Astragalin: A Bioactive Phytochemical with Potential Therapeutic Activities

Natural products, an infinite treasure of bioactive chemical entities, persist as an inexhaustible resource for discovery of drugs. This review article intends to emphasize on one of the naturally occurring flavonoids, astragalin (kaempferol 3-glucoside), which is a bioactive constituent of various traditional medicinal plants such as Cuscuta chinensis. This multifaceted compound is well known for its diversified pharmacological applications such as anti-inflammatory, antioxidant, neuroprotective, cardioprotective, antiobesity, antiosteoporotic, anticancer, antiulcer, and antidiabetic properties. It carries out the aforementioned activities by the regulation and modulation of various molecular targets such as transcription factors (NF-κB, TNF-α, and TGF-β1), enzymes (iNOS, COX-2, PGE2, MMP-1, MMP-3, MIP-1α, COX-2, PGE-2, HK2, AChe, SOD, DRP-1, DDH, PLCγ1, and GPX), kinases (JNK, MAPK, Akt, ERK, SAPK, IκBα, PI3K, and PKCβ2), cell adhesion proteins (E-cadherin, vimentin PAR-2, and NCam), apoptotic and antiapoptotic proteins (Beclin-1, Bcl-2, Bax, Bcl-xL, cytochrome c, LC3A/B, caspase-3, caspase-9, procaspase-3, procaspase-8, and IgE), and inflammatory cytokines (SOCS-3, SOCS-5, IL-1β, IL-4, IL-6, IL-8, IL-13, MCP-1, CXCL-1, CXCL-2, and IFN-γ). Although researchers have reported multiple pharmacological applications of astragalin in various diseased conditions, further experimental investigations are still mandatory to fully understand its mechanism of action. It is contemplated that astragalin could be subjected to structural optimization to ameliorate its chemical accessibility, to optimize its absorption profiles, and to synthesize its more effective analogues which will ultimately lead towards potent drug candidates.

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Sanguiins—Promising Molecules with Broad Biological Potential

International Journal of Molecular Sciences ◽

10.3390/ijms222312972 ◽

2021 ◽

Vol 22 (23) ◽

pp. 12972

Author(s):

Jakub Gesek ◽

Katarzyna Jakimiuk ◽

Atanas G. Atanasov ◽

Michał Tomczyk

Keyword(s):

Dynamics Simulation ◽

Experimental Investigations ◽

Bioactive Constituents ◽

Natural Origin ◽

Drug Candidates ◽

Naturally Occurring ◽

Traditional Medicinal Plants ◽

Biological Potential ◽

Rosaceae Family ◽

Potent Drug

Compounds of natural origin, an infinite treasure of bioactive chemical entities, persist as an inexhaustible resource for discovering new medicines. In this review, we summarize the naturally occurring ellagitannins, sanguiins, which are bioactive constituents of various traditional medicinal plants, especially from the Rosaceae family. In-depth studies of sanguiin H-6 as an antimicrobial, antiviral, anticancer, anti-inflammatory, and osteoclastogenesis inhibitory agent have led to potent drug candidates. In addition, recently, virtual screening studies have suggested that sanguiin H-6 might increase resistance toward SARS-CoV-2 in the early stages of infection. Further experimental investigations on ADMET (absorption, distribution, metabolism, excretion, and toxicity) supplemented with molecular docking and molecular dynamics simulation are still needed to fully understand sanguiins’ mechanism of action. In sum, sanguiins appear to be promising compounds for additional studies, especially for their application in therapies for a multitude of common and debilitating ailments.

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Role of the Mitochondrial Signaling Pathway in Murine Coronavirus-Induced Oligodendrocyte Apoptosis

Journal of Virology ◽

10.1128/jvi.80.1.395-403.2006 ◽

2006 ◽

Vol 80 (1) ◽

pp. 395-403 ◽

Cited By ~ 21

Author(s):

Yin Liu ◽

Yinghui Pu ◽

Xuming Zhang

Keyword(s):

Hepatitis Virus ◽

Mitochondrial Pathway ◽

Caspase 8 ◽

Caspase 9 ◽

Apoptotic Pathway ◽

Antiapoptotic Proteins ◽

Mitochondrial Signaling ◽

Drastic Increase ◽

Infected Cells

ABSTRACT A previous study demonstrated that infection of rat oligodendrocytes by mouse hepatitis virus (MHV) resulted in apoptosis, which is caspase dependent (Y. Liu, Y. Cai, and X. Zhang, J. Virol. 77:11952-11963, 2003). Here we determined the involvement of the mitochondrial pathway in MHV-induced oligodendrocyte apoptosis. We found that caspase-9 activity was 12-fold higher in virus-infected cells than in mock-infected cells at 24 h postinfection (p.i.). Pretreatment of cells with a caspase-9 inhibitor completely blocked caspase-9 activation and partially inhibited the apoptosis mediated by MHV infection. Analyses of cytochrome c release further revealed an activation of the mitochondrial apoptotic pathway. Stable overexpression of the two antiapoptotic proteins Bcl-2 and Bcl-xL significantly, though only partially, blocked apoptosis, suggesting that activation of the mitochondrial pathway is partially responsible for the apoptosis. To identify upstream signals, we determined caspase-8 activity, cleavage of Bid, and expression of Bax and Bad by Western blotting. We found a drastic increase in caspase-8 activity and cleavage of Bid at 24 h p.i. in virus-infected cells, suggesting that Bid may serve as a messenger to relay the signals from caspase-8 to mitochondria. However, treatment with a caspase-8 inhibitor only slightly blocked cytochrome c release from the mitochondria. Furthermore, we found that Bax but not Bad was significantly increased at 12 h p.i. in cells infected with both live and UV-inactivated viruses and that Bax activation was partially blocked by treatment with the caspase-8 inhibitor. These results thus establish the involvement of the mitochondrial pathway in MHV-induced oligodendrocyte apoptosis.

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Brucea javanica Oil Induces Apoptosis in T24 Bladder Cancer Cells via Upregulation of Caspase-3, Caspase-9, and Inhibition of NF-κB and COX-2 Expressions

The American Journal of Chinese Medicine ◽

10.1142/s0192415x10008093 ◽

2010 ◽

Vol 38 (03) ◽

pp. 613-624 ◽

Cited By ~ 20

Author(s):

Guo-Guang Lou ◽

Hang-Ping Yao ◽

Li-Ping Xie

Keyword(s):

Caspase 3 ◽

Flow Cytometric Analysis ◽

Morphological Characteristics ◽

Control Group ◽

Caspase 9 ◽

Brucea Javanica ◽

Flow Cytometric ◽

T24 Cells ◽

Bladder Cancer Cells ◽

Cox 2

The potential molecular mechanism of Brucea javanica oil in the induction of apoptosis of T24 bladder cancer cells was investigated in vitro. T24 cells were divided into two groups: one, treated with B. javanica oil and the other, untreated. The cells were maintained in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS) and 4 mM glutamine. The morphological characteristics of T24 cells were examined microscopically at the 2nd and 5th day of the culture. The drug toxicity spectrum ( IC 50) was estimated by the MTT assay, and viability of T24 cells was assessed on the basis of the percentage of T24 apoptotic cells, as determined by Annexin/PI staining and flow cytometric analysis. The expression of caspase-3, capase-9, NF-κB p65, and COX-2 was analyzed by Western blotting. Morphological characteristics of the cells on the 2nd day showed apoptosis of the treated T24 cells; it was more apparent in the cells on the 5th day. B. javanica oil decreased the cell viability at the testing concentrations spectrum (5–0.156 mg/ml), and this viability was significantly higher as compared to the control group. In this concentration spectrum, B. javanica oil also induced apoptosis of T24 cells, which was analyzed by annexin/PI staining and flow cytometric analysis. These results were also statistically significant as compared to those of the control group. The expressions of caspase-3 and caspase-9 were low in the control T24 cells, while the expressions of NF-κB and COX-2 were high in normal T24 cells. Treatment with B. javanica oil significantly induced the expressions of caspase-3 and caspase-9 proteins in T24 cells, whereas the expressions of NF-κB and COX-2 proteins were inhibited. B. javanica oil significantly reduced the viability of T24 cells and induced T24 cell apoptosis. The molecular mechanism underlying these effects may be the activation of caspase apoptotic pathway by upregulation of the expression of caspase-3 and caspase-9 proteins and inhibition of the expression of NF-κB and COX-2 proteins.

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Screening of FDA Approved Drugs Against COVID-19 Main Protease: Coronavirus Disease

10.20944/preprints202004.0062.v1 ◽

2020 ◽

Cited By ~ 4

Author(s):

Vijayakumar Balakrishnan ◽

Karthik Lakshminarayanan

Keyword(s):

Vaccine Development ◽

New Drugs ◽

World Health ◽

Wuhan City ◽

Drug Candidates ◽

Human Contact ◽

Main Protease ◽

Potent Drug ◽

Approved Drugs ◽

Fda Approved Drugs

In the end of December 2019, a new strain of coronavirus was identified in the Wuhan city of Hubei province in China. Within a shorter period of time, an unprecedented outbreak of this strain was witnessed over the entire Wuhan city. This novel coronavirus strain was later officially renamed as COVID-19 (Coronavirus disease 2019) by the World Health Organization. The mode of transmission had been found to be human-to-human contact and hence resulted in a rapid surge across the globe where more than 1,100,000 people have been infected with COVID-19. In the current scenario, finding potent drug candidates for the treatment of COVID-19 has emerged as the most challenging task for clinicians and researchers worldwide. Identification of new drugs and vaccine development may take from a few months to years based on the clinical trial processes. To overcome the several limitations involved in identifying and bringing out potent drug candidates for treating COVID-19, in the present study attempts were made to screen the FDA approved drugs using High Throughput Virtual Screening (HTVS). The COVID-19 main protease (COVID-19 Mpro) was chosen as the drug target for which the FDA approved drugs were initially screened with HTVS. The drug candidates that exhibited favorable docking score, energy and emodel calculations were further taken for performing Induced Fit Docking (IFD) using Schrodinger’s GLIDE. From the flexible docking results, the following four FDA approved drugs Sincalide, Pentagastrin, Ritonavir and Phytonadione were identified. In particular, Sincalide and Pentagastrin can be considered potential key players for the treatment of COVID-19 disease.

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Homology Modeling and Virtual Screening Studies of Antigen MLAA-42 Protein: Identification of Novel Drug Candidates against Leukemia—An In Silico Approach

Computational and Mathematical Methods in Medicine ◽

10.1155/2020/8196147 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Ihsan A. Shehadi ◽

Huda R. M. Rashdan ◽

Aboubakr H. Abdelmonsef

Keyword(s):

Virtual Screening ◽

Homology Modeling ◽

Protein Identification ◽

Binding Affinities ◽

Monocytic Leukemia ◽

Drug Candidates ◽

Promising Target ◽

Leukemia Treatment ◽

Potent Drug ◽

Novel Drug

Monocytic leukemia-associated antigen-42 (MLAA-42) is associated with excessive cell division and progression of leukemia. Thus, human MLAA-42 is considered as a promising target for designing of new lead molecules for leukemia treatment. Herein, the 3D model of the target was generated by homology modeling technique. The model was then evaluated using various cheminformatics servers. Moreover, the virtual screening studies were performed to explore the possible binding patterns of ligand molecules to MLAA’s active site pocket. Thirteen ligand molecules from the ChemBank™ database were identified as they showed good binding affinities, scaffold diversity, and preferential ADME properties which may act as potent drug candidates against leukemia. The study provides the way to identify novel therapeutics with optimal efficacy, targeting MLAA-42.

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Natural Products as Modulators of Sirtuins

Molecules ◽

10.3390/molecules25143287 ◽

2020 ◽

Vol 25 (14) ◽

pp. 3287 ◽

Cited By ~ 2

Author(s):

Berin Karaman Mayack ◽

Wolfgang Sippl ◽

Fidele Ntie-Kang

Keyword(s):

Natural Products ◽

Drug Discovery ◽

Histone Deacetylases ◽

High Throughput Screening ◽

Chemical Space ◽

Class Iii ◽

Drug Candidates ◽

Starting Point ◽

Recent Developments ◽

Potent Drug

Natural products have been used for the treatment of human diseases since ancient history. Over time, due to the lack of precise tools and techniques for the separation, purification, and structural elucidation of active constituents in natural resources there has been a decline in financial support and efforts in characterization of natural products. Advances in the design of chemical compounds and the understanding of their functions is of pharmacological importance for the biomedical field. However, natural products regained attention as sources of novel drug candidates upon recent developments and progress in technology. Natural compounds were shown to bear an inherent ability to bind to biomacromolecules and cover an unparalleled chemical space in comparison to most libraries used for high-throughput screening. Thus, natural products hold a great potential for the drug discovery of new scaffolds for therapeutic targets such as sirtuins. Sirtuins are Class III histone deacetylases that have been linked to many diseases such as Parkinson`s disease, Alzheimer’s disease, type II diabetes, and cancer linked to aging. In this review, we examine the revitalization of interest in natural products for drug discovery and discuss natural product modulators of sirtuins that could serve as a starting point for the development of isoform selective and highly potent drug-like compounds, as well as the potential application of naturally occurring sirtuin inhibitors in human health and those in clinical trials.

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TREM-1 Protects HIV-1-Infected Macrophages from Apoptosis through Maintenance of Mitochondrial Function

mBio ◽

10.1128/mbio.02638-19 ◽

2019 ◽

Vol 10 (6) ◽

Cited By ~ 7

Author(s):

Grant R. Campbell ◽

Rachel K. To ◽

Stephen A. Spector

Keyword(s):

Hiv Infection ◽

Myeloid Cells ◽

Hiv Treatment ◽

Caspase 9 ◽

Acute Hiv Infection ◽

Antiapoptotic Proteins ◽

Bcl2 Family ◽

Cytopathic Effects ◽

Hiv Eradication ◽

Mitofusin 1

ABSTRACT Macrophages are a reservoir for latent human immunodeficiency type 1 (HIV) infection and a barrier to HIV eradication. In contrast to CD4+ T cells, macrophages are resistant to the cytopathic effects of acute HIV infection. Emerging data suggest a role for TREM1 (triggering receptor expressed on myeloid cells 1) in this resistance to HIV-mediated cytopathogenesis. Here, we show that upon HIV infection, macrophages increase the expression of BCL2, BCLXL, TREM1, mitofusin 1 (MFN1), and MFN2 and the translocation of BCL2L11 (BIM) to the mitochondria and decrease the expression of BCL2-associated agonist of cell death (BAD) and BAX while maintaining a 95% survival rate over 28 days. The HIV proteins Tat and gp120 and the GU-rich single-stranded RNA (ssRNA) (RNA40) from the HIV long terminal repeat region (and a natural Toll-like receptor 8 [TLR8] agonist) induced similar effects. TREM1 silencing in HIV-infected macrophages led to decreased expression of BCL2, BCLXL, MFN1, and MFN2 and increased expression of BAD and BAX. This correlated with a significant increase in apoptosis mediated by a disruption of the mitochondrial membrane potential (Δψm), leading to the release of cytochrome c and caspase 9 cleavage. Exposure of TREM1-silenced macrophages to Tat, gp120, or RNA40 similarly resulted in the disruption of Δψm, cytochrome c release, caspase 9 cleavage, and apoptosis. Thus, our findings identify a mechanism whereby HIV promotes macrophage survival through TREM1-dependent upregulation of BCL2 family proteins and mitofusins that inhibits BCL2L11-mediated disruption of Δψm and subsequent apoptosis. These findings indicate that TREM1 can be a useful target for elimination of the HIV reservoir in macrophages. IMPORTANCE The major challenge to human immunodeficiency virus (HIV) treatment is the development of strategies that lead to viral eradication. A roadblock to accomplishing this goal is the lack of an approach that would safely eliminate HIV from all resting/latent reservoirs, including macrophages. Macrophages are a key part of the innate immune system and are responsible for recognizing invading microbes and sending appropriate signals to other immune cells. Here, we found that HIV induces the upregulation of the protein TREM1 (triggering receptor expressed on myeloid cells 1), which signals an increase in the expression of antiapoptotic proteins, thus promoting survival of HIV-infected macrophages.

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Inhibition of Antiapoptotic BCL-XL, BCL-2, and MCL-1 Proteins by Small Molecule Mimetics

Cancer Informatics ◽

10.4137/cin.s5065 ◽

2010 ◽

Vol 9 ◽

pp. CIN.S5065 ◽

Cited By ~ 6

Author(s):

D.S. Dalafave ◽

G. Prisco

Keyword(s):

Small Molecules ◽

Cancer Cells ◽

Molecular Design ◽

Poor Response ◽

Computational Design ◽

Antiapoptotic Proteins ◽

Drug Candidates ◽

Preclinical Trials ◽

Computer Based ◽

Stress Signals

Informatics and computational design methods were used to create new molecules that could potentially bind antiapoptotic proteins, thus promoting death of cancer cells. Apoptosis is a cellular process that leads to the death of damaged cells. Its malfunction can cause cancer and poor response to conventional chemotherapy. After being activated by cellular stress signals, proapoptotic proteins bind antiapoptotic proteins, thus allowing apoptosis to go forward. An excess of antiapoptotic proteins can prevent apoptosis. Designed molecules that mimic the roles of proapoptotic proteins can promote the death of cancer cells. The goal of our study was to create new putative mimetics that could simultaneously bind several antiapoptotic proteins. Five new small molecules were designed that formed stable complexes with BCL-2, BCL-XL, and MCL-1 antiapoptotic proteins. These results are novel because, to our knowledge, there are not many, if any, small molecules known to bind all three proteins. Drug-likeness studies performed on the designed molecules, as well as previous experimental and preclinical studies on similar agents, strongly suggest that the designed molecules may indeed be promising drug candidates. All five molecules showed “drug-like” properties and had overall drug-likeness scores between 81% and 96%. A single drug based on these mimetics should cost less and cause fewer side effects than a combination of drugs each aimed at a single protein. Computer-based molecular design promises to accelerate drug research by predicting potential effectiveness of designed molecules prior to laborious experiments and costly preclinical trials.

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Mannheimia haemolytica Leukotoxin Induces Apoptosis of Bovine Lymphoblastoid Cells (BL-3) via a Caspase-9-Dependent Mitochondrial Pathway

Infection and Immunity ◽

10.1128/iai.73.9.5504-5513.2005 ◽

2005 ◽

Vol 73 (9) ◽

pp. 5504-5513 ◽

Cited By ~ 32

Author(s):

Dhammika N. Atapattu ◽

Charles J. Czuprynski

Keyword(s):

Mitochondrial Membrane ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Mitochondrial Pathway ◽

Mannheimia Haemolytica ◽

Scanning Electron Micrographs ◽

Caspase 9 ◽

Lymphoblastoid Cells ◽

Antiapoptotic Proteins ◽

Important Virulence Factor

ABSTRACT Mannheimia haemolytica is a key pathogen in the bovine respiratory disease complex. It produces a leukotoxin (LKT) that is an important virulence factor, causing cell death in bovine leukocytes. The LKT binds to the β2 integrin CD11a/CD18, which usually activates signaling pathways that facilitate cell survival. In this study, we investigated mechanisms by which LKT induces death in bovine lymphoblastoid cells (BL-3). Incubation of BL-3 cells with a low concentration of LKT results in the activation of caspase-3 and caspase-9 but not caspase-8. Similarly, the proapoptotic proteins Bax and BAD were significantly elevated, while the antiapoptotic proteins Bcl-2, BclXL and Akt-1 were downregulated. Following exposure to LKT, we also observed a reduction in mitochondrial cytochrome c and corresponding elevation of cytosolic cytochrome c, suggesting translocation from the mitochondrial compartment to the cytosol. Consistent with this observation, tetramethylrhodamine ethyl ester perchlorate staining revealed that mitochondrial membrane potential was significantly reduced. These data suggest that LKT induces apoptosis of BL-3 cells via a caspase-9-dependent mitochondrial pathway. Furthermore, scanning electron micrographs of mitochondria from LKT-treated BL-3 cells revealed lesions in the outer mitochondrial membrane, which are larger than previous reports of the permeability transition pore through which cytochrome c is usually released.

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