Life Sci. 2022 Mar 11:120482. doi: 10.1016/j.lfs.2022.120482. Online ahead of print.

ABSTRACT

Identifying signaling pathways and molecules involved in SARS-CoV-2 pathogenesis is pivotal for developing new effective therapeutic or preventive strategies for COVID-19. Pannexins (PANX) are ATP-release channels in the plasma membrane essential in many physiological and immune responses. Activation of pannexin channels and downstream purinergic receptors play dual roles in viral infection, either by facilitating viral replication and infection or inducing host antiviral defense. The current review provides a hypothesis demonstrating the possible contribution of the PANX1 channel and purinergic receptors in SARS-CoV-2 pathogenesis and mechanism of action. Moreover, we discuss whether targeting these signaling pathways may provide promising preventative therapies and treatments for patients with progressive COVID-19 resulting from excessive pro-inflammatory cytokines and chemokines production. Several inhibitors of this pathway have been developed for the treatment of other viral infections and pathological consequences. Specific PANX1 inhibitors could be potentially included as part of the COVID-19 treatment regimen if, in future, studies demonstrate the role of PANX1 in COVID-19 pathogenesis. Of note, any ATP therapeutic modulation for COVID-19 should be carefully designed and monitored because of the complex role of extracellular ATP in cellular physiology.

PMID:35288174 | DOI:10.1016/j.lfs.2022.120482

Biomed Pharmacother. 2022 Mar 11;149:112803. doi: 10.1016/j.biopha.2022.112803. Online ahead of print.

ABSTRACT

Minocycline is a semi-synthetic tetracycline derivative antibiotic that has been examined for its non-antibiotic properties, such as anti-inflammatory, tumor-suppressive, and neuroprotective effects. In this study, we found that feeding minocycline to Drosophila improves proteostasis during organismal aging. Poly-ubiquitinated protein aggregates increase in the flight muscles as flies age, which are reduced in response to minocycline feeding. Minocycline feeding increases the expression of several autophagy genes and the activity of the autophagy/lysosomal pathway in Drosophila muscles. Interestingly, mutant flies lacking either FOXO or Hsp70 showed increased levels of poly-ubiquitinated protein aggregates with reduced autophagy/lysosomal activity, which was not reversed by minocycline feeding. Our findings suggest that minocycline may improve proteostasis in aging tissues via FOXO-Hsp70 axis, which highlights the multifaceted effects of minocycline as a therapeutic agent in age-associated features.

PMID:35286967 | DOI:10.1016/j.biopha.2022.112803

J Biomol Struct Dyn. 2022 Mar 14:1-14. doi: 10.1080/07391102.2022.2050948. Online ahead of print.

ABSTRACT

Inflammatory bowel disease is a chronic disorder of the large intestine with the prevalence of approximately 400 cases in 100000, and it is rising day by day. However, several drugs like sulfasalazine (composed of sulfapyridine and 5-aminosalicylic acid or 5-ASA), corticosteroids, and immunosuppressants manage the disease. But there are no absolute treatments for the pain and inflammation of the disease. TNFα is an important target, and drugs like infliximab and adalimumab have pharmacological potency but with pronounced toxicity. So, we choose this major target TNFα for the virtual screening of US-FDA-approved drugs for its repurposing using the in silico method. The protein TNFα (PDB ID: 2AZ5) with small molecule inhibitor and the US-FDA-approved drug molecules (from Zinc database) were first imported and prepared using Protein Preparation Wizard and LigPrep, respectively, followed by molecular docking, ADMET analysis and prime MMGBSA. After that, the drugs were shortlisted according to dock score, ADMET parameters and MM GBSA dG binding score. After that, the shortlisted drug molecules were subjected to an induced-fit docking analysis. Two of the most promising molecules, ZINC000003830957 (Iopromide) and ZINC000003830635 (Deferoxamine), were chosen for molecular dynamics simulation. Finally, the bioisosteric replacement was used to improve the ADMET properties of these molecules. This research provides an idea for drug exploration and computational tools for drug discovery in treating inflammatory bowel disease.Communicated by Ramaswamy H. Sarma.

PMID:35285757 | DOI:10.1080/07391102.2022.2050948

Biochem Soc Trans. 2022 Mar 14:BST20200967. doi: 10.1042/BST20200967. Online ahead of print.

ABSTRACT

Over the last decade, for the first time, substantial efforts have been directed at the development of dedicated in silico platforms for drug repurposing, including initiatives targeting cancers and conditions as diverse as cryptosporidiosis, dengue, dental caries, diabetes, herpes, lupus, malaria, tuberculosis and Covid-19 related respiratory disease. This review outlines some of the exciting advances in the specific applications of in silico approaches to the challenge of drug repurposing and focuses particularly on where these efforts have resulted in the development of generic platform technologies of broad value to researchers involved in programmatic drug repurposing work. Recent advances in molecular docking methodologies and validation approaches, and their combination with machine learning or deep learning approaches are continually enhancing the precision of repurposing efforts. The meaningful integration of better understanding of molecular mechanisms with molecular pathway data and knowledge of disease networks is widening the scope for discovery of repurposing opportunities. The power of Artificial Intelligence is being gainfully exploited to advance progress in an integrated science that extends from the sub-atomic to the whole system level. There are many promising emerging developments but there are remaining challenges to be overcome in the successful integration of the new advances in useful platforms. In conclusion, the essential component requirements for development of powerful and well optimised drug repurposing screening platforms are discussed.

PMID:35285479 | DOI:10.1042/BST20200967

Front Microbiol. 2022 Feb 25;13:844615. doi: 10.3389/fmicb.2022.844615. eCollection 2022.

ABSTRACT

[This corrects the article DOI: 10.3389/fmicb.2019.00041.].

PMID:35283839 | PMC:PMC8916107 | DOI:10.3389/fmicb.2022.844615

Curr Genomics. 2021 Dec 30;22(5):328-338. doi: 10.2174/1389202922666210920125800.

ABSTRACT

The drug discovery process has been a crucial and cost-intensive process. This cost is not only monetary but also involves risks, time, and labour that are incurred while introducing a drug in the market. In order to reduce this cost and the risks associated with the drugs that may result in severe side effects, the in silico methods have gained popularity in recent years. These methods have had a significant impact on not only drug discovery but also the related areas such as drug repositioning, drug-target interaction prediction, drug side effect prediction, personalised medicine, etc. Amongst these research areas predicting interactions between drugs and targets forms the basis for drug discovery. The availability of big data in the form of bioinformatics, genetic databases, along with computational methods, have further supported data-driven decision-making. The results obtained through these methods may be further validated using in vitro or in vivo experiments. This validation step can further justify the predictions resulting from in silico approaches, further increasing the accuracy of the overall result in subsequent stages. A variety of approaches are used in predicting drug-target interactions, including ligand-based, molecular docking based and chemogenomic-based approaches. This paper discusses the chemogenomic methods, considering drug target interaction as a classification problem on whether or not an interaction between a particular drug and target would serve as a basis for understanding drug discovery/drug repositioning. We present the advantages and disadvantages associated with their application.

PMID:35283667 | PMC:PMC8844939 | DOI:10.2174/1389202922666210920125800

Front Pharmacol. 2022 Feb 25;13:840639. doi: 10.3389/fphar.2022.840639. eCollection 2022.

ABSTRACT

Since the first reports from December 2019, COVID-19 caused an overwhelming global pandemic that has affected 223 countries, seriously endangering public health and creating an urgent need for effective drugs to treat SARS-CoV-2 infection. Currently, there is a lack of safe, effective, and specific therapeutic drugs for COVID-19, with mainly supportive and symptomatic treatments being administered to patients. The preferred option for responding to an outbreak of acute infectious disease is through drug repurposing, saving valuable time that would otherwise be lost in preclinical and clinical research, hastening clinical introduction, and lowering treatment costs. Alternatively, researchers seek to design and discover novel small-molecule candidate drugs targeting the key proteins in the life cycle of SARS-CoV-2 through an in-depth study of the infection mechanism, thus obtaining a number of candidate compounds with favorable antiviral effects in preclinical and clinical settings. There is an urgent need to further elucidate the efficacy and mechanism of action of potential anti-SARS-CoV-2 small-molecule drugs. Herein, we review the candidate small-molecule anti-SARS-CoV-2 drugs in ongoing clinical trials, with a major focus on their mechanisms of action in an attempt to provide useful insight for further research and development of small-molecule compounds against SARS-CoV-2 infection.

PMID:35281901 | PMC:PMC8916227 | DOI:10.3389/fphar.2022.840639

Biochem Biophys Res Commun. 2022 Mar 6;603:75-81. doi: 10.1016/j.bbrc.2022.03.026. Online ahead of print.

ABSTRACT

Though various therapeutic strategies have been developed to overcome gastric cancer, the overall prognosis and therapeutic effect are still not optimistic. As a novel identified type of cell death, ferroptosis has been considered as a promising tumor suppression mechanism with therapeutic potential against gastric cancer. In this work, we screened a collection of 4890 bioactivity compounds and committed to find novel agents that can induce apoptosis in gastric cancer. Among these compounds, 6-TG was identified as a potential ferroptosis inducer in gastric cancer cells for the first time. It could inactivate system xc-, block the generation of GSH, down-regulate the expression of GPX4, increase the level of lipid ROS, and finally trigger the Fe2+-mediated ferroptosis in MGC-803 and AGS cell lines. The date in vivo also suggested that compound 6-TG performed anti-tumor activity via inducing ferroptosis. These findings gave a support for 6-TG may play as a novel leading compound for gastric cancer treatment as a ferroptosis inducer.

PMID:35278883 | DOI:10.1016/j.bbrc.2022.03.026

Mol Oncol. 2022 Mar 12. doi: 10.1002/1878-0261.13209. Online ahead of print.

ABSTRACT

Metabolic dysregulation is an important hallmark of cancer. Nicotinamide (NAM), a water-soluble amide form of niacin (vitamin B3), is currently available as a supplement for maintaining general physiologic functions. NAM is a crucial regulator of mitochondrial metabolism and redox reactions. In this study, we aimed to identify the mechanistic link between NAM-induced metabolic regulation and the therapeutic efficacy of NAM in triple-negative breast cancer (TNBC). The combined analysis using multi-omics systems biology showed that NAM decreased mitochondrial membrane potential and ATP production but increased the activities of reverse electron transport (RET), fatty acid β-oxidation, and glycerophospholipid/sphingolipid metabolic pathways in TNBC, collectively leading to an increase in the levels of reactive oxygen species (ROS). The increased ROS levels triggered apoptosis and suppressed tumor growth and metastasis of TNBC in both human organoids and xenograft mouse models. Our results showed that NAM treatment leads to cancer cell death in TNBC via mitochondrial dysfunction and activation of ROS by bifurcating metabolic pathways (RET and lipid metabolism); this provides insights into the repositioning of NAM supplement as a next-generation anti-metabolic agent for TNBC treatment.

PMID:35278276 | DOI:10.1002/1878-0261.13209

Sci Rep. 2022 Mar 11;12(1):4279. doi: 10.1038/s41598-022-08073-8.

ABSTRACT

The pandemic threat of COVID-19 has severely destroyed human life as well as the economy around the world. Although, the vaccination has reduced the outspread, but people are still suffering due to the unstable RNA sequence patterns of SARS-CoV-2 which demands supplementary drugs. To explore novel drug target proteins, in this study, a transcriptomics RNA-Seq data generated from SARS-CoV-2 infection and control samples were analyzed. We identified 109 differentially expressed genes (DEGs) that were utilized to identify 10 hub-genes/proteins (TLR2, USP53, GUCY1A2, SNRPD2, NEDD9, IGF2, CXCL2, KLF6, PAG1 and ZFP36) by the protein-protein interaction (PPI) network analysis. The GO functional and KEGG pathway enrichment analyses of hub-DEGs revealed some important functions and signaling pathways that are significantly associated with SARS-CoV-2 infections. The interaction network analysis identified 5 TFs proteins and 6 miRNAs as the key regulators of hub-DEGs. Considering 10 hub-proteins and 5 key TFs-proteins as drug target receptors, we performed their docking analysis with the SARS-CoV-2 3CL protease-guided top listed 90 FDA approved drugs. We found Torin-2, Rapamycin, Radotinib, Ivermectin, Thiostrepton, Tacrolimus and Daclatasvir as the top ranked seven candidate drugs. We investigated their resistance performance against the already published COVID-19 causing top-ranked 11 independent and 8 protonated receptor proteins by molecular docking analysis and found their strong binding affinities, which indicates that the proposed drugs are effective against the state-of-the-arts alternatives independent receptor proteins also. Finally, we investigated the stability of top three drugs (Torin-2, Rapamycin and Radotinib) by using 100 ns MD-based MM-PBSA simulations with the two top-ranked proposed receptors (TLR2, USP53) and independent receptors (IRF7, STAT1), and observed their stable performance. Therefore, the proposed drugs might play a vital role for the treatment against different variants of SARS-CoV-2 infections.

PMID:35277538 | DOI:10.1038/s41598-022-08073-8

J Med Chem. 2022 Mar 11. doi: 10.1021/acs.jmedchem.1c01372. Online ahead of print.

ABSTRACT

Identification of anti-SARS-CoV-2 compounds through traditional high-throughput screening (HTS) assays is limited by high costs and low hit rates. To address these challenges, we developed machine learning models to identify compounds acting via inhibition of the entry of SARS-CoV-2 into human host cells or the SARS-CoV-2 3-chymotrypsin-like (3CL) protease. The optimal classification models achieved good performance with area under the receiver operating characteristic curve (AUC-ROC) values of >0.78. Experimental validation showed that the best performing models increased the assay hit rate by 2.1-fold for viral entry inhibitors and 10.4-fold for 3CL protease inhibitors compared to those of the original drug repurposing screens. Twenty-two compounds showed potent (<5 μM) antiviral activities in a SARS-CoV-2 live virus assay. In conclusion, machine learning models can be developed and used as a complementary approach to HTS to expand compound screening capacities and improve the speed and efficiency of anti-SARS-CoV-2 drug discovery.

PMID:35275639 | DOI:10.1021/acs.jmedchem.1c01372

Trends Mol Med. 2022 Mar 7:S1471-4914(22)00050-8. doi: 10.1016/j.molmed.2022.02.009. Online ahead of print.

ABSTRACT

Mutations that activate growth factor signaling often drive cancer growth. Many also arise in isolation, causing developmental growth disorders. PIK3CA, that encodes a catalytic subunit of phosphatidylinositol 3-kinase (PI3K), is a cardinal example of this paradigm. Recent exciting progress towards the key goal of cancer drug repurposing for PIK3CA-driven overgrowth is discussed.

PMID:35272946 | DOI:10.1016/j.molmed.2022.02.009

Int J Mol Sci. 2022 Feb 27;23(5):2631. doi: 10.3390/ijms23052631.

ABSTRACT

Hepatitis A virus (HAV) is a causative agent of acute hepatitis and can occasionally induce acute liver failure. However, specific potent anti-HAV drug is not available on the market currently. Thus, we investigated several novel therapeutic drugs through a drug repositioning approach, targeting ribonucleic acid (RNA)-dependent RNA polymerase and RNA-dependent deoxyribonucleic acid polymerase. In the present study, we examined the anti-HAV activity of 18 drugs by measuring the HAV subgenomic replicon and HAV HA11-1299 genotype IIIA replication in human hepatoma cell lines, using a reporter assay and real-time reverse transcription polymerase chain reaction, respectively. Mutagenesis of the HAV 5' untranslated region was also examined by next-generation sequencing. These specific parameters were explored because lethal mutagenesis has emerged as a novel potential therapeutic approach to treat RNA virus infections. Favipiravir inhibited HAV replication in both Huh7 and PLC/PRF/5 cells, although ribavirin inhibited HAV replication in only Huh7 cells. Next-generation sequencing demonstrated that favipiravir could introduce nucleotide mutations into the HAV genome more than ribavirin. In conclusion, favipiravir could introduce nucleotide mutations into the HAV genome and work as an antiviral against HAV infection. Provided that further in vivo experiments confirm its efficacy, favipiravir would be useful for the treatment of severe HAV infection.

PMID:35269774 | DOI:10.3390/ijms23052631

Int J Mol Sci. 2022 Feb 26;23(5):2587. doi: 10.3390/ijms23052587.

ABSTRACT

While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well established that neurotransmitters, namely serotonin and norepinephrine, are involved in the biochemical mechanisms of MDD, and consequently, drugs targeting serotonin-norepinephrine reuptake, such as duloxetine, are commonly prescribed for MDD. In this connection, serotonin and norepinephrine are also known to play critical roles in primary hemostasis. Based on these considerations, we investigated if duloxetine can be repurposed as an antiplatelet medication. Our results-using human and/or mouse platelets show that duloxetine dose-dependently inhibited agonist-induced platelet aggregation, compared to the vehicle control. Furthermore, it also blocked agonist-induced dense and α-granule secretion, integrin αIIbβ3 activation, phosphatidylserine expression, and clot retraction. Moreover duloxetine-treated mice had a significantly prolonged occlusion time. Finally, duloxetine was also found to impair hemostasis. Collectively, our data indicate that the antidepressant duloxetine, which is a serotonin-norepinephrine antagonist, exerts antiplatelet and thromboprotective effects and inhibits hemostasis. Consequently, duloxetine, or a rationally designed derivative, presents potential benefits in the context of CVD, including that associated with MDD.

PMID:35269729 | DOI:10.3390/ijms23052587

Int J Mol Sci. 2022 Feb 25;23(5):2557. doi: 10.3390/ijms23052557.

ABSTRACT

Precision medicine emphasizes fine-grained diagnostics, taking individual variability into account to enhance treatment effectiveness. Parkinson's disease (PD) heterogeneity among individuals proves the existence of disease subtypes, so subgrouping patients is vital for better understanding disease mechanisms and designing precise treatment. The purpose of this study was to identify PD subtypes using RNA-Seq data in a combined pipeline including unsupervised machine learning, bioinformatics, and network analysis. Two hundred and ten post mortem brain RNA-Seq samples from PD (n = 115) and normal controls (NCs, n = 95) were obtained with systematic data retrieval following PRISMA statements and a fully data-driven clustering pipeline was performed to identify PD subtypes. Bioinformatics and network analyses were performed to characterize the disease mechanisms of the identified PD subtypes and to identify target genes for drug repurposing. Two PD clusters were identified and 42 DEGs were found (p adjusted ≤ 0.01). PD clusters had significantly different gene network structures (p &lt; 0.0001) and phenotype-specific disease mechanisms, highlighting the differential involvement of the Wnt/β-catenin pathway regulating adult neurogenesis. NEUROD1 was identified as a key regulator of gene networks and ISX9 and PD98059 were identified as NEUROD1-interacting compounds with disease-modifying potential, reducing the effects of dopaminergic neurodegeneration. This hybrid data analysis approach could enable precision medicine applications by providing insights for the identification and characterization of pathological subtypes. This workflow has proven useful on PD brain RNA-Seq, but its application to other neurodegenerative diseases is encouraged.

PMID:35269707 | DOI:10.3390/ijms23052557

Int J Mol Sci. 2022 Feb 22;23(5):2400. doi: 10.3390/ijms23052400.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.

PMID:35269543 | DOI:10.3390/ijms23052400

Nanomaterials (Basel). 2022 Mar 3;12(5):856. doi: 10.3390/nano12050856.

ABSTRACT

As a result of their close similarities to the inorganic mineral components of human bone, hydroxyapatite nanoparticles (n-HAp) are widely used in biomedical applications and for the elaboration of biocompatible scaffold drug delivery systems for bone tissue engineering. In this context, a new efficient and economic procedure was used for the consolidation of n-HAp in the presence of various Nigella sativa (NS) fractions at a near-room temperature. The research conducted in the present study focuses on the physicochemical properties of loaded n-HAp 3D scaffolds by NS fractions and the in vitro antibacterial activity against Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Klebsiella pneumoniae ATCC 27853), and Gram-positive (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 700603) bacteria. In order to better understand the effect of the inserted fractions on the HAp molecular structure, the elaborated samples were subject to Fourier transform infrared (FTIR) and X-ray diffraction (XRD) spectroscopic analyses. In addition, the morphological investigation by scanning electron microscope (SEM) of the loaded n-HAp 3D scaffolds demonstrated the presence of a porous structure, which is generally required in stimulating bone regeneration. Furthermore, the fabricated 3D composites exhibited significant antibacterial activity against all tested bacteria. Indeed, MIC values ranging from 5 mg/mL to 20 mg/mL were found for the HAp-Ethanol fraction (HAp-Et) and HAp-Hexane fraction (HAp-Hex), while the HAp-Aqueous fraction (HAp-Aq) and HAp-Methanol fraction (HAp-Me) showed values between 20 mg/mL and 30 mg/mL on the different strains. These results suggest that the HAp-NS scaffolds were effective as a drug delivery system and have very promising applications in bone tissue engineering.

PMID:35269342 | DOI:10.3390/nano12050856

J Biomol Struct Dyn. 2022 Mar 10:1-11. doi: 10.1080/07391102.2022.2044907. Online ahead of print.

ABSTRACT

Before the rise of SARS-CoV-2, emergence of different coronaviruses such as SARS-CoV and MERS-CoV has been reported that indicates possibility of the future novel pathogen from the coronavirus family at a pandemic level. In this context, explicit studies on identifying inhibitors focused on the coronavirus life cycle, are immensely important. The main protease is critical for the life cycle of coronaviruses. Majority of the work done on the inhibitor studies on the catalytically active dimeric SARS-CoV-2 main protease (Mpro), primarily focussed on the catalytic site of a single protomer, with a few targeting the dimeric site. In this study, we have exploited the FDA-approved drugs, for a computational drug repurposing study against the Mpro. A virtual screening approach was employed with docking and molecular dynamics (MD) methods. Out of 1576, FDA-approved compounds, our study suggests three compounds: netupitant, paliperidone and vilazodone as possible inhibitors with a potential to inhibit both sites (monomeric and dimeric) of the Mpro. These compounds were found to be stable during the MD simulations and their post simulation binding energies were also correlated for both the targeted sites, suggesting equal binding capacity. This unique efficiency of the reported compounds might support further experimental studies on developing inhibitors against SARS-CoV-2 main protease.Communicated by Ramaswamy H. Sarma.

PMID:35266856 | DOI:10.1080/07391102.2022.2044907

Drug Dev Res. 2022 Mar 9. doi: 10.1002/ddr.21927. Online ahead of print.

ABSTRACT

Microtubules are dynamic cytoskeletal filaments composed of alpha- (α) and beta (β)-tubulin proteins. α-tubulin proteins are posttranslationally acetylated, and loss of acetylation is associated with axonal transport defects, a common alteration contributing to the pathomechanisms of several neurodegenerative diseases. Restoring α-tubulin acetylation by pharmacological inhibition of HDAC6, a primary α-tubulin deacetylase, can rescue impaired transport. Therefore, HDAC6 is considered a promising therapeutic target for neurodegenerative diseases, but currently, there is no clinically approved inhibitor for this purpose. In this study, using drug repurposing strategy, we aimed to identify compounds possessing HDAC6 inhibition activity and inducing α-tubulin acetylation. We systematically analyzed the FDA-approved library by utilizing virtual screening and consensus scoring approaches. Inhibition activities of promising compounds were tested using in vitro assays. Motor neuron-like NSC34 cells were treated with the candidate compounds, and α-tubulin acetylation levels were determined by Western blot. Our results demonstrated that rutin, a natural flavonoid, inhibits cellular HDAC6 activity without inducing any toxicity, and it significantly increases α-tubulin acetylation level in motor neuron-like cells.

PMID:35266183 | DOI:10.1002/ddr.21927

Inflammopharmacology. 2022 Mar 10. doi: 10.1007/s10787-022-00945-9. Online ahead of print.

ABSTRACT

Monoamine oxidase inhibitors (MAOI) are presently used to treat depression, parkinsonian, and other psychiatric disorders. The present study was aimed to repurpose the use of MOAI in Rheumatoid Arthritis (RA). The animal model of RA was developed using collagen type II (CII) in Freund's complete adjuvant (FCA) followed by lipopolysaccharide (LPS) and a booster dose of CII in FCA. The effect of MAOI, Selegiline was evaluated whereas the indicators like paw thickness, arthritic score, and the splenic index were measured and compared with the standard drug Methotrexate. Further to explore the molecular mechanism, the expression of serum inflammatory cytokines (IL-6 and TNF-α), radiographical and histopathological study of hind paw were also checked and analyzed. Treatment with MAOI, Selegiline not only reduced the paw thickness, arthritic score, and the splenic index, but also greatly improved the inflammatory biochemical and hematologic parameters and improved the arthritis score. The serum level of IL-6 and TNF-α are considerably decreased dose dependently, however, the notable significant effect (**p < 0.01) observed at concentration of 30 mg/kg b.w. when the RA animals treated by Selegiline. Collectively, Selegiline improved the progression of RA possibly via decreased catecholamine breakdown at synovial fluid resulting decrease hydrogen peroxide (H2O2) generation and inhibition of pro-inflammatory cytokines in situ. Thus, the finding support and indicate the repurposing of MAOI for the treatment of RA meriting further studies on synovial monoamine oxidase as a new therapeutic target to design a new drug for RA.

PMID:35266068 | DOI:10.1007/s10787-022-00945-9