Indian Herb-Derived Phytoconstituent-Based Antiviral, Antimicrobial and Antifungal Formulation: An Oral Rinse Candidate for Oral Hygiene and the Potential Prevention of COVID-19 Outbreaks.

Outbreaks of emerging infectious diseases continue to challenge human health. Novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has triggered a global coronavirus pandemic, known as COVID-19. Multiple variants of SARS-CoV-2 virus are circulating, thus raising questions with respect to the effectiveness of different lines of treatment, such as vaccines and antiviral drugs. To find the appropriate prevention/treatment, 21 plant-based ingredients (Glycyrrhizin, Withanone, Aloe-emodin, Rhein, Emodin, Chrysophanol, Physcion, Kaempferol, Progallin A, Gallic acid, Naringin, Quercetin, Luteolin, and Apigenin) having antiviral, antibacterial and antifungal properties were identified. We pseudo-typed SARS-CoV-2 on a lentiviral vector plasmid and tested the impact of five different herbal formulations in mammalian HEK293T cells. Viral inactivation assay showed that the natural extracts in a herb-derived phytoconstituent-based formulation, BITS-003, comprising Bacopa monnieri, Glycyerrhiza glabra, Asparagus racemosus-wild, and Nigella sativa had strong virucidal properties, inactivating enveloped viruses from 2log10 (or 99%) to >4log10 (or 99.99%). Moreover, bacterial and yeast cells treated with BITS-003 displayed reduced growth. Topical use of the formulation as a mouthwash/gargle could be effective in reducing symptoms of respiratory viral infections, with the potential to decrease the viral load in the buccal/oral cavity. This may inhibit the coronavirus spreading to the lungs of infected persons and at the same time may reduce the risk of viral transmission to other susceptible persons through micro-droplets originating from the oral cavity of the infected person.

Effectiveness of antenatal screening of asymptomatic bacteriuria in reduction of prematurity and low birth weight: Evaluating a point-of-care rapid test in a pragmatic randomized controlled study.

BACKGROUND: Premature babies suffer higher mortality and life-long disabilities. Asymptomatic bacteriuria (ASB) is postulated to induce preterm labor. Routine antenatal screening for ASB using urine culture is not feasible in most developing countries due to long turn-around time, user-unfriendliness, and lack of resources. The current parallel-group superiority pragmatic randomized controlled trial evaluated the effect of screening and evidence-based treatment of ASB using an optical-sensor-based point-of-care rapid-test on the incidence of preterm birth and low birthweight (LBW). METHODS: 240 consenting asymptomatic pregnant women visiting an Indian tertiary public hospital for first antenatal check-up, irrespective of trimester/gravida, who had not consumed antibiotics in the preceding week, were enrolled from February-May 2017. Computer-generated concealed simple randomization allocation sequence was used to assign participants to intervention (120) and control arm (120). Usual hospital-care was provided in the control arm. In the intervention arm, urine samples were additionally screened for ASB using the rapid-test and the positive women were prescribed susceptible antibiotics. Blinded outcome assessors followed up with women post-delivery. The study was registered with the Clinical Trials Registry-India (CTRI/2016/09/007240). FINDINGS: 213 participants were analyzed (intervention: 103, control: 110). 21 women were found positive for ASB and prescribed pathogen-specific antibiotics. The incidence of preterm birth/LBW in intervention arm (n = 27) was lower than control arm (n = 45) by 14·7% (95% CI: 2·2-27·2); RR: 0.64, (95% CI: 0·43-0·95); p = 0·023, X2=5·13. INTERPRETATION: Rapid-test-guided treatment for ASB reduced the incidence of preterm birth/LBW in a pragmatic setting without any adverse event. FUNDING: Department of Biotechnology, Government of India.

Demystifying Excess Immune Response in COVID-19 to Reposition an Orphan Drug for Down-Regulation of NF-κB: A Systematic Review.

The immunological findings from autopsies, biopsies, and various studies in COVID-19 patients show that the major cause of morbidity and mortality in COVID-19 is excess immune response resulting in hyper-inflammation. With the objective to review various mechanisms of excess immune response in adult COVID-19 patients, Pubmed was searched for free full articles not related to therapeutics or co-morbid sub-groups, published in English until 27.10.2020, irrespective of type of article, country, or region. Joanna Briggs Institute's design-specific checklists were used to assess the risk of bias. Out of 122 records screened for eligibility, 42 articles were included in the final review. The review found that eventually, most mechanisms result in cytokine excess and up-regulation of Nuclear Factor-κB (NF-κB) signaling as a common pathway of excess immune response. Molecules blocking NF-κB or targeting downstream effectors like Tumour Necrosis Factor α (TNFα) are either undergoing clinical trials or lack specificity and cause unwanted side effects. Neutralization of upstream histamine by histamine-conjugated normal human immunoglobulin has been demonstrated to inhibit the nuclear translocation of NF-κB, thereby preventing the release of pro-inflammatory cytokines Interleukin (IL) 1ß, TNF-α, and IL-6 and IL-10 in a safer manner. The authors recommend repositioning it in COVID-19.

PMEPA1 Gene Isoforms: A Potential Biomarker and Therapeutic Target in Prostate Cancer.

The identification of prostate transmembrane protein androgen induced 1 (PMEPA1), an androgen responsive gene, came initially from the studies of androgen regulatory gene networks in prostate cancer. It was soon followed by the documentation of the expression and functional analysis of transmembrane prostate androgen-induced protein (TMEPAI)/PMEPA1 in other solid tumors including renal, colon, breast, lung, and ovarian cancers. Further elucidation of PMEPA1 gene expression and sequence analysis revealed the presence of five isoforms with distinct extracellular domains (isoforms a, b, c, d, and e). Notably, the predicted amino acid sequences of PMEPA1 isoforms show differences at the N-termini, a conserved membrane spanning and cytoplasmic domains. PMEPA1 serves as an essential regulator of multiple signaling pathways including androgen and TGF-ß signaling in solid tumors. Structure-function studies indicate that specific motifs present in the cytoplasmic domain (PY, SIM, SH3, and WW binding domains) are utilized to mediate isoform-specific functions through interactions with other proteins. The understanding of the "division of labor" paradigm exhibited by PMEPA1 isoforms further expands our knowledge of gene's multiple functions in tumorigenesis. In this review, we aim to summarize the most recent advances in understanding of PMEPA1 isoform-specific functions and their associations with prostate cancer progression, highlighting the potentials as biomarker and therapeutic target in prostate cancer.

Reversal of Increase in Intestinal Permeability by Mangifera indica Seed Kernel Extract in High-Fat Diet-Induced Obese Mice.

Obesity and hyper-intestinal permeability are interconnected. This study is designed to evaluate the ability of Mangifera indica seed kernel extract (MESK) in restoring the intestinal barrier and preventing obesity and associated metabolic complications in a high-fat diet-induced obese mouse model. Four groups of Swiss albino mice: (1) normal diet (ND), (2) high-fat diet (HFD), (3) HFD + Orlistat (100 µg/kg), and (4) HFD + MESK (75 µg/kg), were used to monitor various biochemical parameters associated with metabolic syndrome (glucose, total cholesterol, triglycerides) and body weight in an eight-week-long study. In vivo intestinal permeability was determined by the FITC-dextran method. Interestingly, MESK significantly reduced HFD-induced body weight gain, hepatic lipid accumulation, hepatic fibrosis, hyperglycemia, and dyslipidemia. Additionally, MESK treatment restored the expression of tight junction protein Zonula Occludens-1 (ZO-1) and Claudin-1 and hence prevented increased intestinal permeability induced by a high-fat diet. Moreover, it also increased the expression of potent satiety molecule Nesfatin-1 in the mouse jejunum. Our results, for the first time, establish MESK as a nutraceutical which prevents disruption of the intestinal barrier and thereby intercepts the adverse consequences of compromised intestinal permeability such as obesity, hyperglycemia, dyslipidemia, and systemic inflammation.

Characterization of unique PMEPA1 gene splice variants (isoforms d and e) from RNA Seq profiling provides novel insights into prognostic evaluation of prostate cancer.

Prostate cancer is a disease with heterogeneity of multiple gene transcriptomes and biological signaling pathways involved in tumor development. The prostate transmembrane protein, androgen induced 1 (PMEPA1), a multifunctional protein played critical roles in prostate tumorigenesis. The pleiotropic nature of PMEPA1 in modulating androgen and TGF-ß signaling as well as splice variants mechanisms for functional regulations of cancer-associated genes prompted us to investigate the biological roles of PMEPA1 isoforms in prostate cancer. In addition to 4 reported PMEPA1 isoforms (a, b, c and d), one novel isoform PMEPA1-e was identified with RNA Seq analysis of hormone responsive VCaP, LNCaP cells and human prostate cancer samples from The Cancer Genome Atlas (TCGA) dataset. We analyzed the structures, expressions, biological functions and clinical relevance of PMEPA1-e isoform and less characterized isoforms c and d in the context of prostate cancer and AR/TGF-ß signaling. The expression of PMEPA1-e was induced by androgen and AR. In contrast, PMEPA1-d was responsive to TGF-ß and inhibited TGF-ß signaling. Both PMEPA1-d and PMPEA1-e promoted the growth of androgen independent prostate cancer cells. Although PMEPA1-c was responsive to TGF-ß, it was found to have no impacts on cell growth and androgen/TGF-ß signaling. The TCGA data analysis from 499 patients showed higher expression ratios of PMEAP1-b versus -d or -e strongly associated with enhanced Gleason score. Taken together, our findings first time defined the prostate tumorigenesis mediated by PMEPA1-d and -e isoforms, providing novel insights into the new strategies for prognostic evaluation and therapeutics of prostate tumor.

Age and Tumor Differentiation-Associated Gene Expression Based Analysis of Non-Familial Prostate Cancers.

Prostate cancer incidence in young men has increased. Patients diagnosed at an earlier age are likely to have aggressive prostate cancer and treatment decisions are continuing to be weighted by patient age and life expectancy. Identification of age-associated gene-expression signatures hold great potential to augment current and future treatment modalities. To investigate age-specific tumor associated gene signatures and their potential biomarkers for disease aggressiveness, this study was designed and stratified into well and poorly differentiated tumor types of young (42-58 years) and old (66-73 years) prostate cancer patients. The differentially expressed genes related to tumor-normal differences between non-familial prostate cancer patients were identified and several genes uniquely associated with the age and tumor differentiation are markedly polarized. Overexpressed genes known to be associated with somatic genomic alterations was predominantly found in young men, such as TMPRESS2-ERG and c-MYC. On the other hand, old men have mostly down-regulated gene expressions indicating the loss of protective genes and reduced cell mediated immunity indicated by decreased HLA-A and HLA-B expression. The normalization for the benign signatures between the age groups indicates a significant age and tumor dependent heterogeneity exists among the patients with a great potential for age-specific and tumor differentiation-based therapeutic stratification of prostate cancer.

Clinical Validation of Innovative Optical-Sensor-Based, Low-Cost, Rapid Diagnostic Test to Reduce Antimicrobial Resistance.

The antibiotic susceptibility test determines the most effective antibiotic treatment for bacterial infection. Antimicrobial stewardship is advocated for the rational use of antibiotics to preserve their efficacy in the long term and provide empirical therapy for disease management. Therefore, rapid diagnostic tests can play a pivotal role in efficient and timely treatment. Here, we developed a novel, rapid, affordable, and portable platform for detecting uropathogens and reporting antibiogram to clinicians in just 4 h. This technology replicates the basic tenets of clinical microbiology including bacterial growth in indigenously formulated medium, and measurement of inhibition of bacterial growth in presence of antibiotic/s. Detection is based on chromogenic endpoints using optical sensors and is analyzed by a lab-developed algorithm, which reports antibiotic sensitivity to the antibiotics panel tested. To assess its diagnostic accuracy, a prospective clinical validation study was conducted in two tertiary-care Indian hospitals. Urine samples from 1986 participants were processed by both novel/index test and conventional Kirby Bauer Disc Diffusion method. The sensitivity and specificity of this assay was 92.5% and 82%, respectively (p < 0.0005). This novel technology will promote evidence-based prescription of antibiotics and reduce the burden of increasing resistance by providing rapid and precise diagnosis in shortest possible time.

Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-ß Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer.

Dysfunctions of androgen/TGF-ß signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-ß signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes bone metastasis. Conflicting reports on the expression and biological functions of PMEPA1 in prostate and other cancers propelled us to investigate isoform specific functions in prostate cancer (PCa). One hundred and twenty laser capture micro-dissection matched normal prostate and prostate tumor tissues were analyzed for correlations between quantitative expression of PMEPA1 isoforms and clinical outcomes with Q-RT-PCR, and further validated with a The Cancer Genome Atlas (TCGA) RNA-Seq dataset of 499 PCa. Cell proliferation was assessed with cell counting, plating efficiency and soft agar assay in androgen responsive LNCaP and TGF-ß responsive PC3 cells. TGF-ß signaling was measured by SMAD dual-luciferase reporter assay. Higher PMEPA1-a mRNA levels indicated biochemical recurrence (p = 0.0183) and lower PMEPA1-b expression associated with metastasis (p = 0.0173). Further, lower PMEPA1-b and a higher ratio of PMEPA1-a vs. -b were correlated to higher Gleason scores and lower progression free survival rate (p < 0.01). TGF-ß-responsive PMEPA1-a promoted PCa cell growth, and androgen-responsive PMEPA1-b inhibited cancer cell proliferation. PMEPA1 isoforms -a and -b were shown to be promising candidate biomarkers indicating PCa aggressiveness including earlier biochemical relapse and lower disease specific life expectancy via interrupting androgen/TGF-ß signaling.

Curcumin-Gene Expression Response in Hormone Dependent and Independent Metastatic Prostate Cancer Cells.

The androgen receptor is one of the key targets for prostate cancer treatment. Despite its less satisfactory effects, chemotherapy is the most common treatment option for metastatic and/or castration-resistant patients. There are constant needs for novel anti-prostate cancer therapeutic/prevention agents. Curcumin, a known chemo-preventive agent, was shown to inhibit prostate cancer cell growth. This study aimed to unravel the inhibitory effect of curcumin in prostate cancer through analyzing the alterations of expressions of curcumin targeting genes clusters in androgen-dependent LNCaP cells and androgen-independent metastatic C4-2B cells. Hierarchical clustering showed the highest number of differentially expressed genes at 12 h post treatment in both cells, suggesting that the androgen-dependent/independent manner of curcumin impacts on prostate cancer cells. Evaluation of significantly regulated top canonical pathways highlighted that Transforming growth factor beta (TGF-ß), Wingless-related integration site (Wnt), Phosphoinositide 3-kinase/Protein Kinase B/ mammalian target of rapamycin (PIK3/AKT(PKB)/mTOR), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling were primarily inhibited, and Phosphatase and tensin homolog (PTEN) dependent cell cycle arrest and apoptosis pathways were elevated with curcumin treatment. The short term (3-24 h) and long term (48 h) effect of curcumin treatment revealed 31 and four genes modulated in both cell lines. TGF-ß signaling, including the androgen/TGF-ß inhibitor Prostate transmembrane protein androgen-induced 1 (PMEPA1), was the only pathway impacted by curcumin treatment after 48 h. Our findings also established that MYC Proto-Oncogene, basic helix-loop-helix (bHLH) Transcription Factor (MYC) signaling was down-regulated in curcumin-treated cell lines. This study established, for the first time, novel gene-networks and signaling pathways confirming the chemo-preventive and cancer-growth inhibitory nature of curcumin as a natural anti-prostate cancer compound.

Role of Ionizing Radiation in Neurodegenerative Diseases.

Ionizing radiation (IR) from terrestrial sources is continually an unprotected peril to human beings. However, the medical radiation and global radiation background are main contributors to human exposure and causes of radiation sickness. At high-dose exposures acute radiation sickness occurs, whereas chronic effects may persist for a number of years. Radiation can increase many circulatory, age related and neurodegenerative diseases. Neurodegenerative diseases occur a long time after exposure to radiation, as demonstrated in atomic bomb survivors, and are still controversial. This review discuss the role of IR in neurodegenerative diseases and proposes an association between neurodegenerative diseases and exposure to IR.

Erratum: ETS Related Gene mediated Androgen Receptor Aggregation and Endoplasmic Reticulum Stress in Prostate Cancer Development.

A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper.

ETS Related Gene mediated Androgen Receptor Aggregation and Endoplasmic Reticulum Stress in Prostate Cancer Development.

Mechanistic studies of deregulated ERG in prostate cancer and other cancers continue to enhance its role in cancer biology and its utility as a biomarker and therapeutic target. Here, we show that ERG, through its physical interaction with androgen receptor, induces AR aggregation and endoplasmic reticulum stress in the prostate glands of ERG transgenic mice. Histomorphological alterations and the expression of ER stress sensors Atf6, Ire1α, Perk, their downstream effectors Grp78/BiP and eIF2α in ERG transgenic mouse prostate glands indicate the presence of chronic ER stress. Transient activation of apoptotic cell death during early age correlated well with the differential regulation of ER stress sensors, in particular Perk. Epithelial cells derived from ERG transgenic mouse prostates have increased prostasphere formation with resistance to radiation induced cell death. Continued activation of cell survival factors, Atf6 and Ire1α during chronic ER stress due to presence of ERG in prostate epithelium induces survival pathways and provides a selection pressure in the continuum of ERG dependent neoplastic process. These novel insights will enhance the understanding of the mechanistic functions of ERG in prostate tumor biology and towards development of early targeted therapeutic strategies for prostate cancer.

Phytochemicals in Wound Healing.

Significance: Traditional therapies, including the use of dietary components for wound healing and skin regeneration, are very common in Asian countries such as China and India. The increasing evidence of health-protective benefits of phytochemicals, components derived from plants is generating a lot of interest, warranting further scientific evaluation and mechanistic studies. Recent Advances: Phytochemicals are non-nutritive substances present in plants, and some of them have the potential to provide better tissue remodeling when applied on wounds and to also act as proangiogenic agents during wound healing. Critical Issues: In this review, we briefly discuss the current understanding, important molecular targets, and mechanism of action(s) of some of the phytochemicals such as curcumin, picroliv, and arnebin-1. We also broadly review the multiple pathways that these phytochemicals regulate to enhance wound repair and skin regeneration. Future Directions: Recent experimental data on the effects of phytochemicals on wound healing and skin regeneration establish the potential clinical utility of plant-based compounds. Additional research in order to better understand the exact mechanism and potential targets of phytochemicals in skin regeneration is needed. Human studies a2nd clinical trials are pivotal to fully understand the benefits of phytochemicals in wound healing and skin regeneration.

Loss of miR-449a in ERG-associated prostate cancer promotes the invasive phenotype by inducing SIRT1.

Epigenetic regulation by SIRT1, a multifaceted NAD+-dependent protein deacetylase, is one of the most common factors modulating cellular processes in a broad range of diseases, including prostate cancer (CaP). SIRT1 is over-expressed in CaP cells, however the associated mechanism is not well understood. To identify whether specific microRNAs might mediate this linkage, we have screened a miRNA library for differential expression in ERG-associated CaP tissues. Of 20 differentially and significantly expressed miRNAs that distinguish ERG-positive tumors from ERG-negative tumors, we find miR-449a is highly suppressed in ERG-positive tumors. We establish that SIRT1 is a direct target of miR-449a and is also induced by ERG in ERG-associated CaP. Our data suggest that attenuation of miR-449a promotes the invasive phenotype of the ERG-positive CaP in part by inducing the expression of SIRT1 in prostate cancer cells. Furthermore, we also find that suppression of SIRT1 results in a significant reduction in ERG expression in ERG-positive CaP cells, indicating a feed-back regulatory loop associated with ERG, miR-449a and SIRT1. We also report that ERG suppresses p53 acetylation perhaps through miR-449a-SIRT1 axis in CaP cells. Our findings provide new insight into the function of miRNAs in regulating ERG-associated CaP. Thus, miR-449a activation or SIRT1 suppression may represent new therapeutic opportunity for ERG-associated CaP.

Silencing of PMEPA1 accelerates the growth of prostate cancer cells through AR, NEDD4 and PTEN.

Androgen Receptor (AR) is the male hormone receptor and a nuclear transcription factor which plays a central role in the growth of normal and malignant prostate gland. Our earlier studies defined a mechanistic model for male hormone dependent regulation of AR protein levels in prostate cancer (CaP) cells through a negative feed-back loop between AR and PMEPA1, an androgen induced NEDD4 E3 ubiquitin ligase binding protein. This report focuses on the impact of PMEPA1 silencing on CaP biology. PMEPA1 knockdown accelerated the growth of CaP tumor cells in athymic nude mice. In cell culture models knockdown of PMEPA1 resulted in resistance to AR inhibitors enzalutamide and bicalutamide. While, AR protein down regulation by NEDD4 was PMEPA1 dependent, we also noted a PMEPA1 independent downregulation of PTEN by NEDD4. In a subset of human CaP, decreased PMEPA1 mRNA expression significantly correlated with increased levels of AR transcription target PSA, as a surrogate for elevated AR. This study highlights that silencing of PMEPA1 accelerates the growth of CaP cells through AR, NEDD4 and PTEN. Thus, the therapeutic restoration of PMEPA1 represents a promising complementary strategy correcting for AR and PTEN defects in CaP. Statement of significance: Here we define that silencing of PMEPA1 facilitates the growth of CaP cells and modulates AR through NEDD4 and PTEN. The restoration of PMEPA1 represents a promising complementary therapeutic strategy correcting for AR and PTEN defects.

ERG monoclonal antibody in the diagnosis and biological stratification of prostate cancer: delineation of minimal epitope, critical residues for binding, and molecular basis of specificity.

Recently we reported the development of a highly specific murine monoclonal antibody (ERG MAb 9FY) against the ERG oncoprotein. ERG is expressed in over half of all prostate cancers (CaP) as a result of specific gene fusions involving ERG and the androgen regulated TMPRSS2 promoter. ERG MAb 9FY has been extensively used in the evaluations of CaP. Increasing use of ERG MAb in CaP has prompted us to characterize the precise ERG epitope it binds to and to define the molecular basis of its specificity to ERG. The 9FY antibody binds to an epitope formed by amino acid residues 42-66 of the ERG protein. To determine the key residues involved in 9FY binding, experiments were carried out using a combination of approaches including overlapping peptides, alanine scanning mutagenesis, ELISA, and immunoblot assays. Analysis of both overlapping and variant peptides harboring truncations of amino acids revealed that a minimal epitope of eight residues (RVPQQDWL) is sufficient for binding to the 9FY antibody. In order to further identify key residues that mediate the binding of the antibody to ERG protein, a 14-residue peptide (P23) with optimal reactivity was subjected to alanine scanning mutagenesis. Alterations to residues QQDW were found to eliminate binding to the antibody, while residues (R50 and L57) were found to contribute to the binding of the antibody. Further experiments showed that peptide P23 competed effectively with ERG protein for binding 9FY. On the other hand, peptides with alanine substitutions for residues Q53 and W56 (P27 and P30, respectively) failed to interfere with binding. These data provide new information about a minimal epitope (RVPQQDWL) within amino acid residues 42-66 of the ERG protein that is recognized by MAb 9FY, which may aid in the diagnosis and also development of antibody based therapeutics against prostate and other cancers showing ERG overexpression.

Methylation of the PMEPA1 gene, a negative regulator of the androgen receptor in prostate cancer.

The prostate transmembrane protein androgen induced 1 (PMEPA1) gene is highly expressed in prostate epithelial cells and is a direct transcriptional target for the androgen receptor (AR). AR protein levels are controlled by the AR-PMEPA1 negative feedback loop through NEDD4-E3 ligase. Reduced expression of PMEPA1 observed in prostate tumors, suggests that loss of PMEPA1 may play critical roles in prostate tumorigenesis. This study focuses on epigenetic mechanisms of reduced PMEPA1 expression in the cancer of the prostate (CaP). Benign (n = 77) and matched malignant (n = 77) prostate epithelial cells were laser capture micro-dissected from optimum cutting temperature embedded frozen prostate sections from 42 Caucasian American (CA) and 35 African American (AA) cases. Purified DNA specimens were analyzed for CpG methylation of the PMEPA1 gene. PMEPA1 mRNA expression levels were evaluated by qRT-PCR. Analysis of PMEPA1 methylation and mRNA expression in the same tumor cell populations indicated a significant inverse correlation between mRNA expression and methylation in CaP (P = 0.0115). We noted higher frequency of CpG methylation within the evaluated first intronic region of the PMEPA1 gene in prostate tumors of CA men as compared with AA. In CaP cell lines, PMEPA1 expression was induced and AR protein levels were diminished in response to treatment with the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine (decitabine). Cell culture-based studies demonstrated that decitabine restores PMEPA1 expression in AR-positive CaP cell lines. This report reveals the potential role of PMEPA1 gene methylation in the regulation of AR stability. Thus, downregulation of PMEPA1 may result in increased AR protein levels and function in CaP cells, contributing to prostate tumorigenesis.

Skin regenerative potentials of curcumin.

Curcumin, an active constituent of the spice turmeric, is well known for its chemopreventive properties and is found to be beneficial in treating various disorders including skin diseases. Curcumin protects skin by quenching free radicals and reducing inflammation through the inhibition of nuclear factor-kappa B. Curcumin also affects other signaling pathways including transforming growth factor-ß and mitogen-activated protein kinase pathway. Curcumin also modulates the phase II detoxification enzymes which are crucial in detoxification reactions and for protection against oxidative stress. In the present review, the biological mechanisms of the chemopreventive potential of curcumin in various skin diseases like psoriasis, vitiligo, and melanoma is discussed. The application of curcumin in skin regeneration and wound healing is also elucidated. We also explored the recent innovations and advances involved in the development of transdermal delivery systems to enhance the bioavailability of curcumin, particularly in the skin. Recent clinical trials pertaining to the use of curcumin in skin diseases establishes its benefits and also the need for additional clinical trials in other diseases are discussed.