Higher Atazanavir plasma exposure in Rats is associated with Gut Microbiota Changes induced by Cotrimoxazole

(E-pub Abstract Ahead of Print)

Author(s): Miantezila Basilua Joe* , Sawoo Olivier , Mangin Irène , Dossou-Yovo Flore , Boussard Aline , Chevillard Lucie , Tona Lutete Gaston , Eto Bruno , Peytavin Gilles , Pochart Philippe .

Journal Name: Current Drug Metabolism

Abstract:

Background: Cotrimoxazole (TMP-SMX) is concomitantly used as primary prophylaxis of opportunistic infections with antiretroviral agents such as Atazanavir (ATV). Results from an ex vivo study showed changes in intestinal absorption of ATV when rats were pretreated with TMP-SMX. The objective of this in vivo study is to determine the effect of TMP-SMX on the pharmacokinetics of ATV in rats. We also studied changes in gut microbiota induced by TMP-SMX.

Methods: We used the non-compartment analysis to compare the pharmacokinetics of ATV in a parallel group of rats treated with a low or therapeutic dose of TMP-SMX for nine days to untreated control rats. Gut microbiota was characterized using qPCR and High Throughput Sequencing of 16S rDNA.

Results: Rats treated with TMP-SMX showed a much broader exposure to ATV compared to the control group (AUC0-8h (ng.mL-1.h), 25975.9±4048.7 versus 2587.6±546.9, p=0.001). The main observation regarding the gut microbiota was a lower proportion of enterobacteria related to the administration of TMP-SMX. Moreover, the Total Gastrointestinal Transit Time (TGTT) was longer in the TMP-SMX treated group.

Conclusion: Concomitant administration of TMP-SMX and ATV significantly increased ATV exposure in rats. This increase could be the result of a prolonged TGTT leading to an increase in the intestinal residence time of ATV favoring its absorption. Gut microbiota changes induced by TMP-SMX could be at the origin of this prolonged TGTT. If demonstrated in humans, this potential interaction could be accompanied by an increase in the adverse effects of ATV.

Keywords: Cotrimoxazole, Atazanavir, Gut microbiota, Gastrointestinal motility, Intestinal absorption, Enterohepatic circulation, Plasma exposure

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DOI: 10.2174/1389200220666191023105609
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Recent Developments and Potential of Mucoadhesive Buccal Drug Delivery System for Oro-mucosal Disorders

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Author(s): Deepak Sharma * , Rajeev Garg .

Journal Name: Current Dentistry

Abstract:

Background: The drug delivery across buccal mucosa acts as very interesting option for the treatment of various oro-mucosal disorders such as aphthous stomatitis, periodontitis, gingivitis, toothache, periodontitis, and sjorgensen syndrome. But it is quite difficult because of target site movements, limited area for drug absorption, drinking of fluids, intake of food and salivary flow at regular interval contribute to poor retention and sub-therapeutic level of drug at target site. Due to this, mucoadhesive buccal drug delivery system has gained so much attention among the various scientists and researchers over the last two decades.

Methods: Mucoadhesion is a process of attachment between the natural or synthetic macromolecule and mucosal epithelial surface with the aid of interfacial attractive forces. The process of mucoadhesion has been extensively encouraged by utilization of mucoadhesive polymers within the formulation that on contact with salivary fluid swells and adheres to buccal epithelium membrane thus prolonging the drug release, retention time and improves therapeutic performance in case of oral diseases. The present review tried to covers the basic anatomy and structure of oral mucosa, pathways of drug absorption, theory of mucoadhesion, mechanisms involved in mucoadhesion and various factors affecting mucoadhesion.

Results: It highlights the properties of mucoadhesive polymers in drug delivery along with various dosage forms such as mucoadhesive tablets, films, patches, gels, and pastes. Furthermore, it also throws a light on recent developments made in the field of mucoadhesive buccal drug delivery system that reflects the potential of this system for the effective treatment of oro-mucosal disorders.

Conclusion: It can be concluded that mucoadhesive buccal drug delivery system has great potential in near future for treating the oro-mucosal disorders.

Keywords: Mucoadhesion, mucoadhesive buccal drug delivery, oro-mucosal disorders, buccal mucosa, mucoadhesive dosage forms, drug absorption pathways

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DOI: 10.2174/2542579X01666191023105423
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Detection of Thyroid Nodules with Ultrasound Images Based on Deep Learning

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Author(s): Xia Yu* , Hongjie Wang , Liyong Ma .

Journal Name: Current Medical Imaging

Abstract:

Background: Thyroid nodules are a common clinical entity with high incidence. Ultrasound is often employed to detect and evaluate thyroid nodules. The development of an efficient automated method to detect thyroid nodules using ultrasound has potential to reduce both physician workload and operator-dependence.

Objective: To study the method of automatic detection of thyroid nodules based on deep learning using ultrasound, and to obtain the detection method with higher accuracy and better performance.

Method: A total of 1200 ultrasound images of thyroid nodules and 800 ultrasound thyroid images without nodule are collected. An improved faster R-CNN based detection method of thyroid nodule is proposed. Instead of using VGG16 as the backbone, ResNet is employed as the backbone for faster R-CNN. SVM, CNN and Faster-RCNN methods are used for thyroid nodule detection test. Precision, sensitivity, specificity and F1-score indicators are used to evaluate the detection performance of different methods.

Results: The method based on deep learning is superior to that based on SVM. Faster R-CNN method and the improved method are better than CNN method. Compared with VGG16 as the backbone, RestNet101 backbone based faster R-CNN method achieves better thyroid detection effect. From the accuracy index, the proposed method is 0.084, 0.032 and 0.019 higher than SVM, CNN and faster R-CNN, respectively. Similar results can be seen in precision, sensitivity, specificity and F1-Score indicators.

Conclusion: The proposed method of deep learning achieves the best performance values with highest true positive and true negative detection compared to other methods and performs best in the detection of thyroid nodules.

Keywords: Thyroid nodule, classification, ultrasound image, deep learning, convolutional neural network (CNN), faster R-CNN

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DOI: 10.2174/1573405615666191023104751
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Amyloid-β Oligomers-induced Mitochondrial DNA Repair Impairment Contributes to Altered Human Neural Stem Cell Differentiation

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Author(s): Jing Lu , Yi Li , Cristiana Mollinari , Enrico Garaci , Daniela Merlo , Gang Pei* .

Journal Name: Current Alzheimer Research

Abstract:

Background: Amyloid-β42 oligomers (Aβ42O), the proximate effectors of neurotoxicity observed in Alzheimer’s disease (AD), can induce mitochondrial oxidative stress and impair mitochondrial function besides causing mitochondrial DNA (mtDNA) damage. Aβ42O also regulate the proliferative and differentiative properties of stem cells.

Objective: We aimed to study whether Aβ42O-induced mtDNA damage is involved in the regulation of stem cell differentiation.

Method: Human iPSCs-derived neural stem cell (NSC) was applied to investigate the effect of Aβ42O on reactive oxygen species (ROS) production and DNA damage using mitoSOX staining and long-range PCR lesion assay, respectively. mtDNA repair activity was measured by non-homologous end joining (NHEJ) in vitro assay using mitochondria isolates and the expression and localization of NHEJ components were determined by Western blot and immunofluorescence assay. The expressions of Tuj-1 and GFAP, detected by immunofluorescence and qPCR, respectively, were examined as an index of neurons and astrocytes production.

Results: We show that in NSC Aβ42O treatment induces ROS production and mtDNA damage and impairs DNA end joining activity. NHEJ components, such as Ku70/80, DNA- PKcs, and XRCC4, are localized in mitochondria and silencing of XRCC4 significantly exacerbates the effect of Aβ42O on mtDNA integrity. On the contrary, pre-treatment with Phytic Acid (IP6), which specifically stimulates DNA-PK-dependent end-joining, inhibits Aβ42O-induced mtDNA damage and neuronal differentiation alteration.

Conclusion: Aβ42O-induced mtDNA repair impairment may change cell fate thus shifting human NSC differentiation toward an astrocytic lineage. Repair stimulation counteracts Aβ42O neurotoxicity, suggesting mtDNA repair pathway as a potential target for the treatment of neurodegenerative disorders like AD.

Keywords: Amyloid-β; mitochondria; DNA damage; DNA repair; human neural stem cell; differentiation.

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DOI: 10.2174/1567205016666191023104036
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Diospyros lotus mediated synthesis of iron oxide nanoparticles and their application as catalyst in Fenton reaction

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Author(s): Sadaf Batool , Zakir Hussain* .

Journal Name: Current Nanoscience

Abstract:

Background: Iron Oxide nanoparticles find enormous applications in environmental remediation and catalysis. Synthesis of such nanoparticles through green approach provides huge advantage due to non-toxic nature of ingredients involved.

Method: In the present work, Diospyros lotus fruit extract was used for the synthesis of iron oxide nanoparticles (NPs). The plant biomolecules were extracted employing two different solvents i.e. water and methanol. Effect of both extracts on the reduction of metal salt as well as on the shape and size of the produced NPs was investigated.

Results: UV-Visible spectroscopy confirmed the synthesis of iron oxide NPs, Fourier Transform Infrared (FTIR) spectrum depicted the presence of biomolecules on the surface of NPs as capping agents, X-ray Diffraction (XRD) diffractogram confirmed the crystalline structure of mixed iron oxide NPs and Scanning Electron Microscopy (SEM) images showed NPs are of spherical shape. The as synthesized NPs were exploited to catalyze the degradation of methylene blue dye in Fenton type catalytic reaction. The degradation reaction was monitored using UV-Visible spectroscopy, which indicated that the percent degradation increased from 15 % (without iron oxide NPs) to 91 % in the presence of organic extract prepared iron oxide NPs and 81 % for aqueous extract prepared iron oxide NPs. Effect of the concentration of methylene blue and iron oxide NPs on the degradation process was also investigated.

Keywords: Biogenic synthesis; Green chemistry; iron oxide nanoparticles, Fenton reaction; organic pollutants remediation

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DOI: 10.2174/1573413715666191023103729
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Influence of β-D-mannuronic acid, as a new member of non-steroidal anti-inflammatory drugs family, on expression pattern of chemokines and their receptors in rheumatoid arthritis

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Author(s): Mona Aslani , Arman Ahmadzadeh , Zahra Aghazadeh , Majid Zaki-Dizaji , Laleh Sharifi , Mostafa Hosseini , Abbas Mirshafiey* .

Journal Name: Current Drug Discovery Technologies

Abstract:

Background: Based on the encouraging results of phase III clinical trial of β-D-mannuronic acid (M2000) (as a new anti-inflammatory drug) in patients with RA, in this study, we aimed to evaluate the effects of this drug on the expression of chemokines and their receptors in PBMCs of RA patients.

Methods: PBMCs of RA patients and healthy controls were separated and the patients' cells were treated with low, moderate and high doses (5, 25 and 50 μg/mL) of M2000 and optimum dose (1 μg/mL) of diclofenac, as a control in RPMI-1640 medium. Real-time PCR was used for evaluating the mRNA expression of CXCR3, CXCR4, CCR2, CCR5 and CCL2/MCP-1. Cell surface expression of CCR2 was investigated using flow cytometry.

Results: CCR5 mRNA expression reduced significantly, after treatment of the patients' cells with all three doses of M2000 and optimum dose of diclofenac. CXCR3 mRNA expression down-regulated significantly followed by treatment of these cells with moderate and high doses of M2000 and optimum dose of diclofenac. CXCR4 mRNA expression declined significantly after treatment of these cells with moderate and high doses of M2000. CCL2 mRNA expression significantly reduced only followed by treatment of these cells with high dose of M2000, whereas, mRNA and cell surface expressions of CCR2 diminished significantly followed by treatment of these cells with high dose of M2000 and optimum dose of diclofenac.

Conclusion: According to our results, M2000 through the down-regulation of chemokines and their receptors may restrict the infiltration of immune cells into the synovium.

Keywords: Rheumatoid arthritis; β-D-mannuronic acid; M2000; non-steroidal anti-inflammatory drug (NSAID); target molecules (CXCR3, CXCR4, CCR2, CCR5, CCL2/MCP-1)

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DOI: 10.2174/1570163816666191023103118
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Receptor-Interacting Protein Kinase 1 (RIPK1) as a Potential Therapeutic Target: An Overview of Its Possible Role in the Pathogenesis of Alzheimer’s Disease

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Author(s): Hong Hao Chan , Rhun Yian Koh* , Chooi Ling Lim , Chee Onn Leong .

Journal Name: Current Alzheimer Research

Abstract:

Alzheimer’s disease (AD) is an age-dependent neurodegenerative disorder, the most common type of dementia that is clinically characterized by the presence of beta-amyloid (Aβ) extracellularly and intraneuronal tau protein tangles that eventually leads to the onset of memory and cognition impairment, development of psychiatric symptoms and behavioral disorders that affect basic daily activities. Current treatment approved by the U.S Food and Drug Administration (FDA) for AD is mainly focused on the symptoms but not on the pathogenesis of the disease. Recently, receptor-interacting protein kinase 1 (RIPK1) has been identified as a key component in the pathogenesis of AD through necroptosis. Furthermore, genetic and pharmacological suppression of RIPK1 has been shown to revert the phenotype of AD and its mediating pathway is yet to be deciphered. This review is aimed to provide an overview of the pathogenesis and current treatment of AD with the involvement of autophagy as well as providing a novel insight into RIPK1 in reverting the progression of AD, probably through an autophagy machinery.

Keywords: Alzheimer`s disease, neurodegenerative disorder, dementia, beta amyloid, receptor interacting protein kinase 1, autophagy

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DOI: 10.2174/1567205016666191023102422
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In silico identification of novel flavonoids targeting epidermal growth factor receptor

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Author(s): Ashish Shah* , Avinash Kumar Seth .

Journal Name: Current Drug Discovery Technologies

Abstract:

Background: Epidermal growth factor receptor (EGFR, ErBb) belongs to family of receptor tyrosine kinase (RTKs) played important role in multiple cell signaling pathways, which includes cell growth, multiplication and apoptosis etc. Overexpression of EGFR results in to development of malignant cells. Therefore EGFR considered as one of the important target for cancer therapy.

Objective: In this study we performed virtual screening of 329 flavonoids obtained from Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target (NPACT) database to identify novel EGFR inhibitors.

Materials and methods: Virtual screening carried out using different insilico methods which includes molecular docking studies, prediction of druglikeness, insilico toxicity studies and bioactivity prediction.

Results: Six flavonoids NPACT00061, NPACT00062, NPACT00066, NPACT00280, NPACT00700 and NPACT00856 were identified as potential EGFR inhibitors with good docking score and druglikeness properties. In the insilico toxicity studies, compound NPACT00061, NPACT00062, NPACT00066 and NPACT00856 were found to be carcinogenic. Finally, two flavonoids NPACT00280 and NPACT00700 were recognized as novel EGFR inhibitors. Conclusion: Our findings suggest that compound NPACT00280 and NPACT00700 could be further explored as novel EGFR inhibitors.

Keywords: Virtual screening, Flavonoids, NPACT database, EGFR inhibitors, In silico, Epidermal growth factor

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DOI: 10.2174/1570163816666191023102112
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Meet Our Editor-in-Chief

Author(s): Yuntao Wu Wu .

Journal Name: Current HIV Research

Volume 17 , Issue 3 , 2019

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VOLUME: 17
ISSUE: 3
Year: 2019
Page: [147 - 147]
Pages: 1
DOI: 10.2174/1570162X1703191023101524
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The promise of miRNA replacement therapy for Hepatocellular carcinoma

(E-pub Abstract Ahead of Print)

Author(s): Mahmoud Elhefnawi* , Zeinab Salah , Bangly Soliman .

Journal Name: Current Gene Therapy

Abstract:

Background: MicroRNA modulation therapy has shown great promise to treat hepatocellular carcinoma (HCC).

Objective: the present review will discuss the prominent examples of tumor silencer miRNA in terms of their efficient delivery using vectors, nano-delivery systems their successful models either in vitro or in vivo and pre-clinical trials.

Discussion: Hepatocellular carcinoma is a devastating tumor which accounts for death mortality rate 94% globally, and about 780,000 new cases each year. Tumor suppressor miRNAs represent a class of noncoding RNAs, which exhibit decreased or inhibited expression in case of carcinogenesis. Therefore, replacement of these molecules leads to post transcriptional regulation of tens to hundreds of oncogenic targets and limiting the tumor.

Conclusion: tumor suppressor miRNAs can act as novel therapeutics for HCC and more studies should be directed toward these promising therapeutics.

Keywords: RNA therapeutics, tumor suppressor miRNAs, nanodelivery, Hepatocellular carcinoma, replacement therapy , efficient delivery

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DOI: 10.2174/1566523219666191023101433
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