Identification of differentially expressed hematopoiesis-associated genes in term low birth weight newborns by systems genomics approach

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Author(s): Sakshi Singh, Vinay Kumar Singh, Geeta Rai*.

Journal Name: Current Genomics

Abstract:

Background: Low birth weight (LBW) (birth weight <2.5 Kg) newborns are associated with a high risk of infection, morbidity, and mortality during their perinatal period. Compromised innate immune responses and inefficient hematopoietic differentiation in term LBW newborns led us to evaluate the gene expression status of hematopoiesis.

Materials and Methods: In this study, we compared our microarray datasets of LBW-Normal birth weight (NBW) newborns with two reference datasets to identify hematopoietic stem cells genes, and their differential expression in the LBW newborns, by hierarchical clustering algorithm using gplots and RcolorBrewer package in R.

Results: Comparative analysis revealed 108 differentially expressed hematopoiesis genes (DEHGs), of which 79 genes were up-regulated, and 29 genes were down-regulated in LBW newborns compared to their NBW counterparts. Moreover, protein-protein interactions, functional annotation, and pathway analysis demonstrated that the up-regulated genes were mainly involved in cell proliferation and differentiation, MAPK signaling, and Rho GTPases signaling, and the down-regulated genes were engaged in cell proliferation and regulation, immune system regulation, hematopoietic cell lineage and JAK-STAT pathway. The binding of down-regulated genes (LYZ and GBP1) with growth factor GM-CSF using docking and MD simulation techniques, indicated that GM-CSF has a potential to alleviate the repressed hematopoiesis in the term LBW newborns.

Conclusion: Our study revealed that DEHGs belonged to erythroid and myeloid-specific lineages and may serve as potential targets for improving hematopoiesis in term LBW newborns to help build up their weak immune defense against life-threatening infections.

Keywords: LBW And NBW Newborns, Hematopoietic-Associated Genes, Genomics, Molecular Docking

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DOI: 10.2174/1389202920666191203123025
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1,3-Dipolar Cycloadditions Involving Allenes: Synthesis of Five-Membered Rings

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Author(s): Ana L. Cardoso, Maria I. L. Soares*.

Journal Name: Current Organic Chemistry

Abstract:

The 1,3-dipolar cycloaddition reaction is a powerful and versatile strategy for the synthesis of carbocyclic and heterocyclic five-membered rings. Herein, the most recent developments on the [3+2] cycloaddition reactions using allenes acting either as dipolarophiles or 1,3-dipole precursors, are highlighted. The recent contributions on the phosphine- and transition metal-catalyzed [3+2] annulations involving allenes as substrates are also covered, with the exception of those in which the formation of a 1,3-dipole (or synthetic equivalent) is not invoked.

This review summarizes the most relevant research in which allenes are used as building blocks for the construction of structurally diverse five-membered rings via [3+2] annulation reactions.

Keywords: Allenes, Allenoates, Annulation, Carbocycles, Cycloaddition, Dipoles, Five-membered ring, Heterocycles, Phosphine catalysis

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DOI: 10.2174/1385272823666191203122959
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Anticancer activity of natural flavonoids: inhibition of HIF-1α signaling pathway

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Author(s): Xiangping Deng, Yijiao Peng, Jingduo Zhao, Xiaoyong Lei, Xing Zheng, Zhizhong Xie, Guotao Tang*.

Journal Name: Current Organic Chemistry

Abstract:

Rapid tumor growth is dependent on the capability of tumor blood vessels and glycolysis to provide oxygen and nutrients. Tumor hypoxia is a common characteristic of many solid tumors, and it essentially happens when the growth of the tumor exceeds the concomitant angiogenesis. Hypoxia-inducible factor 1 (HIF-1) as the critical transcription factor in hypoxia regulation is activated to adapting to this hypoxia situation. Flavonoids widely distribute in plants comprise many polyphenolic secondary metabolites, possessing broadspectrum pharmacological activities including their potentiality as anticancer agents. Due to their low toxicity, the intense effort has been made in investigating natural flavonoids and its derivatives that can be used as HIF-1α inhibitors for cancer therapy during the past few decades. In this review, we sum up the findings concerning inhibition of HIF-1α by natural flavonoids in the last few years and propose the idea of designing tumor vascular and glycolytic multi-target inhibitors with HIF-1α as one of the targets.

Keywords: HIF-1α, natural flavonoids, anticancer, inhibition, signaling pathway, hypoxia situation

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DOI: 10.2174/1385272823666191203122030
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Molecular and Genomic Characterization of PFAB2: A Non-virulent Bacillus anthracis Strain Isolated from an Indian Hot Spring

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Author(s): Aparna Banerjee, Vikas Kumar Somani, Priyanka Chakraborty, Rakesh Bhatnagar, Rajeev K. Varshney, Alex Echeverría-Vega, Sara Cuadros-Orellana, Raib Bandopadhyay*.

Journal Name: Current Genomics

Abstract:

Background: Thermophilic bacilli in both aerobic or facultative anaerobic forms have been isolated for over a hundred years from different mesophilic or thermophilic environments as they are potential source of bioactive secondary metabolites. But the taxonomic resolution in the Bacillus genus at species or at strain levelis very challenging for the insufficient divergence of the 16S rRNA genes. One such recurring problem is among Bacillus anthracis, B. cereus and B.thuringiensis. The disease-causing B. anthracis strains have their characteristic virulence factors coded in two well-known plasmids, namely pXO1 (toxin genes) and pXO2 (capsule genes).

Objectives: The present study aimed at the molecular and genomic characterization of a recently reported thermophilic and environmental isolate of B. anthracis, strain PFAB2.

Methodology: We performed comparative genomics between the PFAB2 genome and different strains of B. anthracis,along with closely related B. cereus strains.

Results and Discussion: The pangenomic analysis suggests that the PFAB2 genomeharbors no complete prophage genes. Cluster analysis of Bray-Kurtis similarity resemblance matrix revealed that gene content PFAB2 is more closely related toother environmental strains of B. anthracis. The secretome analysis and the in vitro and in vivo pathogenesis experiments corroborate the avirulent phenotype of this strain. The most probable explanation for this phenotype is the apparent absence of plasmids harboring genes for capsule biosynthesis and toxins secretion in the draft genome. Additional features of PFAB2 are good spore-forming and germinating capabilities and rapid replication ability.

Conclusion: The high replication rate in a wide range of temperatures and culture media, the non-pathogenicity, the good spore forming capability and its genomic similarity to the Ames straintogether make PFAB2an interesting model strain for the study of thepathogenic evolution of B.anthracis.

Keywords: Bacillus anthracis, Avirulence, Comparative genomics, Pangenomics, Pathogenesis

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DOI: 10.2174/1389202920666191203121610
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Progress in Target Drug Molecules for Alzheimer's Disease

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Author(s): Jiayang Xie, Ruirui Liang, Yajiang Wang, Junyi Huang, Xin Cao*, Bing Niu*.

Journal Name: Current Topics in Medicinal Chemistry

Abstract:

Alzheimer's disease (AD) is a chronic neurodegenerative disease that is widespread in the elderly. The etiology of AD is complicated, and its pathogenesis is still unclear. Although there are many researches on anti-AD drugs, they are limited to reverse relief symptoms and cannot treat diseases. Therefore, the development of high-efficiency anti-AD drugs with no side effects has become an urgent need. Based on the published literature, this paper summarizes the main targets of AD and their drugs, and focuses on the research and development progress of these drugs in recent years.

Keywords: Amyloid beta (Aβ), Acetylcholinesterase (AChE), Amyloid-beta binding alcohol dehydrogenase ( ABAD), Butyrylcholinesterase (BChE), B-site APP cleaving enzyme 1 (BACE1), Cyclin-dependent kinase-5 (CDK-5), Glycogen synthase kinase-3β, (GSK-3β), Monoamine oxidase (MAO), Tau protein

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DOI: 10.2174/1568026619666191203113745
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The Chemical Structure and Bioactivity of Cycloartane-type Compounds

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Author(s): Wenyan Gao, Xiaoyan Dong, Taiming Wei, Wenmin Xing*.

Journal Name: Current Organic Chemistry

Abstract:

For decades now, compounds in the cycloartane-type series have been shown to have versatile pharmacological activities. However, no extensive review has been written to summarize these health-beneficial activities. Therefore, the purpose of this paper is to systematically highlight the biological activities of these compounds, including their antitumor and anti-osteoporosis effects, their effects on receptors, cytokine release, and chronic renal failure, as well as their tyrosinase inhibitory, anticomplement, anti-parasite, anti-HIV, and antituberculosis activities. In this review, we summarize the structures of over 200 compounds based on their characteristics. Also described are their structure-activity relationships (SARs), and potential mechanisms of action.

Keywords: Cycloartane, Structure-Activity Relationships, Tetracyclic Triterpene, Biological Activities, Antitumor Effect, Anti-Inflammatory Activity

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DOI: 10.2174/1385272823666191203113221
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A comprehensive review of the genus Pyrola herbs in traditional uses, phytochemistry and pharmacological activities.

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Author(s): Xiliang Yang*, Jianglian She, Jinping Liu, Tao Yang, Gege An, Qingru Chen, Cheng Fan, Shuangjun Li, Qian Liu, Chunguo Qian, Ying Liu, Yajie zhou, Jingyi Zhao.

Journal Name: Current Topics in Medicinal Chemistry

Abstract:

Pyrola (Pyrolaceae), also known as Luxiancao/鹿衔草in China, was recorded in Sheng Nong’s Herbal Classic listed in top grade. Pyrola herbs were used as medicinal plants for a long history with wide-ranging activities of nourishing kidney-yang, strengthening muscles and bones, activating blood, stopping bleeding, dispelling rheumatism, eliminating dampness. Currently, the research on Pyrola plants is increasing year by year but there is no comprehensive and detailed review concerning genus Pyrola. This review aims to sum up updated and comprehensive information about botany and traditional use, phytochemistry, pharmacological activities and safety by analyzing the information available on Pyrola plants via internationally accepted scientific databases. Collectively, more than 100 compounds have been isolated from the Pyrola plants. What’s more, a total of 33 prescriptions containing Pyrola plants are compiled in this review. Pyrola plants are used as indispensable agents in traditional Chinese medicine due to its activities of antimicrobial, anti-inflammatory, antioxidant, lipid-lowering, cardiovascular and cerebrovascular protection, proliferation of osteoblasts promoting, antineoplastic and etc. Further work should be developed on the elucidation of structure-function relationship, understanding of multi-target pharmacological effects, as well as developing its application both in clinical usage and functional food for research and development of Pyrola plants.

Keywords: Pyrola, Traditional Chinese Medicine, Phytochemistry, Pharmacological activity, Natural products, Botany, Safety

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DOI: 10.2174/1568026619666191203112412
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N-alpha-Aminoacyl Colchicines as Promising Anticancer Agents

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Author(s): Ana Marzo-Mas, Laura Conesa-Milián, Sam Noppen, Sandra Liekens, Eva Falomir*, Juan Murga, Miguel Carda, J. Alberto Marco.

Journal Name: Medicinal Chemistry

Abstract:

Background: In the last years, many efforts have been made to find colchicine derivatives with reduced toxicity. Additionally, the deregulation of amino acids uptake by cancer cells provides an opportunity to improve anticancer drug effectiveness.

Objective: To design new colchicine derivatives with reduced cytotoxicity and enhanced selectivity by means of introducing aminoacyl groups.

Method: 34 colchicine analogues bearing L- and D-amino acid pendants were synthetized and characterized by NMR, IR and MS techniques. Cytotoxicity and antimitotic properties were assessed by spectrophotometry and cell cycle assays. Oncogene downregulation was studied by RT-qPCR whereas in vivo studies were performed in SCID mice.

Results: Compounds exhibit high antiproliferative activities at the nanomolar level while being, in general, less cytotoxic than colchicine. Most compounds inhibit the polymerization of tubulin in a way similar to colchicine itself, with L-amino acid derivatives being the most active in the inhibition of tubulin polymerization. All selected compounds caused cell cycle arrest at the G2/M phase when tested at 1 μM. More specifically, Boc-L-proline derivative 6 arrested half of the population and showed one of the highest Selectivity Indexes. Derivatives 1 (Boc-glycine), 27 (D-leucine) and 31 (Boc-glycine-glycine) proved fairly active in downregulating the expression of the c-Myc, hTERT and VEGF oncogenes, with compound 6 (Boc-L-proline) having the highest activity. This compound was shown to exert a potent anti-tumor effect when administered intraperitoneally (LD50 > 100 mg/kg for 6, compared with 2.5 mg/kg for colchicine).

Conclusion: Compound 6 offers an opportunity to be used in cancer therapy with less toxicity problems than colchicine.

Keywords: Colchicine, L- And D- Amino Acid, Cancer, Non-Toxic, Cell Cycle, Tubulin, In Vivo, Oncogene Downregulation

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DOI: 10.2174/1573406415666191203112406
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Exploring PLAC1 Structure and Underlying Mechanisms to Design a Derivative Vaccine against Breast Cancer Progression; in-silico study

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Author(s): Farzaneh Afzali, Parisa Ghahremanifard, Mohammad Mehdi Ranjbar, Mahdieh Salimi*.

Journal Name: Current Proteomics

Abstract:

The tolerogenic homeostasis in breast cancer (BC) can be surpassed by rationally designed immune-encouraging constructs against tumor-specific antigens through immunoinformatics approach. Availability of high throughput data providing the underlying concept of diseases and awarded computational simulations, lead to screening the potential medications and strategies in less time and cost. Despite the extensive effects of Placenta Specific 1 (PLAC1) in BC progression, immune tolerance, invasion, cell cycle regulation, and being a tumor-specific antigen the fundamental mechanisms and regulatory factors were not fully explored. It is also worth to design an immune response inducing construct to surpass the hurdles of traditional anti-cancer treatments.

The study was initiated by predicting and modelling the PLAC1 secondary and tertiary structures and then engineering the fusion pattern of PLAC1 derived immunodominant predicted CD8+ and B-cell epitopes to form a multi-epitope immunogenic construct. The construct was analyzed considering the physiochemical characterization, safety, antigenicity, post-translational modification, solubility, and intrinsically disordered regions. After modelling its tertiary structure, protein-protein docking simulation was carried out to ensure the attachment of construct with Toll-like receptor 4 (TLR4) as an immune receptor. To guarantee the highest expression of the designed construct in E. coli k12 as an expressional host, the codon optimization and in-silico cloning were performed. The PLAC1 related miRNAs in BC were excavated and validated through TCGA BC miRNA-sequencing and databases; the common pathways then were introduced as other probable mechanisms of PLAC1 activity.

Regarding the obtained in-silico results, the designed anti-PLAC1 multi-epitope construct can probably trigger humoral and cellular immune responses and inflammatory cascades, therefore may have the potential of halting BC progression and invasion engaging predicted pathways.

Keywords: Antigenicity, CTA, Multi-epitope, miRNA, Network analysis, Epitope

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DOI: 10.2174/1570164617666191203111451
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Dose-Related Effects Of Resveratrol In Different Models Of Pulmonary Arterial Hypertension: Systematic Review

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Author(s): Andressa Coelho Ferreira, Jerdianny Silva Serejo, Rafael Durans, Jadna Maryane Pereira Costa, Antonio Woodson Santos Maciel, Adeilson Serra Mendes Vieira, Carlos Alberto Alves Dias-Filho, Carlos José Dias, Maria Rosa Quaresma Bomfim, Cristiano Teixeira Mostarda, Janaina de Oliveira Brito-Monzani*.

Journal Name: Current Cardiology Reviews

Abstract:

Background: Pulmonary arterial hypertension (PAH) is a severe and progressive disease of pulmonary arterioles. This pathology is characterized by elevation of the pulmonary vascular resistance and pulmonary arterial pressure, leading to right heart failure and death. Studies have demonstrated that resveratrol possesses a protective effect in the mechanisms related to the genesis of the PAH-induced by different models.

Objective: This study aimed to investigate the dose-related effects of resveratrol in different models of pulmonary arterial hypertension.

Methods: To identify eligible papers, we performed a systematic literature search on Scielo, PubMed, and Scholar Google. The research was limited to articles written in English in the last 10 years. We use the following descriptors to search: Pulmonary Arterial Hypertension and Resveratrol, OR Resveratrol, and Animal models of Pulmonary Arterial Hypertension, OR Resveratrol, and in vitro models of Pulmonary Arterial Hypertension.

Results: 1724 studies were identified through the descriptors employed, fifty-five studies with different models of pulmonary arterial hypertension were selected for the full review, forty-four were excluded after application of exclusion and inclusion criteria, totalizing eleven studies included in this systematic review.

Conclusion: The results showed that resveratrol, at low and high doses, protects in a dose-dependent manner against the development of PAH induced through monocrotaline, normoxia and hypoxia models. In addition to having chemopreventive, anti-inflammatory, antioxidant and antiproliferative properties. In the case of PAH-related myocardial injury, resveratrol protects cells from apoptosis, thus working as an antiapoptotic agent.

Keywords: Pulmonary Arterial Hypertension, Cardiovascular, In vivo, In vitro, Resveratrol, Dosage

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DOI: 10.2174/1573403X15666191203110554
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