An Update on Genetic Predisposition for Prostate Cancer: Perspectives and Prospects.

Prostate cancer (PC) is a heterogeneous disease that kills a significant number of people all over the world. It is the most common cancer in men, especially in the western world, and causes morbidity and mortality. There are several important risk factors known for PC like age, ethnicity, and inherited genetic variants which contribute significantly. The current research studies are endeavoring to identify genetic markers for PC and to understand underlying molecular mechanisms, so that new diagnostic and screening tests based on genetics can be developed for PC. The present review discusses candidate genes such as HOXB13, BRCA1, BRCA2, ATM, MMR gene, RAD51C, CHECK2, etc., and family-based linkage studies which defined the location of loci on chromosomal regions like 1q24-25, 1q42-43, Xq27-28, 1p36, 20q13, 17q21. Furthermore, the major part of the review focuses on important PC susceptible loci (8q24, 10q11, 17q12, 17q24, and 19q13, etc.) and risk variants identified by population-based genome-wide association studies (GWAS).

Pomegranate juice anthocyanidins induce cell death in human cancer cells by mobilizing intracellular copper ions and producing reactive oxygen species.

Anthocyanidins are the most abundant polyphenols in pomegranate juice. This class of molecules includes Delphinidin (Del), Cyanidin (Cya), and Pelargonidin (Pel). Using prostate, breast and pancreatic cancer cell lines PC3, MDA-MB-231, BxPC-3 and MiaPaCa-2, we show that anthocyanidins inhibit cell proliferation (measured by MTT assay) and induce apoptosis like cell death (measured by DNA/Histone ELISA). Copper chelator neocuproine and reactive oxygen species scavengers (thiourea for hydroxyl radical and superoxide dismutase for superoxide anion) significantly inhibit this reaction thus demonstrating that intracellular copper reacts with anthocyanidins in cancer cells to cause DNA damage via ROS generation. We further show that copper-supplemented media sensitizes normal breast epithelial cells (MCF-10A) to Del-mediated growth inhibition as determined by decreased cell proliferation. Copper supplementation results in increased expression of copper transporters Ctr1 and ATP7A in MCF-10A cells, which is attenuated by the addition of Del in the medium. We propose that the copper mediated, ROS-induced mechanism of selective cell death of cancer cells may in part explain the anticancer effects of anthocyanidins.

Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and Other Coronaviruses: A Genome-wide Comparative Annotation and Analysis.

Novel strain of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) causes mild to severe respiratory illness. The early symptoms may be fever, dry cough, sour throat, and difficulty in breathing which may lead to death in severe cases. Compared to previous outbreaks like SARS-CoV and Middle East Respiratory Syndrome (MERS), SARS-CoV2 disease (COVID-19) outbreak has been much distressing due to its high rate of infection but low infection fatality rate (IFR) with 1.4% around the world. World Health Organization (WHO) has declared (COVID-19) a pandemic on March 11, 2020. In the month of January 2020, the whole genome of SARS-CoV2 was sequenced which made work easy for researchers to develop diagnostic kits and to carry out drug repurposing to effectively alleviate the pandemic situation in the world. Now, it is important to understand why this virus has high rate of infectivity or is there any factor involved at the genome level which actually facilitates this virus infection globally? In this study, we have extensively analyzed the whole genomes of different coronaviruses infecting humans and animals in different geographical locations around the world. The main aim of the study is to identify the similarity and the mutational adaptation of the coronaviruses from different host and geographical locations to the SARS-CoV2 and provide a better strategy to understand the mutational rate for specific target-based drug designing. This study is focused to every annotation in a comparative manner which includes SNPs, repeat analysis with the different categorization of the short-sequence repeats and long-sequence repeats, different UTR's, transcriptional factors, and the predicted matured peptides with the specific length and positions on the genomes. The extensive analysis on SNPs revealed that Wuhan SARS-CoV2 and Indian SARS-CoV2 are having only eight SNPs. Collectively, phylogenetic analysis, repeat analysis, and the polymorphism revealed the genomic conserveness within the SARS-CoV2 and few other coronaviruses with very less mutational chances and the huge distance and mutations from the few other species.

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.].

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.

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.

3D printing for drug delivery and biomedical applications.

Pharmaceutical product development is continuously witnessing innovations for the design of new delivery systems to improve the therapeutic efficacy of drugs. 3D-printing technology has been used to design customized personalized medication to provide maximal therapeutic benefits for patients. I addition, 3D printing has also been used to manufacture drug delivery systems and biomedical devices to establish a paradigm shift in the healthcare industry. In this review, we provide an update on current progress, technological gaps, and regulatory considerations in 3D-printing technology.

Depression linked to higher antibodies production against estrogenized insulin in type 1 diabetes.

Depression has been commonly associated with type 1 diabetes (T1D) and insulin covalently modified with catecholestrogens (CEs) was found in serum of these T1D patients. This study aimed to know whether depression link to higher antibodies against estrogenized insulin in T1D. ELISA (direct binding and competition) and quantitative precipitin titration were used to detect antibodies and their affinities against estrogenized insulin in the serum of 66 depressed T1D (DT1D) patients (out of 110 T1D) and 41 control subjects. Antibodies from DT1D patients showed high binding specificity to estrogenized insulin (2-hydroestradiol-insulin; 2-OHE2-Ins) in comparison to overall T1D patients (p < 0.05) or control subjects (p < 0.001). However, T1D sera demonstrate high recognition to 2-OHE2-Ins as compared to Ins (p < 0.05) or 2-OHE2 (p < 0.001). The affinity of antibodies from DT1D and T1D patients was 1.32 × 10-7 M and 1.43 × 10-7 M, respectively. Depression linked to higher antibodies production against estrogenized insulin in T1D. Furthermore, depression in T1D generates inflammatory conditions that further increased antibodies production in T1D patients.

Estrogenization of insulin by catecholestrogen produced high affinity autoantibodies and altered the normal function of insulin in type 1 diabetes.

AIMS: Insulin (Ins) covalently modified by catecholestrogens (CEs) was commonly found in diabetic patients who have developed insulin resistance. Estrogenization of insulin altered its molecular function and effect carbohydrates metabolisms in these patients. Insulin resistance is a common phenomenon in diabetes but the exact mechanism remains unknown. In this study, binding specificity and affinity of autoantibodies against estrogenized insulin (4-hydroxyestradiol-insulin; 4-OHE2-Ins) were assayed in the serum of type 1 diabetes (T1D) patients in order to explain the phenomena behind insulin resistance. MATERIALS AND METHODS: Specificity and affinity of autoantibodies from the sera of 66 T1D patients and 41 controls were analyzed by direct binding, competition ELISA and quantitative precipitin titration. Insulin was also estimated in the serum of T1D patients by ELISA. KEY FINDING: Estrogenized insulin (4-OHE2-Ins) exhibited high affinity and specificity to T1D autoantibodies in comparison to Ins (p < .05) or 4-OHE2 (p < .001). Estrogenization of insulin alters its interaction with the insulin receptor (IR). The affinity constant of 4-OHE2-Ins with the T1D autoantibodies was found to be 1.41 × 10-7 M. SIGNIFICANCE: Estrogenization of insulin by catecholestrogen makes these molecules highly antigenic and produced high-affinity autoantibodies in T1D patients. As a result, patients develop insulin resistance and presented this molecule as a potential biomarker for T1D.

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.

Structure-based virtual screening and molecular docking for the identification of potential novel EGFRkinase inhibitors against ovarian cancer.

Epidermal Growth Factor Receptor (EGFR) is, for the most part, deregulated and over-communicated in ovarian disease, which is legitimately connected with STAT3 enactment that prompts the collection of hostile to apoptotic occasions and along these lines, docetaxel medicate obstruction happens. As to, expanding of docetaxel medicate affectability by focusing on EGFR receptor alongside docetaxel drugs is one of the real techniques in ovarian disease treatment. In this specific circumstance, utilizing atomic recreation considers, the present examination depicted the auxiliary and pragmatic properties of IBS Database mixes as a potential inhibitor of EGFR tyrosine kinase, and furthermore ADMET had researched its Pharmacokinetic profile. As indicated by the outcomes, STOCK1N-98911, STOCK1N- 98869, and STOCK1N-98896 have appeared tremendous restricting vitality by associating with critical build ups in the dynamic site. Natural movement range forecast of these mixes indicated potential anticancer properties by demonstrating important collaboration with EGFR tyrosine kinase. Besides, the investigation is likewise valuable for further clinical based examinations and furthermore for the approval of toxicological and pharmacokinetic contemplate.

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.

A dietary anthocyanidin delphinidin induces apoptosis of human prostate cancer PC3 cells in vitro and in vivo: involvement of nuclear factor-kappaB signaling.

Delphinidin, a major anthocyanidin present in many pigmented fruits and vegetables, possesses antioxidant, anti-inflammatory, and antiangiogenic properties. In this study, we provide evidence that it could be developed as a novel agent against human prostate cancer (PCa). We observed that delphinidin treatment to human PCa LNCaP, C4-2, 22Rnu1, and PC3 cells resulted in a dose-dependent inhibition of cell growth without having any substantial effect on normal human prostate epithelial cells. We selected PC3 cells as a test model system because of their highly aggressive proliferative nature. Delphinidin treatment of cells resulted in a dose-dependent induction of apoptosis and arrest of cells in G(2)-M phase. This induction of apoptosis seems to be mediated via activation of caspases because N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluromethylketone significantly reduced apoptosis induced by delphinidin. We also observed that delphinidin treatment of cells resulted in a dose-dependent decrease in (a) phosphorylation of IkappaB kinase gamma (NEMO), (b) phosphorylation of nuclear factor-kappaB (NF-kappaB) inhibitory protein IkappaBalpha, (c) phosphorylation of NF-kappaB/p65 at Ser(536) and NF-kappaB/p50 at Ser(529), (d) NF-kappaB/p65 nuclear translocation, and (e) NF-kappaB DNA binding activity. Delphinidin administration (2 mg, i.p. thrice weekly) to athymic nude mice implanted with PC3 cells resulted in a significant inhibition of tumor growth. Analysis of tumors from delphinidin-treated mice showed significant decrease in the expression of NF-kappaB/p65, Bcl2, Ki67, and PCNA. Taken together, our data suggest that delphinidin could be developed as an agent against human PCa.

Combined inhibitory effects of green tea polyphenols and selective cyclooxygenase-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo.

PURPOSE: Cyclooxygenase-2 (COX-2) inhibitors hold promise for cancer chemoprevention; however, recent toxicity concerns suggest that new strategies are needed. One approach to overcome this limitation is to use lower doses of COX-2 inhibitors in combination with other established agents with complementary mechanisms. In this study, the effect of (-)epigallocatechin-3-gallate (EGCG), a promising chemopreventive agent from green tea, was tested alone and in combination with specific COX-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo. EXPERIMENTAL DESIGN: Human prostate cancer cells LNCaP, PC-3, and CWR22Rnu1 were treated with EGCG and NS398 alone and in combination, and their effect on growth and apoptosis was evaluated. In vivo, athymic nude mice implanted with androgen-sensitive CWR22Rnu1 cells were given green tea polyphenols (0.1% in drinking water) and celecoxib (5 mg/kg, i.p., daily, 5 days per week), alone and in combination, and their effect on tumor growth was evaluated. RESULTS: Combination of EGCG (10-40 micromol/L) and NS-398 (10 micromol/L) resulted in enhanced (a) cell growth inhibition; (b) apoptosis induction; (c) expression of Bax, pro-caspase-6, and pro-caspase-9, and poly(ADP)ribose polymerase cleavage; (d) inhibition of peroxisome proliferator activated receptor gamma; and (e) inhibition of nuclear factor-kappaB compared with the additive effects of the two agents alone, suggesting a possible synergism. In vivo, combination treatment with green tea polyphenols and celecoxib resulted in enhanced (a) tumor growth inhibition, (b) lowering of prostate-specific antigen levels, (c) lowering of insulin-like growth factor-I levels, and (d) circulating levels of serum insulin-like growth factor binding protein-3 compared with results of single-agent treatment. CONCLUSIONS: These data suggest synergistic and/or additive effects of combinatorial chemopreventive agents and underscore the need for rational design of human clinical trials.

Delphinidin, an anthocyanidin in pigmented fruits and vegetables, protects human HaCaT keratinocytes and mouse skin against UVB-mediated oxidative stress and apoptosis.

Solar UV radiation, in particular its UVB component, is the primary cause of many adverse biological effects, the most damaging of which is skin cancer. Here, we assessed the photochemopreventive effect of delphinidin, a major anthocyanidin present in many pigmented fruits and vegetables, on UVB-mediated responses in human immortalized HaCaT keratinocytes and SKH-1 hairless mouse skin. We found that pretreatment of cells with delphinidin (1-20 microM for 24 hours) protected against UVB (15-30 mJ/cm2, 24 hours)-mediated (i) decrease in cell viability and (ii) induction of apoptosis. Furthermore, we found that pretreatment of HaCaT cells with delphinidin inhibited UVB-mediated (i) increase in lipid peroxidation; (ii) formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG); (iii) decrease in proliferating cell nuclear antigen expression; (iv) increase in poly(ADP-ribose) polymerase cleavage; (v) activation of caspases; (vi) increase in Bax; (vii) decrease in Bcl-2; (viii) upregulation of Bid and Bak; and (ix) downregulation of Bcl-xL. Topical application of delphinidin (1 mg/0.1 ml DMSO/mouse) to SKH-1 hairless mouse skin inhibited UVB-mediated apoptosis and markers of DNA damage such as cyclobutane pyrimidine dimers and 8-OHdG. Taken together our results suggest that treatment of HaCaT cells and mouse skin with delphinidin inhibited UVB-mediated oxidative stress and reduced DNA damage, thereby protecting the cells from UVB-induced apoptosis.