Design, synthesis and analysis of charged RGD derivatives.

In the present study, negatively charged N-Biotin-RGD and positively charged C-Biotin-RGD were designed, synthesized, and characterized with docking analysis. The fixation of MDA-MB-231 cells with formalin made their cell surface neutrally charged thus removing the electrostatic interactions between charged biotinylated RGD derivatives and MDA-MB-231 cells. The results of the binding affinity of biotinylated RGD derivatives against MDA-MB-231 cells showed that N-Biotin-RGD had higher binding affinity than C-Biotin-RGD. The cytotoxic effect was analyzed by incubating charged biotinylated RGD derivatives with live MDA-MB-231 cells. MDA-MB-231 cell surface is negatively charged due to high hypersialyliation of polyglycans and Warburg effect. The results of their cytotoxic activities against live MDA-MB-231 cells were found to be electrostatic in nature. C-Biotin-RGD had an attractive interaction with the MDA-MB-231 cell surface resulting in a higher cytotoxic effect. In comparison, N-Biotin-RGD had a repulsive interaction with the MDA-MB-231 cell surface resulting in a lower cytotoxic effect. Hence, positively charged C-Biotin-RGD is a better cytotoxic agent than a negatively charged N-Biotin-RGD against MDA-MB-231 cells.

Cytotoxic Effects of Nanoliposomal Cisplatin and Diallyl Disulfide on Breast Cancer and Lung Cancer Cell Lines.

Dual drug delivery has become the choice of interest nowadays due to its increased therapeutic efficacy in targeting the tumor site precisely. As quoted in recent literature, it has been known to treat several cancers with an acute course of action. Even so, its use is restricted due to the drug's low pharmacological activity, which leads to poor bioavailability and increases first-pass metabolism. To overcome these issues, a drug delivery system using nanomaterials which would not only encapsulate the drugs of interest but also carry them to the target site of action is needed. Given all these attributes, we have formulated dual drug-loaded nanoliposomes with cisplatin (cis-diamminedichloroplatinum(II) (CDDP)), an effective anti-cancer drug, and diallyl disulfide (DADS), an organosulfur compound derived from garlic. The CDDP and DADS-loaded nanoliposomes (Lipo-CDDP/DADS) exhibited better physical characteristics such as size, zeta potential, polydispersity index, spherical shape, optimal stability, and satisfactory encapsulation percentage. The in vitro anti-cancer activity against MDA-MB-231 and A549 cell lines revealed that Lipo-CDDP/DADS showed significant efficacy against the cancer cell lines, depicted through cell nucleus staining. We conclude that Lipo-CDDP/DADS hold exceptional pharmacological properties with better anti-cancer activity and would serve as a promising formulation to treat various cancers.

Development of optimized novel liposome loaded with 6-gingerol and assessment of its therapeutic activity against NSCLC In vitro and In vivo experimental models.

6-Gingerol (Gn) is an active compound derived from ginger which possesses various biological activities. The therapeutic applications of Gn are limited due to its hydrophobic nature. To ease its administration, one of the nano-emulsion methods, liposome was selected to encapsulate Gn. Response Surface Methodology (RSM) was used to optimize liposome ratio. 97.2% entrapment efficiency was achieved at the ratio of 1:20:2 (Drug: Lipid: Cholesterol). The optimized liposome attained size below 200 d nm, spherical shape, negative surface charge and showed sustain release upon physical characterization methods such as FESEM, DLS, Zeta potential, Drug release. The signature FTIR peaks of both free Gn and free liposome (FL) were also observed in Lipo-Gn peak. Lipo-Gn showed significant cytotoxic effect on A549 cells (IC50 160.5 ± 0.74 µM/ml) as well as inhibits the cell migration. DAPI staining showed higher apoptotic nuclear morphological change in the cells treated with Lipo-Gn, and also Lipo-Gn increased the apoptotic percentage in A549 as 39.89 and 70.32 for 12 and 24 h respectively which were significantly more than free Gn. Moreover, the formulation of Lipo-Gn showed significant cell cycle arrest at the G2/M phase compared with free Gn (28.9% and 34.9% in Free Gn vs. 42.7% and 50.1% in Lipo -Gn for 12 and 24 h respectively). Lipo-Gn have been assessed in NSCLC induced BALB/c mice and showed significantly improved pharmacological properties compared to those of free Gn. Thus, Lipo-Gn may be considered for its widening applications against lung cancer.

Mapping Research on miRNAs in Cancer: A Global Data Analysis and Bibliometric Profiling Analysis.

miRNAs biomarkers are emerging as an essential part of clinical oncology. Their oncogenic and tumour suppressor properties playing a role in malignancy has generated interest in their potential for use in disease prognosis. While several studies on miRNA have been carried out across the globe, evaluating the clinical implications of miRNAs in cancer diagnosis and prognosis research has currently not been attempted. A study delineating the area of miRNA research, including the topics presently being focused on, the seminal papers in this field, and the direction of research interest, does not exist. This study aims to conduct a large-scale, global data analysis and bibliometric profiling analysis of studies to evaluate the research output of clinical implications of miRNAs in cancer diagnosis and prognosis listed in the SCOPUS database. A systematic search strategy was followed to identify and extract all relevant studies, subsequently analysed to generate a bibliometric map. SPSS software (version 27) was used to calculate bibliometric indicators or parameters for analysis, such as year and country of affiliation with leading authors, journals, and institutions. It is also used to analyse annual research outputs, including total citations and the number of times it has been cited with productive nations and H-index. The number of global research articles retrieved for miRNA-Cancer research over the study period 2003 to 2019 was 18,636. Between 2012 and 2019, the growth rate of global publications is six times (n = 15,959; 90.71 percent articles) that of 2003 to 2011. (2704; 9.29 per cent articles). China published the most publications in the field of miRNA in cancer (n = 7782; 41%), while the United States had the most citations (n = 327,538; 48%) during the time span. Of these journals, Oncotarget has the highest percentage of article publications. The journal Cancer Research had the most citations (n = 41,876), with 6.20 per cent (n = 41,876). This study revealed a wide variety of journals in which miRNA-Cancer research are published; these bibliometric parameters exhibit crucial clinical information on performance assessment of research productivity and quality of research output. Therefore, this study provides a helpful reference for clinical oncologists, cancer scientists, policy decision-makers and clinical data researchers.

Molecular Investigation of miRNA Biomarkers as Chemoresistance Regulators in Melanoma: A Protocol for Systematic Review and Meta-Analysis.

INTRODUCTION: Melanoma is a global disease that is predominant in Western countries. However, reliable data resources and comprehensive studies on the theragnostic efficiency of miRNAs in melanoma are scarce. Hence, a decisive study or comprehensive review is required to collate the evidence for profiling miRNAs as a theragnostic marker. This protocol details a comprehensive systematic review and meta-analysis on the impact of miRNAs on chemoresistance and their association with theragnosis in melanoma. Methods and analysis: The articles will be retrieved from online bibliographic databases, including Cochrane Review, EMBASE, MEDLINE, PubMed, Scopus, Science Direct, and Web of Science, with different permutations of 'keywords'. To obtain full-text papers of relevant research, a stated search method will be used, along with selection criteria. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Protocols 2015 (PRISMA-P) standards were used to create this study protocol. The hazard ratio (HR) with a 95% confidence interval will be analyzed using Comprehensive Meta-Analysis (CMA) software 3.0. (CI). The pooled effect size will be calculated using a random or fixed-effects meta-analysis model. Cochran's Q test and the I2 statistic will be used to determine heterogeneity. Egger's bias indicator test, Orwin's and the classic fail-safe N tests, the Begg and Mazumdar rank collection test, and Duval and Tweedie's trim and fill calculation will all be used to determine publication bias. The overall standard deviation will be evaluated using Z-statistics. Subgroup analyses will be performed according to the melanoma participants' clinicopathological and biological characteristics and methodological factors if sufficient studies and retrieved data are identified and available. The source of heterogeneity will be assessed using a meta-regression analysis. A pairwise matrix could be developed using either a pairwise correlation or expression associations of miRNA with patients' survival for the same studies.

Clinical Theragnostic Relationship between Chemotherapeutic Resistance, and Sensitivity and miRNA Expressions in Head and Neck Cancers: A Systematic Review and Meta-Analysis Protocol.

Background: The microRNAs (miRNAs) are small noncoding single-stranded RNAs typically 19-25 nucleotides long and regulated by cellular and epigenetic factors. These miRNAs plays important part in several pathways necessary for cancer development, an altered miRNA expression can be oncogenic or tumor-suppressive. Recent experimental results on miRNA have illuminated a different perspective of the molecular pathogenesis of head and neck cancers. Regulation of miRNA can have a detrimental effect on the efficacy of chemotherapeutic drugs in both neoadjuvant and adjuvant settings. This miRNA-induced chemoresistance can influence the prognosis and survival rate. The focus of the study is on how regulations of various miRNA levels contribute to chemoresistance in head and neck cancer (HNC). Recent findings suggest that up or down-regulation of miRNAs may lead to resistance towards various chemotherapeutic drugs, which may influence the prognosis. Methods: Studies on miRNA-specific chemoresistance in HNC were collected through literary (bibliographic) databases, including SCOPUS, PubMed, Nature, Elsevier, etc., and were systematically reviewed following PRISMA-P guidelines (Preferred Reporting Items for Systematic Review and Meta-analysis Protocol). We evaluated various miRNAs, their up and downregulation, the effect of altered regulation on the patient's prognosis, resistant cell lines, etc. The data evaluated will be represented in the form of a review and meta-analysis. Discussion: This meta-analysis aims to explore the miRNA-induced chemoresistance in HNC and thus to aid further researches on this topic. PROSPERO registration: CRD42018104657.

The Significance of miRNAs as a Prognostic Biomarker for Survival Outcome in T Cell - Acute Lymphoblastic Leukemia Patients: A Systematic Review and Meta-Analysis.

PURPOSE: T-cell acute lymphoblastic leukemia (T-ALL) affects lymphoid cells. Previous studies have reported that miRNAs play a significant role in T-ALL prognosis and have the potential to function as biomarkers in T-ALL. Therefore, this systematic review and meta-analysis study was designed to evaluate the overall prognostic impact of miRNAs in T-ALL patients. METHODS: Eligible studies published between Jan 2010 and April 2018 were retrieved from online bibliographic databases based on multiple keywords to generate search strings. Meta-analysis was performed using the outcome measure, Hazard Ratio (HR). A survival analysis of all studies was conducted and a subsequent forest plot was generated to evaluate the pooled effect size, across all T-ALL patients. Subgroup analysis was conducted based on demographic characteristics and commonly represented miRNAs among the included studies. RESULTS: A total of 17 studies were included for systematic review, among which 16 studies were eligible for meta-analysis, which, in total discussed 32 different miRNAs. The mean effect size of HR value was 0.929 (CI 0.878-0984), which indicates a decrease in risk of death by 7.1%. The analysis was based on the random effects model with the heterogeneity measure index (I2) being 84.92%. The pooled effect size (HR) of upregulated and downregulated miRNA expressions on survival outcome in the T-ALL patient was 0.787 (CI 0.732-0.845) and 1.225 (CI 1.110-1.344) respectively. The subgroup analysis was performed based on demographic characteristics (age, gender, lactate dehydrogenase, WBC count) and expression of miR221 and miR46a. CONCLUSION: Our systematic review and meta-analysis findings suggest that the overall miRNA expression is potentially associated with a decreased likelihood of death in T-ALL patients. Although our findings are inconclusive, the results point toward miRNA expression allowing for prognostic evaluation of T-ALL patients.

Presentation of Antibacterial and Therapeutic Anti-inflammatory Potentials to Hydroxyapatite via Biomimetic With Azadirachta indica: An in vitro Anti-inflammatory Assessment in Contradiction of LPS-Induced Stress in RAW 264.7 Cells.

In the present study, for the first time, biomimetization of hydroxyapatite (HA) with Azadirachta indica (AI) was proposed and established its antioxidant, antibacterial, and anti-inflammatory potential on lipopolysaccharide (LPS). The ethanolic extract of AI was found rich with phenolics and flavonoids, and determined their concentration as 8.98 ± 1.41 mg gallic acid equivalents/g and 5.46 ± 0.84 mg catechin equivalents/g, respectively. The HA was prepared by sol-gel method from calcium nitrate tetrahydrate and orthophosphoric acid, and successfully biomimetization was performed with ethanolic extract of AI. The FTIR analysis settled that as-synthesized HA-AI composite was comprised of both HA and AI. The XRD pattern and Zeta potential revealed that the HA-AI composite was crystalline and negative in charge (-24.0 mV). The average-size distribution, shape, and size of the HA-AI composite was determined as 238.90 d.nm, spherical, and 117.90 nm from size distribution, SEM, and HR-TEM analysis, respectively. The SEM-EDX concluded that the HA-AI composite was comprised of elements of HA as well as AI. The HA-AI composite presented potential antioxidant activity and its EC50 values (dose required to inhibit about half of the radicals) for ABTS and DPPH assays were determined as 115.72 ± 2.33 and 128.51 ± 1.04 µg/ml, respectively. The HA-AI composite showed potent antibacterial activity, and minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) towards S. aureus (ATCC 700699) and E. coli (ATCC 10536) were correspondingly determined as 266.7 ± 28.87 and 600.0 ± 50.0 µg/ml, and 400.0 ± 86.6 and 816.7 ± 76.38 µg/ml. Most importantly, HA-AI composite presented the potential anti-inflammatory response toward lipopolysaccharide (LPS) in RAW 264.7 cells. The dose of 250 µg/ml of HA-AI composite has shown optimum protection against LPS-induced stress (1 µg/ml) by scavenging oxidants and regulating mitochondrial membrane potential (MMP), inflammatory and apoptotic factors. Thus, this study concluded that the impartation of potential biofunctional features to HA from plant sources through biomimetic approach is much beneficial and could find potential application in dentistry and orthopedic.

Prognostic significance of blood inflammatory biomarkers NLR, PLR, and LMR in cancer-A protocol for systematic review and meta-analysis.

BACKGROUND: The neutrophil-lymphocyte-ratio, platelet-lymphocyte-ratio, and monocyte-lymphocyte-ratio have been explored as a simple, inexpensive, and effective method for cancer prognosis. However, there are no studies that have investigated the comparative utility of these markers, in multiple cancers. METHODS: The preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) guidelines were used to design this meta-analysis protocol. The final study will also be conducted under the PRISMA guidelines for systematic reviews and meta-analyses. The core bibliographic database search will be carried out by 2 reviewers working individually, with each conducting an initial screening based on titles and abstracts. The shortlisted articles will be selected for review and quantitative analysis, based on predefined inclusion and exclusion criteria. Study characteristics, relevant clinicopathological characteristics, and statistical data required for meta-analysis (hazard ratios [HRs] and 95% confidence intervals [CIs]) will be extracted and compiled into a MS Excel datasheet. Meta-analysis will be performed, using a random-effects model, and the results (pooled HR and 95% CI) will be presented in the form of a forest plot. Publication bias will also be assessed by use of Egger bias indicator test and funnel plot symmetry. If statistical data from included studies is insufficient, a qualitative literature review will be pursued.PROSPERO registration: PROSPERO CRD42019121008.

Prognostic miRNA classifiers in t cell acute lymphoblastic leukemia: Study protocol for a systematic review and meta-analysis of observational clinical studies.

BACKGROUND: The prognostic value of microRNA (miRNA) expression in T-cell acute lymphoblastic leukemia (T-ALL) has generated significant research interest in recent years. However, most diagnostic and prognostic studies with regards to miRNA expression have been focused on combined B cell and T cell lymphoblastic leukemia. There are very few studies reporting the prognostic effects of miRNA expression on T-ALL. Therefore, a pioneer systematic review and meta-analysis was proposed to explore the possibilities of miRNAs as viable prognostic markers in T-ALL. This study is intended to be useful as a guideline for future research into drug evaluation and targeting miRNA as a biomarker for the treatment and prognosis of T-ALL. METHODS: The systematic review will be reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. The study search will be conducted by using Cochrane, EMBASE, Medline, Science Direct, and SCOPUS bibliographic databases. The reference lists of included studies will be manually searched to further bolster the search results. A combination of keywords will be used to search the databases. DISCUSSION: To explore the effect of miRNA on prognosis, forest plots will be generated to assess pooled HR and 95% CI. Upregulation, downregulation, and deregulation of specific miRNAs will be individually noted and used to extrapolate patient prognosis when associated with risk factors involved in T-ALL. Subgroup analysis will be carried out to analyze the effect of deregulation of miRNA expression on patient prognosis. A fixed or random-effects model of meta-analysis will be used depending upon between-study heterogeneity. This systematic review and meta-analysis will identify and synthesize evidence to determine the prognosis of miRNA in T-ALL and suggest the possible miRNA from meta-analysis results to predict as a biomarker for further detection and treatment of T-ALL.