signaling cascade is an intriguing facet of molecular oncology. In this review, we have provided an overview of the translational and foundational advancements in dissecting the genomic and proteomic cartography of TRAIL signaling exclusively in the context of bladder cancer. We have also summarized how different natural products sensitized drug-resistant bladder cancer cells to TRAIL-mediated apoptosis. Interestingly, different death receptors that activate agonistic antibodies have been tested in various phases of clinical trials against different cancers. Certain clues of scientific evidence have provided encouraging results about efficacy of these agonistic antibodies (lexatumumab and mapatumumab) against bladder cancer cell lines. Therefore, multipronged approaches consisting of natural products, chemotherapeutics, and agonistic antibodies will realistically and mechanistically provide proof-of-concept for the translational potential of these combinatorial strategies in well-designed clinical trials.