Receptor-based targeting of engineered nanocarrier against solid tumors: Recent progress and challenges ahead.

Background In past few decades, the research on engineered nanocarriers (NCs) has gained significant attention in cancer therapy due to selective delivery of drug molecules on the diseased cells thereby preventing unwanted uptake into healthy cells to cause toxicity. Scope of review The applicability of enhanced permeability and retention (EPR) effect for the delivery of nanomedicines in cancer therapy has gained limited success due to poor accessibility of the drugs to the target cells where non-specific payload delivery to the off target region lack substantial reward over the conventional therapeutic systems. Major conclusions In spite of the fact, nanomedicines fabricated from the biocompatible nanocarriers have reduced targeting potential for meaningful clinical benefits. However, over expression of receptors on the tumor cells provides opportunity to design functional nanomedicine to bind substantially and deliver therapeutics to the cells or tissues of interest by alleviating the bio-toxicity and unwanted effects. This critique will give insight into the over expressed receptor in various tumor and targeting potential of functional nanomedicine as new therapeutic avenues for effective treatment. General significance This review shortly shed light on EPR-based drug targeting using nanomedicinal strategies, their limitation, and advances in therapeutic targeting to the tumor cells.

Nanomedicinal strategies as efficient therapeutic interventions for delivery of cancer vaccines.

The applications of gene therapy-based treatment of cancers were started almost two decades back as a boon over the chemotherapeutic treatment strategies. Gene therapy helps in correcting the genetic sequences for treatment of cancers, thus also acts like a vaccine to induce the cellular and humoral immunity. However, the cancer vaccines typically suffer from a series of biopharmaceutical challenges due to poor solubility, low systemic availability and lack of targeting ability. Owing to these challenges, the physicians and pharmaceutical scientists have explored the applications of nanocarriers as quite promising systems for effective treatment against the tumors. A series of nanotherapeutic systems are available to date for diverse drug therapy applications. Systematic understanding on the preparation, evaluation and application of nanomedicines as a carrier system for delivering the cancer vaccines is highly important. The present review article provides an in-depth understanding on the challenges associated with cancer vaccine delivery and current opportunities with diverse nanomedicinal carriers being available for treatment of cancers.

Molecular and Clinical Aspects of COVID-19 Vaccines and Other Therapeutic Interventions Apropos Emerging Variants of Concern.

Coronavirus disease 2019 (COVID-19) has overwhelmed the healthcare and economy of the world, with emerging new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) posing an everlasting threat to humanity. While most COVID-19 vaccines provide adequate protective immunological response against the original SARS-CoV-2 variant, there is a pressing need to understand their biological and clinical responses. Recent evidence suggests that some of the new variants of SARS-CoV-2 evade the protection conferred by the existing vaccines, which may impede the ongoing efforts to expedite the vaccination programs worldwide. These concerns have also highlighted the importance of a pan-COVID-19 vaccine, which is currently in the making. Thus, it is imperative to have a better molecular and clinical understanding of the various COVID-19 vaccines and their immunological trajectory against any emerging variant of concerns (VOCs) in particular to break this vicious cycle. Furthermore, other treatment regimens based on cellular therapies and monoclonal antibodies should be explored systematically as an alternative and readily available option considering the possibility of the emergence of more virulent SARS-CoV-2 mutants. In this review, we shed light on the various molecular mechanisms and clinical responses of COVID-19 vaccines. Importantly, we review the recent findings of their long-term immune protection and efficacy against emerging VOCs. Considering that other targeted and effective treatments will complement vaccine therapy, we provide a comprehensive understanding of the role of cell-based therapies, monoclonal antibodies, and immunomodulatory agents as alternative and readily available treatment modalities against any emerging SARS-CoV-2 variant.

Erratum: Molecular docking and pharmacokinetic evaluation of natural compounds as targeted inhibitors against Crz1 protein in Rhizoctonia solani.

[This corrects the article on p. 227 in vol. 15, PMID: 31285645.].

Functional and Structural Analysis of Predicted Proteins Obtained from Homo sapiens' Minisatellite 33.15-Tagged Transcript pAKT-45 Variants.

The spermatozoa are transcriptionally dormant entities which have been recognized to be an archive of mRNA, coding for a variety of functionally crucial cellular proteins. This significant repository of mRNA is predicted to be associated with early embryogenesis and postfertilization. The mRNA transcripts which are tagged with minisatellites have been involved in the regulation of the gene functions as well as their organization. However, very little information is available regarding the expression of the transcripts tagged with minisatellites in spermatozoa. Therefore, in order to understand the functions and the conformational behavior of the proteins expressed from these minisatellite-tagged transcripts, we have performed a detailed in silico analysis using the sequences of the transcripts. The protein predicted from KF274549 showed the functionalities similar to uncharacterized C4orf26 proteins, while that obtained from KF274557 predicted to be a metallophosphoesterase. Furthermore, the structural folds in the structure of these predicted proteins were analyzed by using the homology modeling and their conformational behaviors in the explicit water conditions were analyzed by using the techniques of Molecular Dynamics (MD) simulations. This detailed analysis will facilitate the understanding of these proteins in the spermatozoon region and can be used for uncovering other attributes of the metabolic network.

Analysis of predicted proteasomal cleavages in the methyltransferase domain from JEV.

The methyltransferase (MTase, a 265 amino acid residues long region at the N-terminal end of the viral nonfunctional supermolecule NS5 domain) is key for viral replication in Japanese Encephalitis Virus (JEV). Sequence to structure to functional information with adequate knowledge on MTase from JEV is currently limited. Therefore, it is of interest to document a report on the comprehensive analysis of predicted proteasomal cleavage data in the methyltransferase domain from JEV. This data is relevant in the design and development of vaccine and other therapeutic candidates for further consideration.

Analysis of methyltransferase (MTase) domain from Zika virus (ZIKV).

A comprehensive analysis of methyltransferase (MTase) from Zika virus (ZIKV) is of interest in the development of drugs and biomarkers in the combat and care of ZIKA fever with impulsive joint pain and conjunctivitis. MTase sequence is homologous in several viral species. We analyzed the MTase domain from ZIKV using Bioinformatics tools such as SMART, PROSITE, PFAM, PANTHER, and InterProScan to glean insights on the sequence to structure to function data. We document inclusive information on MTase from ZIKV for application in the design of drugs and biomarkers to fight against the disease.

Networking of predicted post-translational modification (PTM) sites in human EGFR.

Epidermal growth factor receptor (EGFR) binds to EGF activating tyrosine phosphorylation through receptor dimerization prompting uncontrolled multiplication. Domain organization, secondary structure combinations in motifs and interactome define such transitory changes responsible for the multi-functionality of human EGFR. We report the predicted phosphorylation sites on Ser, Thr and Tyr residues in addition to 74 auto-phosphorylation sites on Tyr in human EGFR. These data suggest a complex interplay between phosphorylation types for modification resulting in the modulation of human EGFR functionality. It is of further interest in future to thoroughly understand the associated data to clarify the various roles played by post translational modifications (PTM) in human EGFR.

Molecular docking and pharmacokinetic evaluation of natural compounds as targeted inhibitors against Crz1 protein in Rhizoctonia solani.

Crz1p regulates Calcineurin, a serine-threonine-specific protein phosphatase, in Rhizoctonia solani. It has attracted consideration as a novel target of antifungal therapy based on studies in numerous pathogenic fungi, including, Cryptococcus neoformans, Candida albicans and Aspergillus fumigatus. To investigate whether Calcineurin can be a useful target for the treatment of Crz1 protein in R. solani causing wet root rot in Chickpea. The work presented here reports the in-silico studies of Crz1 protein against natural compounds. This study Comprises of quantitative structure-toxicity relationship (QSTR) and quantitative structure-activity relationship (QSAR). All compounds showed high binding energy for Crz1 protein through molecular docking. Further, a pharmacokinetic study revealed that these compounds had minimal side effects. Biological activity spectrum prediction of these compounds showed potential antifungal properties by showing significant interaction with Crz1. Hence, these compounds can be used for the prevention and treatment of wet root rot in Chickpea.

Garcinol Sensitizes NSCLC Cells to Standard Therapies by Regulating EMT-Modulating miRNAs.

Garcinol, a dietary factor obtained from Garcinia indica, modulates several key cellular signaling pathways as well as the expression of miRNAs. Acquired resistance to standard therapies, such as erlotinib and cisplatin, is a hallmark of non-small cell lung cancer (NSCLC) cells that often involves miRNA-regulated epithelial-to-mesenchymal transition (EMT). We used A549 cells that were exposed to transforming growth factor beta 1 (TGF-ß1), resulting in A549M cells with mesenchymal and drug resistant phenotype, and report that garcinol sensitized resistant cells with mesenchymal phenotype to erlotinib as well as cisplatin with significant decrease in their IC50 values. It also potentiated the apoptosis-inducing activity of erlotinib in A549M and the endogenously mesenchymal H1299 NSCLC cells. Further, garcinol significantly upregulated several key EMT-regulating miRNAs, such as miR-200b, miR-205, miR-218, and let-7c. Antagonizing miRNAs, through anti-miRNA transfections, attenuated the EMT-modulating activity of garcinol, as determined by mRNA expression of EMT markers, E-cadherin, vimentin, and Zinc Finger E-Box Binding Homeobox 1 (ZEB1). This further led to repression of erlotinib as well as cisplatin sensitization, thus establishing the mechanistic role of miRNAs, particularly miR-200c and let-7c, in garcinol-mediated reversal of EMT and the resulting sensitization of NSCLC cells to standard therapies.

Influence of ellagic acid on prostate cancer cell proliferation: a caspase-dependent pathway.

OBJECTIVE: To evaluate the effect of allagic acid treatment on the cell viability of human prostate cancer cells. METHODS: Ellagic acid (10-100 mol/L) treatment (48 h) of human prostate carcinoma PC3 cells was found to result in a dose-dependent inhibition of cell growth and apoptosis of PC3 cells as assessed by MTT assay, western blotting, flow cytometry and confocal microscopy. RESULTS: We observed that ellagic acid treatment of PC3 cells resulted in a dose dependent inhibition of cell growth/cell viability. This ellagic acid caused cell growth inhibition was found to be accompanied by induction of apoptosis, as assessed by the cleavage of poly (ADP-ribose) polymerase (PARP) and morphological changes. Further, induction of apoptosis accompanied a decrease in the levels of antiapoptotic protein Bcl-2 and increase in proapoptotic protein Bax, thus shifting the Bax: Bcl-2 ratio in favor of apoptosis. Ellagic acid treatment of PC3 cells was also found to result in significant activation of caspases, as shown by the dose dependent decrease in the protein expression of procaspase-3, -6, -8 and -9. This ellagic acid-mediated induction of apoptosis was significantly (80%-90%) inhibited by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone (Z-VAD-FMK). Thus these data suggested an essential role of caspases in ellagic acid-mediated apoptosis of PC3 cells. CONCLUSIONS: It is tempting to suggest that consumption of tropical pigmented fruits and vegetables could be an effective strategy to combat prostate cancer.