scholarly journals Mining of high throughput screening database reveals AP-1 and autophagy pathways as potential targets for COVID-19 therapeutics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hu Zhu ◽  
Catherine Z. Chen ◽  
Srilatha Sakamuru ◽  
Jinghua Zhao ◽  
Deborah K. Ngan ◽  
...  
Keyword(s):  
Clinical Trials ◽  
High Throughput Screening ◽  
Animal Studies ◽  
Cytopathic Effect ◽  
Mechanisms Of Action ◽  
Activity Profile ◽  
Pathway Activity ◽  
Global Pandemic ◽  
Approved Drugs

AbstractThe recent global pandemic of the Coronavirus disease 2019 (COVID-19) caused by the new coronavirus SARS-CoV-2 presents an urgent need for the development of new therapeutic candidates. Many efforts have been devoted to screening existing drug libraries with the hope to repurpose approved drugs as potential treatments for COVID-19. However, the antiviral mechanisms of action of the drugs found active in these phenotypic screens remain largely unknown. In an effort to deconvolute the viral targets in pursuit of more effective anti-COVID-19 drug development, we mined our in-house database of approved drug screens against 994 assays and compared their activity profiles with the drug activity profile in a cytopathic effect (CPE) assay of SARS-CoV-2. We found that the autophagy and AP-1 signaling pathway activity profiles are significantly correlated with the anti-SARS-CoV-2 activity profile. In addition, a class of neurology/psychiatry drugs was found to be significantly enriched with anti-SARS-CoV-2 activity. Taken together, these results provide new insights into SARS-CoV-2 infection and potential targets for COVID-19 therapeutics, which can be further validated by in vivo animal studies and human clinical trials.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

scholarly journals Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease?

Thorax ◽  
2018 ◽  
Vol 73 (6) ◽  
pp. 565-574 ◽  
Author(s):  
Winifred Broekman ◽  
Padmini P S J Khedoe ◽  
Koen Schepers ◽  
Helene Roelofs ◽  
Jan Stolk ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Animal Studies ◽  
Chronic Obstructive ◽  
Tissue Destruction ◽  
Novel Therapy ◽  
Model Studies

COPD is characterised by tissue destruction and inflammation. Given the lack of curative treatments and the progressive nature of the disease, new treatments for COPD are highly relevant. In vitro cell culture and animal studies have demonstrated that mesenchymal stromal cells (MSCs) have the capacity to modify immune responses and to enhance tissue repair. These properties of MSCs provided a rationale to investigate their potential for treatment of a variety of diseases, including COPD. Preclinical models support the hypothesis that MSCs may have clinical efficacy in COPD. However, although clinical trials have demonstrated the safety of MSC treatment, thus far they have not provided evidence for MSC efficacy in the treatment of COPD. In this review, we discuss the rationale for MSC-based cell therapy in COPD, the main findings from in vitro and in vivo preclinical COPD model studies, clinical trials in patients with COPD and directions for further research.

scholarly journals Proteasome inhibition as a therapeutic approach in atypical teratoid/rhabdoid tumors

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Andrew Morin ◽  
Caroline Soane ◽  
Angela Pierce ◽  
Bridget Sanford ◽  
Kenneth L Jones ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Lines ◽  
Proteasome Inhibitor ◽  
High Grade Glioma ◽  
Proteasome Inhibition ◽  
Atypical Teratoid ◽  
Rhabdoid Tumors ◽  
Approved Drugs

Abstract Background Atypical teratoid/thabdoid tumor (AT/RT) remains a difficult-to-treat tumor with a 5-year overall survival rate of 15%–45%. Proteasome inhibition has recently been opened as an avenue for cancer treatment with the FDA approval of bortezomib (BTZ) in 2003 and carfilzomib (CFZ) in 2012. The aim of this study was to identify and characterize a pre-approved targeted therapy with potential for clinical trials in AT/RT. Methods We performed a drug screen using a panel of 134 FDA-approved drugs in 3 AT/RT cell lines. Follow-on in vitro studies used 6 cell lines and patient-derived short-term cultures to characterize selected drug interactions with AT/RT. In vivo efficacy was evaluated using patient derived xenografts in an intracranial murine model. Results BTZ and CFZ are highly effective in vitro, producing some of the strongest growth-inhibition responses of the evaluated 134-drug panel. Marizomib (MRZ), a proteasome inhibitor known to pass the blood–brain barrier (BBB), also strongly inhibits AT/RT proteasomes and generates rapid cell death at clinically achievable doses in established cell lines and freshly patient-derived tumor lines. MRZ also significantly extends survival in an intracranial mouse model of AT/RT. Conclusions MRZ is a newer proteasome inhibitor that has been shown to cross the BBB and is already in phase II clinical trials for adult high-grade glioma (NCT NCT02330562 and NCT02903069). MRZ strongly inhibits AT/RT cell growth both in vitro and in vivo via a moderately well-characterized mechanism and has direct translational potential for patients with AT/RT.

scholarly journals DDIS-28. A HIGH THROUGHPUT SCREENING PLATFORM TO IDENTIFY RADIOSENSITIZERS FOR DIPG

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi69-vi69
Author(s):  
Matt Clutter ◽  
Megan Romero ◽  
Oren Becher
Keyword(s):  
Clinical Trials ◽  
Mouse Model ◽  
High Throughput ◽  
High Throughput Screening ◽  
Animal Studies ◽  
Ex Vivo ◽  
Genetically Engineered ◽  
Clinical Activity ◽  
K27m Mutation ◽  
Genetically Engineered Mouse Model

Abstract Diffuse intrinsic pontine glioma (DIPG) is an incurable brainstem tumor and the leading cause of death in children with brain cancer. Despite numerous clinical trials, no drugs have been found to prolong survival for DIPG patients, suggesting an urgent need to test therapeutics in preclinical models more predictive of clinical activity. To address this gap, we developed a genetically engineered mouse model incorporating the Histone H3.3 K27M mutation, p53 deletion, and PDGFR-α amplification, which co-occur in up to 40% of human DIPG. Here we report the results of a drug screen to identify radiosensitizers of DIPG cells isolated from our mouse model and cultured ex vivo as neurospheres. Although previous clinical trials combining radiotherapy with radiosensitizing agents failed to benefit DIPG patients, they incorporated general radiosensitizers. We hypothesize that searching for radiosynergy using 3-dimensional neurospheres derived from genetically defined primary cell DIPG models will enhance our ability to prioritize clinically relevant radiosensitizers. To identify candidates, we developed high throughput radiation and imaging protocols to quantify the number, size, and viability of neurospheres following treatment. We screened 1,280 FDA-approved drugs and 1,600 molecules with a history of clinical use. Two mechanistic classes of compounds were identified that sensitized DIPG neurospheres to radiotherapy, both targeting epigenetic factors. An HDAC1/3 inhibitor along with several different BET bromodomain inhibitors increased cell death 2–3 fold beyond the effect of radiation with minimal activity from the compounds alone. In addition to optimizing the dosing and timing of these compounds for animal studies, we are investigating whether radiosensitization occurs in H3.3 wildtype neurospheres. In the current molecular era of cancer, genetic features like the H3.3 K27M mutation could present an opportunity to develop therapeutics that preferentially radiosensitize diseased cells relative to normal cells. Such “precision radiosensitizers” would advance radiotherapy by enhancing tumor-specific toxicity while sparing bystander cells.

scholarly journals Repurposing Approved Drugs for Guiding COVID-19 Prophylaxis: A Systematic Review

2020 ◽  
Vol 11 ◽  
Author(s):  
Bruno Silva Andrade ◽  
Fernanda de Souza Rangel ◽  
Naiane Oliveira Santos ◽  
Andria dos Santos Freitas ◽  
Wagner Rodrigues de Assis Soares ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Large Scale ◽  
Post Exposure Prophylaxis ◽  
Drug Candidates ◽  
Global Pandemic ◽  
The World ◽  
Approved Drugs ◽  
Exposure Prophylaxis

The SARS-CoV-2 outbreak originally appeared in China in December 2019 and became a global pandemic in March 2020. This infectious disease has directly affected public health and the world economy. Several palliative therapeutic treatments and prophylaxis strategies have been used to control the progress of this viral infection, including pre-(PrEP) and post-exposure prophylaxis. On the other hand, research groups around the world are still studying novel drug prophylaxis and treatment using repurposing approaches, as well as vaccination options, which are in different pre-clinical and clinical testing phases. This systematic review evaluated 1,228 articles from the PubMed and Scopus indexing databases, following the Kitchenham bibliographic searching protocol, with the aim to list drug candidates, potentially approved to be used as new options for SARS-CoV-2 prophylaxis clinical trials and medical protocols. In searching protocol, we used the following keywords: “Covid-19 or SARS-CoV-2” or “Coronavirus or 2019 nCoV,” “prophylaxis,” “prophylactic,” “pre-exposure,” “COVID-19 or SARS-CoV-2 Chemoprophylaxis,” “repurposed,” “strategies,” “clinical,” “trials,” “anti-SARS-CoV-2,” “anti-covid-19,” “Antiviral,” “Therapy prevention in vitro,” in cells “and” human testing. After all protocol steps, we selected 60 articles that included: 15 studies with clinical data, 22 studies that used in vitro experiments, seven studies using animal models, and 18 studies performed with in silico experiments. Additionally, we included more 22 compounds between FDA approved drugs and drug-like like molecules, which were tested in large-scale screenings, as well as those repurposed approved drugs with new mechanism of actions. The drugs selected in this review can assist clinical studies and medical guidelines on the rational repurposing of known antiviral drugs for COVID-19 prophylaxis.

scholarly journals Bioactive Surfaces vs. Conventional Surfaces in Titanium Dental Implants: A Comparative Systematic Review

2020 ◽  
Vol 9 (7) ◽  
pp. 2047 ◽  
Author(s):  
Nansi López-Valverde ◽  
Javier Flores-Fraile ◽  
Juan Manuel Ramírez ◽  
Bruno Macedo de Sousa ◽  
Silvia Herrero-Hernández ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Dental Implants ◽  
Animal Studies ◽  
Statistical Significance ◽  
Cochrane Collaboration ◽  
In Vivo Experiments ◽  
Bone To Implant Contact ◽  
Bioactive Surfaces

Animal studies and the scarce clinical trials available that have been conducted suggest that bioactive surfaces on dental implants could improve the osseointegration of such implants. The purpose of this systematic review was to compare the effectiveness of osseointegration of titanium (Ti) dental implants using bioactive surfaces with that of Ti implants using conventional surfaces such as sandblasted large-grit acid-etched (SLA) or similar surfaces. Applying the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, the MEDLINE, PubMed Central and Web of Science databases were searched for scientific articles in April 2020. The keywords used were “dental implants”, “bioactive surfaces”, “biofunctionalized surfaces”, and “osseointegration”, according to the question: “Do bioactive dental implant surfaces have greater osseointegration capacity compared with conventional implant surfaces?” Risk of bias was assessed using the Cochrane Collaboration tool. 128 studies were identified, of which only 30 met the inclusion criteria: 3 clinical trials and 27 animal studies. The average STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) and ARRIVE (Animal Research: Reporting of In Vivo Experiments) scores were 15.13 ± 2.08 and 17.7±1.4, respectively. Implant stability quotient (ISQ) was reported in 3 studies; removal torque test (RTT)—in 1 study; intraoral periapical X-ray and microcomputed tomography radiological evaluation (RE)—in 4 studies; shear force (SF)—in 1 study; bone-to-implant contact (BIC)—in 12 studies; and BIC and bone area (BA) jointly—in 5 studies. All animal studies reported better bone-to-implant contact surface for bioactive surfaces as compared to control implants with a statistical significance of p < 0.05. Regarding the bioactive surfaces investigated, the best results were yielded by the one where mechanical and chemical treatment methods of the Ti surfaces were combined. Hydroxyapatite (HA) and calcium–phosphate (Ca–Ph) were the most frequently used bioactive surfaces. According to the results of this systematic review, certain bioactive surfaces have a positive effect on osseointegration, although certain coating biomolecules seem to influence early peri-implant bone formation. Further and more in-depth research in this field is required to reduce the time needed for osseointegration of dental implants.

Traditional Medicines, HIV, and Related Infections

2011 ◽  
Vol 23 (1) ◽  
pp. 159-164 ◽  
Author(s):  
M. Patel ◽  
P. Bessong ◽  
H. Liu
Keyword(s):  
Clinical Trials ◽  
Immune System ◽  
Ethical Issues ◽  
Mechanisms Of Action ◽  
Antiretroviral Drugs ◽  
In Vivo Studies ◽  
Traditional Medicines ◽  
Anti Hiv

Traditional medicines are an integral part of health care worldwide, even though their efficacy has not been scientifically proven. HIV-infected individuals may use them singularly or in combination with conventional medicines. Many in vitro studies have proven the anti-HIV, anti- Candida, and anti–herpes simplex virus potential of traditional plants and identified some of the mechanisms of action. Very few in vivo studies are available that involve a small number of participants and show controversial results. In addition, knowledge is limited of the role of traditional medicines in the enhancement of the immune system. The use of traditional medicines with antiretroviral drugs (ARVs) has created a problem because drug interactions compromise the efficacy of ARVs. Several currently popular plants have been studied in the laboratory for their interaction with ARVs, with disadvantageous results. Unfortunately, no clinical trials are available. The science of traditional medicines is relatively new and is at present being modernized worldwide. However, there are still ethical issues regarding traditional medicines that need to be addressed—for example, regulations regarding quality control and standardization of medicines, regulation and education of healers who deliver these medicines, and unregulated clinical trials. The workshop addressed the following questions about traditional medicine and their use in HIV infection: What are the mechanisms of action of anti-HIV traditional medicines? Should traditional medicines be used in conjunction with ARV? Do traditional medicines enhance the immune system? Should medicinal plants be used for the control of oral infections associated with HIV? What are the ethical issues surrounding the use of traditional medicines for the treatment of HIV and associated infections?

scholarly journals A cautionary perspective regarding the isolation and serial propagation of SARS-CoV-2 in Vero cells

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Simon G. P. Funnell ◽  
Babak Afrough ◽  
John James Baczenas ◽  
Neil Berry ◽  
Kevin R. Bewley ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Genetic Variants ◽  
Animal Studies ◽  
Vero Cells ◽  
In Vitro Assays ◽  
Critical Research ◽  
Furin Cleavage ◽  
Furin Cleavage Site

AbstractAn array of SARS-CoV-2 virus variants have been isolated, propagated and used in in vitro assays, in vivo animal studies and human clinical trials. Observations of working stocks of SARS-CoV-2 suggest that sequential propagation in Vero cells leads to critical changes in the region of the furin cleavage site, which significantly reduce the value of the working stock for critical research studies. Serially propagating SARS-CoV-2 in Vero E6 cells leads to rapid increases in genetic variants while propagation in other cell lines (e.g. Vero/hSLAM) appears to mitigate this risk thereby improving the overall genetic stability of working stocks. From these observations, investigators are urged to monitor genetic variants carefully when propagating SARS-CoV-2 in Vero cells.

scholarly journals Identification of SARS-CoV-2–induced pathways reveals drug repurposing strategies

2021 ◽  
Vol 7 (27) ◽  
pp. eabh3032
Author(s):  
Namshik Han ◽  
Woochang Hwang ◽  
Konstantinos Tzelepis ◽  
Patrick Schmerer ◽  
Eliza Yankova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Viral Replication ◽  
Rapid Development ◽  
Drug Repurposing ◽  
Mechanisms Of Action ◽  
Neural Network Analysis ◽  
Cell Assays ◽  
Artificial Neural Network Analysis ◽  
Approved Drugs ◽  
Disease Signatures

The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019 (COVID-19) infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2–induced protein network, based on disease signatures defined by COVID-19 multiomics datasets, and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2–induced pathways, 40 of which are already in COVID-19 clinical trials, testifying to the validity of the approach. Using artificial neural network analysis, we classified these 200 drugs into nine distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (126) and immune response (74). Two drugs (proguanil and sulfasalazine) implicated in viral replication were shown to inhibit replication in cell assays. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.

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