Role of Antioxidant Natural Products in Management of Infertility: A Review of Their Medicinal Potential.

Antioxidants (Basel). 2020 Oct 07;9(10):

Authors: Noh S, Go A, Kim DB, Park M, Jeon HW, Kim B

Abstract
Infertility, a couple's inability to conceive after one year of unprotected regular intercourse, is an important issue in the world. The use of natural products in the treatment of infertility has been considered as a possible alternative to conventional therapies. The present study aimed to investigate the effects and the mechanisms of various natural products on infertility. We collected articles regarding infertility and natural products using the research databases PubMed and Google Scholar. Several natural products possess antioxidant properties and androgenic activities on productive factors and hormones. Antioxidants are the first defense barrier against free radicals produced by oxidative stress (OS). They remove reactive oxygen stress (ROS), reducing insulin resistance, total cholesterol, fat accumulation, and cancer growth. Moreover, various natural products increase endometrial receptivity and fertility ability showing androgenic activities on productive factors and hormones. For example, Angelica keiskei powder and Astragalus mongholicus extract showed anti-infertility efficacies in males and females, respectively. On the other hand, adverse effects and acute toxicity of natural products were also reported. Tripterygium glycoside decreased fertility ability both in males and females. Results indicate that management of infertility with natural products could be beneficial with further clinical trials to evaluate the safety and effect.

PMID: 33036328 [PubMed - as supplied by publisher]

DeepACTION: A Deep Learning-Based Method for Predicting Novel Drug-Target Interactions.

Anal Biochem. 2020 Oct 06;:113978

Authors: Hasan Mahmud SM, Chen W, Jahan H, Dai B, Din SU, Dzisoo AM

Abstract
Drug-target interactions (DTIs) play a key role in drug development and discovery processes. Wet lab prediction of DTIs is time-consuming, expensive, and tedious. Fortunately, computational approaches can identify new interactions (drug-target pairs) and accelerate the process of drug repurposing. However, a vast number of interactions remain undiscovered; therefore, we proposed a deep learning-based method (deepACTION) for predicting potential or unknown DTIs. Here, each drug chemical structure and protein sequence are transformed according to structural and sequence information using different descriptors to represent their features correctly. There have been some challenges, such as the high dimensionality and class imbalance of data during the prediction process. To address these problems, we developed the MMIB technique to balance the majority and minority instances in the dataset and utilized a LASSO model to handle the high dimensionality of the data. In addition, we trained the convolutional neural network algorithm with balanced and reduced features for accurate prediction of DTIs. In this study, the AUC is considered a primary evaluation metric for comparing the performance of the deep ACTION model with that of existing methods by a 5-fold cross-validation test. Our experiential dataset obtained from the DrugBank database and our deepACTION model achieved an AUC of 0.9836 for this dataset. The experimental results ensured that the model can predict significant numbers of new DTIs and provide complete information to motivate scientists to develop drugs.

PMID: 33035462 [PubMed - as supplied by publisher]

Drug Repurposing Patent Applications April to June 2020.

Assay Drug Dev Technol. 2020 Oct 09;:

Authors: Mucke HAM

PMID: 33035066 [PubMed - as supplied by publisher]

Repurposing of a thromboxane receptor inhibitor based on a novel role in metastasis identified by Phenome Wide Association Study.

Mol Cancer Ther. 2020 Oct 08;:

Authors: Werfel TA, Hicks DJ, Rahman B, Bindeman WE, Duvernay MT, Maeng JG, Hamm H, Lavieri RR, Joly MM, Pulley JM, Elion DL, Brantley-Sieders DM, Cook RS

Abstract
While new drug discoveries are revolutionizing cancer treatments, repurposing existing drugs would accelerate the timeline and lower the cost for bringing treatments to cancer patients. Our goal was to repurpose CPI211, a potent and selective antagonist of the thromboxane A2-prostanoid receptor (TPr), a G-protein coupled receptor that regulates coagulation, blood pressure, and cardiovascular homeostasis. To identify potential new clinical indications for CPI211, we performed a Phenome Wide Association Study (PheWAS) of the gene encoding TPr, TBXA2R, using robust de-identified health records and matched genomic data from >29,000 patients. Specifically, PheWAS was used to identify clinical manifestations correlating with a TBXA2R single nucleotide polymorphism (rs200445019), which generates a T399A substitution within TPr that enhances TPr signaling. Previous studies have correlated 200445019 with chronic venous hypertension, which was recapitulated by this PheWAS analysis. Unexpectedly, PheWAS uncovered a rs200445019 correlation with cancer metastasis across several cancer types. When tested in several mouse models of metastasis, TPr inhibition using CPI211 potently blocked spontaneous metastasis from primary tumors, without affecting tumor cell proliferation, motility, or tumor growth. Further, metastasis following intravenous tumor cell delivery was blocked in mice treated with CPI211. Interestingly, TPr signaling in vascular endothelial cells induced VE-cadherin internalization, diminished endothelial barrier function, and enhanced trans-endothelial migration by tumor cells, phenotypes that were decreased by CPI211. These studies provide evidence that TPr signaling promotes cancer metastasis, supporting the study of TPr inhibitors as anti-metastatic agents, and highlighting the use of PheWAS as an approach to accelerate drug repurposing.

PMID: 33033174 [PubMed - as supplied by publisher]

The use of aliskiren as an antifibrotic drug in experimental models: A systematic review.

Drug Dev Res. 2020 02;81(1):114-126

Authors: Altarejo Marin T, Machado Bertassoli B, Alves de Siqueira de Carvalho A, Feder D

Abstract
Aliskiren is an oral antihypertensive medication that acts by directly inhibiting renin. High levels of circulating renin and prorenin activate the pathological signaling pathway of fibrosis. This drug also reduces oxidative stress. Thus, the aim of this systematic review is to analyze experimental studies that show the actions of aliskiren on fibrosis. PubMed and LILACS databases were consulted using the keywords aliskiren and fibrosis within the period between 2005 and 2017. Fifty-three articles were analyzed. In the heart, aliskiren attenuated remodeling, hypertrophy, inflammatory cytokines, collagen deposition, and oxidative stress. In the kidneys, there was a reduction in interstitial fibrosis, the infiltration of inflammatory cells, apoptosis, proteinuria, and in the recruitment of macrophages. In diabetic models, an improvement in the albumin/creatinine relationship and in the insulin pathway in skeletal muscles was observed; aliskiren was beneficial to pancreatic function and glucose tolerance. In the liver, aliskiren reduced fibrosis, steatosis, inflammatory cytokines, and collagen deposition. In the lung and peritoneal tissues, there was a reduction in fibrosis. Many studies have reported on the beneficial effects of aliskiren on endothelial function and arterial rigidity. A reduction in fibrosis in different organs is cited by many authors, which complies with the results found in this review. However, studies diverge on the use of the drug in diabetic patients. Aliskiren has antifibrotic potential in several experimental models, interfering with the levels of fibrogenic cytokines and oxidative stress. Therefore, its use in diseases in which fibrosis plays an important pathophysiological role is suggested.

PMID: 31605544 [PubMed - indexed for MEDLINE]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/10/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/10/08

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Single-cell Study of Two Rat Models of Pulmonary Arterial Hypertension Reveals Connections to Human Pathobiology and Drug Repositioning.

Am J Respir Crit Care Med. 2020 Oct 06;:

Authors: Hong J, Arneson D, Umar S, Ruffenach G, Cunningham CM, Ahn IS, Diamante G, Bhetraratana M, Park JF, Said E, Huynh C, Le T, Medzikovic L, Humbert M, Soubrier F, Montani D, Girerd B, Trégouët DA, Channick R, Saggar R, Eghbali M, Yang X

Abstract
RATIONALE: The cellular and molecular landscape and translational value of commonly used models of pulmonary arterial hypertension (PAH) are poorly understood. Single-cell transcriptomics can enhance molecular understanding of preclinical models and facilitate their rational use and interpretation.
OBJECTIVES: We aim to determine and prioritize dysregulated genes, pathways, and cell types in lungs of PAH rat models to assess relevance to human PAH and identify drug repositioning candidates.
METHODS: Single-cell RNA-seq was performed on the lungs of monocrotaline, Sugen-hypoxia, and control rats to identify altered genes and cell types, followed by validation using flow-sorted cells, RNA in situ hybridization, and immunofluorescence. Relevance to human PAH was assessed by histology of lungs from patients and via integration with human PAH genetic loci and known disease genes. Candidate drugs were predicted using Connectivity Map.
MEASUREMENTS AND MAIN RESULTS: Distinct changes in genes and pathways in numerous cell types were identified in Sugen-hypoxia and monocrotaline lungs. Widespread upregulation of NF-κB signaling and downregulation of interferon signaling was observed across cell types. Sugen-hypoxia non-classical monocytes and monocrotaline conventional dendritic cells showed particularly strong NF-κB pathway activation. Genes altered in Sugen-hypoxia non-classical monocytes were significantly enriched for PAH-associated genes and genetic variants, and candidate drugs predicted to reverse the changes were identified. An open-access online platform was developed to share single-cell data and drug candidates (http://mergeomics.
RESEARCH: idre.ucla.edu/PVDSingleCell/).
CONCLUSIONS: Our study revealed the distinct and shared dysregulation of genes and pathways in two commonly used PAH models for the first time at single-cell resolution and demonstrated their relevance to human PAH and utility for drug repositioning.

PMID: 33021809 [PubMed - as supplied by publisher]

The role of aspirin in the prevention of ovarian, endometrial and cervical cancers.

Womens Health (Lond). 2020 Jan-Dec;16:1745506520961710

Authors: Joharatnam-Hogan N, Cafferty FH, Macnair A, Ring A, Langley RE

Abstract
Drug repurposing is the application of an existing licenced drug for a new indication and potentially provides a faster and cheaper approach to developing new anti-cancer agents. Gynaecological cancers contribute significantly to the global cancer burden, highlighting the need for low cost, widely accessible therapies. A large body of evidence supports the role of aspirin as an anti-cancer agent, and a number of randomized trials are currently underway aiming to assess the potential benefit of aspirin in the treatment of cancer. This review summarizes the evidence underpinning aspirin use for the prevention of the development and recurrence of gynaecological cancers (ovarian, endometrial and cervical) and potential mechanisms of action.

PMID: 33019903 [PubMed - in process]

Benefits and adverse effects of hydroxychloroquine, methotrexate and colchicine: searching for repurposable drug candidates.

Rheumatol Int. 2020 11;40(11):1741-1751

Authors: Misra DP, Gasparyan AY, Zimba O

Abstract
Repurposing of antirheumatic drugs has garnered global attention. The aim of this article is to overview available evidence on the use of widely used antirheumatic drugs hydroxychloroquine, methotrexate and colchicine for additional indications. Hydroxychloroquine has endothelial stabilizing and anti-thrombotic effects. Its use has been explored as an adjunctive therapy in refractory thrombosis in antiphospholipid syndrome. It may also prevent recurrent pregnancy losses in the absence of antiphospholipid antibodies. Hydroxychloroquine favourably modulates atherogenic lipid and glycaemic profiles. Methotrexate has been tried for modulation of cardiovascular events in non-rheumatic clinical conditions, although a large clinical trial failed to demonstrate a benefit. Colchicine has been shown to successfully reduce the risk of recurrent cardiovascular events in a large multicentric trial. Potential antifibrotic effects of colchicine require further exploration. Hydroxychloroquine, methotrexate and colchicine are also being tried at different stages of the ongoing Coronavirus Disease 19 (COVID-19) pandemic for prophylaxis and treatment. While the use of these agents is being diversified, their adverse effects should be timely diagnosed and prevented. Hydroxychloroquine can cause retinopathy and rarely cardiac and auditory toxicity, retinopathy being dose and time dependent. Methotrexate can cause transaminitis, cytopenias and renal failure, particularly in acute overdoses. Colchicine can rarely cause myopathies, cardiomyopathy, cytopenias and transaminitis. Strong evidence is warranted to keep balance between benefits of repurposing these old antirheumatic drugs and risk of their adverse effects.

PMID: 32880032 [PubMed - indexed for MEDLINE]

Old and re-purposed drugs for the treatment of COVID-19.

Expert Rev Anti Infect Ther. 2020 09;18(9):843-847

Authors: Jean SS, Hsueh PR

Abstract
Introduction: The coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has developed since December 2019. It has caused a global pandemic with more than three hundred thousand case fatalities. However, apart from supportive care by respirators, no standard medical therapy is validated. Areas covered: This paper presents old drugs with potential in vitro efficacy against SARS-CoV-2. The in vitro database, adverse effects, and potential toxicities of these drugs are reviewed regarding their feasibility of clinical prescription for the treatment of patients with COVID-19. To obtain convincing recommendations, we referred to opinions from the US National Institute of Health regarding drugs repurposed for COVID-19 therapy. Expert opinion: Although strong evidence of well-designed randomized controlled studies regarding COVID-19 therapy is presently lacking, remdesivir, teicoplanin, hydroxychloroquine (not in combination with azithromycin), and ivermectin might be effective antiviral drugs and are deemed promising candidates for controlling SARS-CoV-2. In addition, tocilizumab might be considered as the supplementary treatment for COVID-19 patients with cytokine release syndrome. In future, clinical trials regarding a combination of potentially effective drugs against SARS-CoV-2 need to be conducted to establish the optimal regimen for the treatment of patients with moderate-to-severe COVID-19.

PMID: 32419524 [PubMed - indexed for MEDLINE]

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/10/06

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Repurposing of niclosamide as a STAT3 inhibitor to enhance the anticancer effect of chemotherapeutic drugs in treating colorectal cancer.

Life Sci. 2020 Oct 01;:118522

Authors: Wu MM, Zhang Z, Tong CWS, Yan VW, Cho WCS, To KKW

Abstract
AIMS: Colorectal cancer (CRC) is the third most common cancer worldwide. Mutation of various cell signaling molecules or aberrant activation of signaling pathways leads to poor response to chemotherapy in CRC. Signal transducer and activator of transcription protein 3 (STAT3) is an important signaling molecule, which plays crucial roles in regulating cell survival and growth. In this study, the potentitation of chemotherapy by putative STAT3 inhibitors for treating CRC was investigated.
MAIN METHODS: A few putative STAT3 inhibitors were investigated. Niclosamide, originally indicated for the treatment of tapeworm infection, was chosen for further investigation in five CRC cell lines (HCT116, HT29, HCC2998, LoVo and SW480). Western blot analysis was used to evaluate the expression of STAT3/phospho-STAT3 and its downstream targets. Sulforhodamine B assay was used to evaluate the cytotoxicity of drug combinations. Flow cytometric assays were used to investigate the apoptotic and cell cycle effect.
KEY FINDINGS: Niclosamide was found to inhibit expression and activation of STAT3 in a concentration- and time-dependent manner, thereby downregulating STAT3 downstream targets including survivin and cyclin-D1 to induce apoptosis and cell cycle arrest. When combined with niclosamide or specific STAT3 inhibitor (C188-9), the cytotoxicity and DNA damage response from SN38 (the active metabolite from irinotecan) were significantly enhanced. The sequential exposure of SN38 followed by niclosamide was found to be the most potent treatment sequence for the drug combination.
SIGNIFICANCE: Niclosamide represents a promising candidate for repurposing to potentiate the anticancer activity of chemotherapeutic drugs.

PMID: 33011217 [PubMed - as supplied by publisher]

Commentary: Computational Drug Repositioning Identifies Potentially Active Therapies for Chordoma.

Neurosurgery. 2020 Oct 02;:

Authors: Eichberg DG, Komotar RJ, Ivan ME

PMID: 33009573 [PubMed - as supplied by publisher]

RepCOOL: computational drug repositioning via integrating heterogeneous biological networks.

J Transl Med. 2020 Oct 02;18(1):375

Authors: Fahimian G, Zahiri J, Arab SS, Sajedi RH

Abstract
BACKGROUND: It often takes more than 10 years and costs more than 1 billion dollars to develop a new drug for a particular disease and bring it to the market. Drug repositioning can significantly reduce costs and time in drug development. Recently, computational drug repositioning attracted a considerable amount of attention among researchers, and a plethora of computational drug repositioning methods have been proposed. This methodology has widely been used in order to address various medical challenges, including cancer treatment. The most common cancers are lung and breast cancers. Thus, suggesting FDA-approved drugs via drug repositioning for breast cancer would help us to circumvent the approval process and subsequently save money as well as time.
METHODS: In this study, we propose a novel network-based method, named RepCOOL, for drug repositioning. RepCOOL integrates various heterogeneous biological networks to suggest new drug candidates for a given disease.
RESULTS: The proposed method showed a promising performance on benchmark datasets via rigorous cross-validation. The final drug repositioning model has been built based on a random forest classifier after examining various machine learning algorithms. Finally, in a case study, four FDA approved drugs were suggested for breast cancer stage II.
CONCLUSION: Results show the potency of the proposed method in detecting true drug-disease relationships. RepCOOL suggested four new drugs for breast cancer stage II namely Doxorubicin, Paclitaxel, Trastuzumab, and Tamoxifen.

PMID: 33008415 [PubMed - as supplied by publisher]

Drug repurposing through drug-gene interaction profiles for hidradenitis suppurativa/acne inversa treatment.

J Eur Acad Dermatol Venereol. 2020 Oct 02;:

Authors: Zouboulis CC, Nogueira da Costa A

Abstract
Despite the evidence-based effectiveness of several drugs,1 treatment of hidradenitis suppurativa (HS) is still empirical and challenging. The required discovery of candidate treatment targets, may be accomplished through an integrated approach using combined molecular tools.2 Current transcriptome and proteome studies have identified potential biomarkers for HS both in entire involved skin3 and in involved skin apocrine glands.4 These and other studies may support the identification of novel therapeutic targets for HS. Computational drug repurposing/repositioning screening approaches have been previously engaged to identify existing compounds as potential drugs for dermatologic conditions including a study on moderate-to-severe HS.5.

PMID: 33007126 [PubMed - as supplied by publisher]

In-silico drug repurposing study predicts the combination of pirfenidone and melatonin as a promising candidate therapy to reduce SARS-CoV-2 infection progression and respiratory distress caused by cytokine storm.

PLoS One. 2020;15(10):e0240149

Authors: Artigas L, Coma M, Matos-Filipe P, Aguirre-Plans J, Farrés J, Valls R, Fernandez-Fuentes N, de la Haba-Rodriguez J, Olvera A, Barbera J, Morales R, Oliva B, Mas JM

Abstract
From January 2020, COVID-19 is spreading around the world producing serious respiratory symptoms in infected patients that in some cases can be complicated by the severe acute respiratory syndrome, sepsis and septic shock, multiorgan failure, including acute kidney injury and cardiac injury. Cost and time efficient approaches to reduce the burthen of the disease are needed. To find potential COVID-19 treatments among the whole arsenal of existing drugs, we combined system biology and artificial intelligence-based approaches. The drug combination of pirfenidone and melatonin has been identified as a candidate treatment that may contribute to reduce the virus infection. Starting from different drug targets the effect of the drugs converges on human proteins with a known role in SARS-CoV-2 infection cycle. Simultaneously, GUILDify v2.0 web server has been used as an alternative method to corroborate the effect of pirfenidone and melatonin against the infection of SARS-CoV-2. We have also predicted a potential therapeutic effect of the drug combination over the respiratory associated pathology, thus tackling at the same time two important issues in COVID-19. These evidences, together with the fact that from a medical point of view both drugs are considered safe and can be combined with the current standard of care treatments for COVID-19 makes this combination very attractive for treating patients at stage II, non-severe symptomatic patients with the presence of virus and those patients who are at risk of developing severe pulmonary complications.

PMID: 33006999 [PubMed - as supplied by publisher]

Disruption of redox homeostasis for combinatorial drug efficacy in K-Ras tumors as revealed by metabolic connectivity profiling.

Cancer Metab. 2020;8:22

Authors: Gaglio D, Bonanomi M, Valtorta S, Bharat R, Ripamonti M, Conte F, Fiscon G, Righi N, Napodano E, Papa F, Raccagni I, Parker SJ, Cifola I, Camboni T, Paci P, Colangelo AM, Vanoni M, Metallo CM, Moresco RM, Alberghina L

Abstract
Abstract:
Background: Rewiring of metabolism induced by oncogenic K-Ras in cancer cells involves both glucose and glutamine utilization sustaining enhanced, unrestricted growth. The development of effective anti-cancer treatments targeting metabolism may be facilitated by the identification and rational combinatorial targeting of metabolic pathways.
Methods: We performed mass spectrometric metabolomics analysis in vitro and in vivo experiments to evaluate the efficacy of drugs and identify metabolic connectivity.
Results: We show that K-Ras-mutant lung and colon cancer cells exhibit a distinct metabolic rewiring, the latter being more dependent on respiration. Combined treatment with the glutaminase inhibitor CB-839 and the PI3K/aldolase inhibitor NVP-BKM120 more consistently reduces cell growth of tumor xenografts. Maximal growth inhibition correlates with the disruption of redox homeostasis, involving loss of reduced glutathione regeneration, redox cofactors, and a decreased connectivity among metabolites primarily involved in nucleic acid metabolism.
Conclusions: Our findings open the way to develop metabolic connectivity profiling as a tool for a selective strategy of combined drug repositioning in precision oncology.

PMID: 33005401 [PubMed]

Recognition of Potential COVID-19 Drug Treatments through the Study of Existing Protein-Drug and Protein-Protein Structures: An Analysis of Kinetically Active Residues.

Biomolecules. 2020 09 21;10(9):

Authors: Perišić O

Abstract
We report the results of our in silico study of approved drugs as potential treatments for COVID-19. The study is based on the analysis of normal modes of proteins. The drugs studied include chloroquine, ivermectin, remdesivir, sofosbuvir, boceprevir, and α-difluoromethylornithine (DMFO). We applied the tools we developed and standard tools used in the structural biology community. Our results indicate that small molecules selectively bind to stable, kinetically active residues and residues adjoining them on the surface of proteins and inside protein pockets, and that some prefer hydrophobic sites over other active sites. Our approach is not restricted to viruses and can facilitate rational drug design, as well as improve our understanding of molecular interactions, in general.

PMID: 32967116 [PubMed - indexed for MEDLINE]

Using "old" medications to fight new COVID-19: Re-purposing with a purpose.

J Mol Cell Cardiol. 2020 09;146:41-42

Authors: Wang Y, Foo R, Thum T

PMID: 32687852 [PubMed - indexed for MEDLINE]