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Anticancer Research Jun 2024Coumarins are a broad class of naturally occurring oxygen-heterocyclic compounds found in plants with diverse biological properties, making them attractive for...
BACKGROUND/AIM
Coumarins are a broad class of naturally occurring oxygen-heterocyclic compounds found in plants with diverse biological properties, making them attractive for evaluation as novel therapeutic agents. We herein report the in vitro cytotoxic and monoamine oxidase (MAO) inhibitory activities of 3-acetylcoumarins ().
MATERIALS AND METHODS
The cytotoxic activity was evaluated using crystal violet dye binding assay, and those compounds unable to induce cytotoxicity were further tested for the monoamine oxidase (MAO) activity using the MAO-GloTM kit.
RESULTS
The 3-acetylcoumarins () were non-cytotoxic (inactive) against MDA MB-231 (estrogen receptor-negative, ER-, highly invasive) and MCF-7 (estrogen receptor-positive, ER+, weakly invasive) breast cancer cell lines, but showed interesting MAOs inhibition activities. Among the synthesized compounds, 3-acetylcoumarin bearing dichloro (-diCl) (; IC=0.31±0.04 μM) at Carbon-7, 8 positions showed higher inhibition, MAO B/A non-selectivity (selectivity index, SI=3.10), reversible inhibition against the hMAO-B enzyme, and neuroprotection against HO-treated human neuroblastoma (N2a) cells.
CONCLUSION
Compound () can be considered a promising scaffold for further investigation in developing hMAO-B inhibitors (MAOIs).
Topics: Humans; Monoamine Oxidase; Coumarins; Monoamine Oxidase Inhibitors; Cell Line, Tumor; MCF-7 Cells; Breast Neoplasms
PubMed: 38821578
DOI: 10.21873/anticanres.17040 -
International Journal of Biological... Jun 2024Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug...
Neurodegenerative diseases with progressive cellular loss of the central nervous system and elusive disease etiology provide a continuous impetus to explore drug discovery programmes aiming at identifying robust and effective inhibitors of cholinesterase and monoamine oxidase enzymes. We herein present a concise library of anthranilamide derivatives involving a palladium-catalyzed Suzuki-Miyaura cross-coupling reaction to install the diverse structural diversity required for the desired biological action. Using Ellman's method, cholinesterase inhibitory activity was performed against AChE and BuChE enzymes. In vitro assay results demonstrated that anthranilamides are potent inhibitors with remarkable potency. Compound 6k emerged as the lead candidate and dual inhibitor of both enzymes with IC values of 0.12 ± 0.01 and 0.49 ± 0.02 μM against AChE and BuChE, respectively. Several other compounds were found as highly potent and selective inhibitors. Anthranilamide derivatives were also tested against monoamine oxidase (A and B) enzymes using fluorometric method. In vitro data revealed compound 6h as the most potent inhibitor against MAO-A, showing an IC value of 0.44 ± 0.02 μM, whereas, compound 6k emerged as the top inhibitor of MAO-B with an IC value of 0.06 ± 0.01 μM. All the lead inhibitors were analyzed for the identification of their mechanism of action using Michaelis-Menten kinetics experiments. Compound 6k and 6h depicted a competitive mode of action against AChE and MAO-A, whereas, a non-competitive and mixed-type of inhibition was observed against BuChE and MAO-B by compounds 6k. Molecular docking analysis revealed remarkable binding affinities of the potent inhibitors with specific residues inside the active site of receptors. Furthermore, molecular dynamics simulations were performed to explore the ability of potent compounds to form energetically stable complexes with the target protein. Finally, in silico ADME calculations also demonstrated that the potent compounds exhibit promising pharmacokinetic profile, satisfying the essential criteria for drug-likeness. Altogether, the findings reported in the current work clearly suggest that the identified anthranilamide derivatives have the potential to serve as effective drug candidates for future investigations.
Topics: Cholinesterase Inhibitors; ortho-Aminobenzoates; Monoamine Oxidase; Molecular Docking Simulation; Humans; Monoamine Oxidase Inhibitors; Drug Design; Neurodegenerative Diseases; Structure-Activity Relationship; Drug Discovery; Cholinesterases; Molecular Dynamics Simulation
PubMed: 38821306
DOI: 10.1016/j.ijbiomac.2024.132748 -
European Journal of Medicinal Chemistry Aug 2024A structure-based drug design approach was focused on incorporating phenyl ring heterocyclic bioisosteres into coumarin derivative 1, previously reported as potent dual...
A structure-based drug design approach was focused on incorporating phenyl ring heterocyclic bioisosteres into coumarin derivative 1, previously reported as potent dual AChE-MAO B inhibitor, with the aim of improving drug-like features. Structure-activity relationships highlighted that bioisosteric rings were tolerated by hMAO B enzymatic cleft more than hAChE. Interestingly, linker homologation at the basic nitrogen enabled selectivity to switch from hAChE to hBChE. In the present work, we identified thiophene-based isosteres 7 and 15 as dual AChE-MAO B (IC = 261 and 15 nM, respectively) and BChE-MAO B (IC = 375 and 20 nM, respectively) inhibitors, respectively. Both 7 and 15 were moderately water-soluble and membrane-permeant agents by passive diffusion (PAMPA-HDM). Moreover, they were able to counteract oxidative damage induced by both HO and 6-OHDA in SH-SY5Y cells and predicted to penetrate into CNS in a cell-based model mimicking blood-brain barrier. Molecular dynamics (MD) simulations shed light on key differences in AChE and BChE recognition processes promoted by the basic chain homologation from 7 to 15.
Topics: Cholinesterase Inhibitors; Humans; Acetylcholinesterase; Structure-Activity Relationship; Drug Design; Butyrylcholinesterase; Molecular Structure; Dose-Response Relationship, Drug; Molecular Dynamics Simulation; Coumarins; Cell Line, Tumor
PubMed: 38820854
DOI: 10.1016/j.ejmech.2024.116511 -
Molecular Neurobiology May 2024Inflammation is an important pathogenic driving force in the genesis and development of epilepsy. The latest researches demonstrated that IL-17A mediated blood-brain...
Inflammation is an important pathogenic driving force in the genesis and development of epilepsy. The latest researches demonstrated that IL-17A mediated blood-brain barrier (BBB) dysfunction through disruption of tight junction protein expression. To investigate whether IL-17A is involved in BBB disruption after acute seizure attack, the pilocarpine model was established with C57BL/6 J (wild type, WT) and IL-17R-deficient mice in vivo and with primary cultured rat brain microvascular endothelial cells in vitro. The mortality rate and brain water content were evaluated at 24 h after status epilepticus, and IL-17A concentration, endothelial tight junction, adherens junction proteins, and albumin leakage were assessed at 0 h, 4 h, 12 h, and 24 h after status epilepticus (SE). IL-17R-deficient mice showed lessen severity of epilepsy than WT mice, accompanied by less albumin leakage, reduced brain water content, decreased IL-17A, and upregulated expression of target proteins (ZO-1, Occludin and VE-cadherin). IL-17R knockout abrogated abnormal upregulation of Src kinase and phosphorylated Src kinase in the setting of SE, and Src kinase inhibitor PP1 abrogated IL-17A-induced SE related endothelial injury in vitro. In conclusion, IL-17A inhibition might be a promising therapeutic option to attenuate endothelial cell injury and further BBB disruption by reducing Src kinase activation.
PubMed: 38819634
DOI: 10.1007/s12035-024-04203-7 -
Recent Patents on Biotechnology 2024Since the COVID-19 outbreak in early 2020, researchers and studies are continuing to find drugs and/or vaccines against the disease. As shown before, medicinal plants...
The Inhibitory Effects of the Herbals Secondary Metabolites (7α-acetoxyroyleanone, Curzerene, Incensole, Harmaline, and Cannabidiol) on COVID-19: A Molecular Docking Study.
BACKGROUND
Since the COVID-19 outbreak in early 2020, researchers and studies are continuing to find drugs and/or vaccines against the disease. As shown before, medicinal plants can be very good sources against viruses because of their secondary compounds which may cure diseases and help in survival of patients. There is a growing trend in the filed patents in this field.
AIMS
In the present study, we test and suggest the inhibitory potential of five herbal based extracts including 7α-acetoxyroyleanone, Curzerene, Incensole, Harmaline, and Cannabidiol with antivirus activity on the models of the significant antiviral targets for COVID-19 like spike glycoprotein, Papain-like protease (PLpro), non-structural protein 15 (NSP15), RNA-dependent RNA polymerase and core protease by molecular docking study.
METHODS
The root was extracted, dried, and pulverized by a milling machine. The aqueous phase and the dichloromethane phase of the root extractive were separated by two-phase extraction using a separatory funnel. The separation was performed using the column chromatography method. The model of the important antivirus drug target of COVID-19 was obtained from the Protein Data Bank (PDB) and modified. TO study the binding difference between the studied molecules, the docking study was performed.
RESULTS
These herbal compounds are extracted from , and , respectively. The binding energies of all compounds on COVID-19 main targets are located in the limited area of 2.22-5.30 kcal/mol. This range of binding energies can support our hypothesis for the presence of the inhibitory effects of the secondary metabolites of mentioned structures on COVID-19. Generally, among the investigated herbal structures, Cannabidiol and 7α- acetoxyroyleanone compounds with the highest binding energy have the most inhibitory potential. The least inhibitory effects are related to the Curzerene and Incensole structures by the lowest binding affinity.
CONCLUSION
The general arrangement of the basis of the potential barrier of binding energies is in the order below: Cannabidiol > 7α-acetoxyroyleanone > Harmaline> Incensole > Curzerene. Finally, the range of docking scores for investigated herbal compounds on the mentioned targets indicates that the probably inhibitory effects on these targets obey the following order: main protease> RNA-dependent RNA polymerase> PLpro> NSP15> spike glycoprotein.
Topics: Molecular Docking Simulation; Antiviral Agents; Cannabidiol; SARS-CoV-2; Humans; COVID-19 Drug Treatment; Plant Extracts; Harmaline; COVID-19; Viral Nonstructural Proteins; Spike Glycoprotein, Coronavirus; Patents as Topic; Secondary Metabolism
PubMed: 38817009
DOI: 10.2174/0118722083246773231108045238 -
Journal of Nanobiotechnology May 2024Intervertebral disc degeneration (IVDD) is the primary factor contributing to low back pain (LBP). Unlike elderly patients, many young IVDD patients usually have a...
Intervertebral disc degeneration (IVDD) is the primary factor contributing to low back pain (LBP). Unlike elderly patients, many young IVDD patients usually have a history of trauma or long-term abnormal stress, which may lead to local inflammatory reaction causing by immune cells, and ultimately accelerates degeneration. Research has shown the significance of M1-type macrophages in IVDD; nevertheless, the precise mechanism and the route by which it influences the function of nucleus pulposus cell (NPC) remain unknown. Utilizing a rat acupuncture IVDD model and an NPC degeneration model induced by lipopolysaccharide (LPS), we investigated the function of M1 macrophage-derived exosomes (M1-Exos) in IVDD both in vivo and in vitro in this study. We found that M1-Exos enhanced LPS-induced NPC senescence, increased the number of SA-β-gal-positive cells, blocked the cell cycle, and promoted the activation of P21 and P53. M1-Exos derived from supernatant pretreated with the exosome inhibitor GW4869 reversed this result in vivo and in vitro. RNA-seq showed that Lipocalin2 (LCN2) was enriched in M1-Exos and targeted the NF-κB pathway. The quantity of SA-β-gal-positive cells was significantly reduced with the inhibition of LCN2, and the expression of P21 and P53 in NPCs was decreased. The same results were obtained in the acupuncture-induced IVDD model. In addition, inhibition of LCN2 promotes the expression of type II collagen (Col-2) and inhibits the expression of matrix metalloproteinase 13 (MMP13), thereby restoring the equilibrium of metabolism inside the extracellular matrix (ECM) in vitro and in vivo. In addition, the NF-κB pathway is crucial for regulating M1-Exo-mediated NPC senescence. After the addition of M1-Exos to LPS-treated NPCs, p-p65 activity was significantly activated, while si-LCN2 treatment significantly inhibited p-p65 activity. Therefore, this paper demonstrates that M1 macrophage-derived exosomes have the ability to deliver LCN2, which activates the NF-κB signaling pathway, and exacerbates IVDD by accelerating NPC senescence. This may shed new light on the mechanism of IVDD and bring a fresh approach to IVDD therapy.
Topics: Animals; Exosomes; Nucleus Pulposus; Intervertebral Disc Degeneration; Lipocalin-2; Rats; NF-kappa B; Signal Transduction; Cellular Senescence; Macrophages; Male; Rats, Sprague-Dawley; Lipopolysaccharides; Disease Models, Animal
PubMed: 38816771
DOI: 10.1186/s12951-024-02556-8 -
European Journal of Pharmacology May 2024Corneal neovascularization (CoNV) is predominantly initiated by inflammatory processes, resulting in aberrant vascular proliferation and consequent visual impairment....
Corneal neovascularization (CoNV) is predominantly initiated by inflammatory processes, resulting in aberrant vascular proliferation and consequent visual impairment. Existing therapeutic interventions for CoNV demonstrate limited efficacy and potential for adverse reactions. Protein arginine methyltransferase 1 (PRMT1) is associated with the regulation of inflammation and M2 macrophage polarization. Nevertheless, the precise mechanism by which PRMT1 operates in CoNV remains uncertain. This study explored the impact of PRMT1 inhibition in a murine model of CoNV induced by alkali burn. Our findings indicated a direct relationship between PRMT1 levels and corneal damage. Moreover, our observations indicated an increase in fibroblast growth factor 2 (FGF2) expression in CoNV, which was reduced after treatment with a PRMT1 inhibitor. The inhibition of PRMT1 alleviated both corneal injury and CoNV, as evidenced by decreased corneal opacity and neovascularization. Immunofluorescence analysis and evaluation of inflammatory factor expression demonstrated that PRMT1 inhibition attenuated M2 macrophage polarization, a phenomenon that was reversed by the administration of recombinant FGF2 protein. These results were confirmed through experimentation on Human Umbilical Vein Endothelial Cells (HUVECs) and Mouse leukemia cells of monocyte macrophage cells (RAW264.7). Furthermore, it was established that FGF2 played a role in PI3K/Akt signal transduction, a critical regulatory pathway for M2 macrophage polarization. Importantly, the activity of this pathway was found to be suppressed by PRMT1 inhibitors. Mechanistically, PRMT1 was shown to promote M2 macrophage polarization, thereby contributing to CoNV, through the FGF2/PI3K/Akt pathway. Therefore, targeting PRMT1 may offer a promising therapeutic approach.
PubMed: 38815785
DOI: 10.1016/j.ejphar.2024.176673 -
Chemical Research in Toxicology Jun 2024Multiple myeloma is a hematological cancer that can be treated but remains incurable. With the advancement of science and technology, more drugs have been developed for...
Multiple myeloma is a hematological cancer that can be treated but remains incurable. With the advancement of science and technology, more drugs have been developed for myeloma chemotherapy that greatly improve the quality of life of patients. However, relapse remains a serious problem puzzling patients and doctors. Thus, developing more highly active and specific inhibitors is urgent for myeloma-targeted therapy. In this study, we identified the SIRT3 inhibitor 3-TYP (3-(1-1,2,3-triazol-4-yl) pyridine) after screening a histone modification compound library, which showed high cytotoxicity and induced DNA damage in myeloma cells. Furthermore, the inhibitory effect of 3-TYP in our xenograft tumor studies also confirmed that compound 3-TYP could inhibit primary myeloma growth by reducing c-Myc protein stability by decreasing c-Myc Ser62 phosphorylation levels. Taken together, the results of our study identified 3-TYP as a novel c-Myc inhibitor, which could be a potential chemotherapeutic agent to target multiple myeloma.
Topics: Multiple Myeloma; Humans; Proto-Oncogene Proteins c-myc; Sirtuin 3; Animals; Antineoplastic Agents; Cell Proliferation; Mice; Pyridines; Triazoles; Cell Line, Tumor; Molecular Structure; Drug Screening Assays, Antitumor; Protein Stability; Mice, Nude
PubMed: 38815162
DOI: 10.1021/acs.chemrestox.4c00142 -
Biomedicine & Pharmacotherapy =... Jul 2024Multitargeting has become a promising strategy for the development of anti-Alzheimer's disease (AD) drugs, considering the complexity of molecular mechanisms in AD...
Multitargeting has become a promising strategy for the development of anti-Alzheimer's disease (AD) drugs, considering the complexity of molecular mechanisms in AD pathology. In most pre-clinical studies, the effectiveness of these multi-targeted anti-AD drugs has been demonstrated but comprehensive safety assessments are lacking. Here, the safety evaluation of a novel multi-targeted candidate in AD (XYY-CP1106), characterized by its dual-property of iron chelation and monoamine oxidase B inhibition, was conducted by multifaceted analysis. Acute toxicity in mice was conducted to investigate the safety of oral administration and the maximum tolerated dose of the agent. In vitro Ames analysis, CHL chromosomal aberration analysis, and bone marrow micronucleus analysis were executed to evaluate the genotoxicity. A teratogenesis investigation in pregnant mice were meticulously performed to evaluate the teratogenesis of XYY-CP1106. Furthermore, a 90-day long-term toxicity analysis in rats was investigated to evaluate the cumulative toxicity after long-term administration. Strikingly, no toxic phenomena were found in all investigations, demonstrating relatively high safety profile of the candidate compound. The securing of safety heightened the translational significance of XYY-CP1106 as a novel multi-targeted anti-AD candidate, supporting the rationality of multitargeting strategy in the designs of smart anti-AD drugs.
Topics: Animals; Alzheimer Disease; Female; Mice; Male; Pregnancy; Rats; Rats, Sprague-Dawley; Mice, Inbred ICR; Maximum Tolerated Dose; Monoamine Oxidase Inhibitors; Chromosome Aberrations; Teratogenesis
PubMed: 38805971
DOI: 10.1016/j.biopha.2024.116786 -
Journal of Nanobiotechnology May 2024Stroke is a devastating disease affecting populations worldwide and is the primary cause of long-term disability. The inflammatory storm plays a crucial role in the...
BACKGROUND
Stroke is a devastating disease affecting populations worldwide and is the primary cause of long-term disability. The inflammatory storm plays a crucial role in the progression of stroke. In the acute phase of ischemic stroke, there is a transient increase in anti-inflammatory M2 microglia followed by a rapid decline. Due to the abundant phospholipid in brain tissue, lipid peroxidation is a notable characteristic of ischemia/reperfusion (I/R), constituting a structural foundation for ferroptosis in M2 microglia. Slowing down the decrease in M2 microglia numbers and controlling the inflammatory microenvironment holds significant potential for enhancing stroke recovery.
RESULTS
We found that the ferroptosis inhibitor can modulate inflammatory response in MCAO mice, characterizing that the level of M2 microglia-related cytokines was increased. We then confirmed that different subtypes of microglia exhibit distinct sensitivities to I/R-induced ferroptosis. Adipose-derived stem cells derived exosome (ADSC-Exo) effectively decreased the susceptibility of M2 microglia to ferroptosis via Fxr2/Atf3/Slc7a11, suppressing the inflammatory microenvironment and promoting neuronal survival. Furthermore, through plasmid engineering, a more efficient M2 microglia-targeted exosome, termed M2pep-ADSC-Exo, was developed. In vivo and in vitro experiments demonstrated that M2pep-ADSC-Exo exhibits significant targeting specificity for M2 microglia, further inhibiting M2 microglia ferroptosis and improving neurological function in ischemic stroke mice.
CONCLUSION
Collectively, we illustrated a novel potential therapeutic mechanism that Fxr2 in ADSC-Exo could alleviate the M2 microglia ferroptosis via regulating Atf3/Slc7all expression, hence inhibiting the inflammatory microenvironment, improving neurofunction recovery in cerebral I/R injury. We obtained a novel exosome, M2pep-ADSC-Exo, through engineered modification, which exhibits improved targeting capabilities toward M2 microglia. This provides a new avenue for the treatment of stroke.
Topics: Animals; Exosomes; Microglia; Mice; Ischemic Stroke; Ferroptosis; Male; Mice, Inbred C57BL; Amino Acid Transport System y+; Disease Models, Animal; Cytokines; Brain Ischemia
PubMed: 38802919
DOI: 10.1186/s12951-024-02560-y