Pharmaceutics. 2022 Mar 4;14(3):567. doi: 10.3390/pharmaceutics14030567.

ABSTRACT

BACKGROUND: With the Coronavirus becoming a new reality of our world, global efforts continue to seek answers to many questions regarding the spread, variants, vaccinations, and medications. Particularly, with the emergence of several strains (e.g., Delta, Omicron), vaccines will need further development to offer complete protection against the new variants. It is critical to identify antiviral treatments while the development of vaccines continues. In this regard, the repurposing of already FDA-approved drugs remains a major effort. In this paper, we investigate the hypothesis that a combination of FDA-approved drugs may be considered as a candidate for COVID-19 treatment if (1) there exists an evidence in the COVID-19 biomedical literature that suggests such a combination, and (2) there is match in the clinical trials space that validates this drug combination.

METHODS: We present a computational framework that is designed for detecting drug combinations, using the following components (a) a Text-mining module: to extract drug names from the abstract section of the biomedical publications and the intervention/treatment sections of clinical trial records. (b) a network model constructed from the drug names and their associations, (c) a clique similarity algorithm to identify candidate drug treatments.

RESULT AND CONCLUSIONS: Our framework has identified treatments in the form of two, three, or four drug combinations (e.g., hydroxychloroquine, doxycycline, and azithromycin). The identifications of the various treatment candidates provided sufficient evidence that supports the trustworthiness of our hypothesis.

PMID:35335943 | DOI:10.3390/pharmaceutics14030567

Pharmaceutics. 2022 Mar 1;14(3):552. doi: 10.3390/pharmaceutics14030552.

ABSTRACT

Multidrug-resistant (MDR) Gram-negative bacteria are the top-priority pathogens to be eradicated. Drug repurposing (e.g., the use of non-antibiotics to treat bacterial infections) may be helpful to overcome the limitations of current antibiotics. Zidovudine (azidothymidine, AZT), a licensed oral antiviral agent, is a leading repurposed drug against MDR Gram-negative bacterial infections. However, the rapid emergence of bacterial resistance due to long-term exposure, overuse, or misuse limits its application, making it necessary to develop new alternatives. In this study, we investigated the efficacy of ciclopirox (CPX) as an alternative to AZT. The minimum inhibitory concentrations of AZT and CPX against MDR Gram-negative bacteria were determined; CPX appeared more active against β-lactamase-producing Escherichia coli, whereas AZT displayed no selectivity for any antibiotic-resistant strain. Motility assays revealed that β-lactamase-producing Escherichia coli strains were less motile in nature and more strongly affected by CPX than a parental strain. Resistance against CPX was not observed in E. coli even after 25 days of growth, whereas AZT resistance was observed in less than 2 days. Moreover, CPX effectively killed AZT-resistant strains with different resistance mechanisms. Our findings indicate that CPX may be utilized as an alternative or supplement to AZT-based medications to treat opportunistic Gram-negative bacterial infections.

PMID:35335928 | DOI:10.3390/pharmaceutics14030552

Birth Defects Res. 2022 Mar 25. doi: 10.1002/bdr2.2004. Online ahead of print.

ABSTRACT

The study of human brain development and neurodevelopmental defects has remained challenging so far due to unique, specific, and complex underlying processes. Recent advances in the technologies and protocols of in vitro human brain organoid development have led to immense possibilities of understanding these processes. Human brain organoids are stem-cell derived three-dimensional in vitro tissues that resemble the developing fetal brain. Major advances in stem cell techniques pioneering the development of in vitro human brain development include reprogramming human somatic cells into induced pluripotent cells (iPSCs) followed by the targeted differentiation of iPSCs into the cells of three embryonic germ cell layers. The neural progenitor cells produced by the directed differentiation of iPSCs undergo some level of self-organization to generate in vitro human brain like tissue. A three-dimensional differentiation approach applied to create region-specific brain organoids has successfully led to develop highly specialized cortical, forebrain, pallium, and subpallium in vitro human brain organoid models. These stem cell-based brain organoids are novel models to study human brain development, neurodevelopmental defects, chemical toxicity testing, and drug repurposing screening. This review focuses on the fundamentals of brain organoid development and applications. The novel applications of using cortical organoids in understanding the mechanisms of Zika virus-induced microcephaly, congenital microcephaly, and lissencephaly are also discussed.

PMID:35332709 | DOI:10.1002/bdr2.2004

Cold Spring Harb Mol Case Stud. 2022 Mar 24;8(2):a006200. doi: 10.1101/mcs.a006200. Print 2022 Feb.

ABSTRACT

Rare neurogenetic disorders are collectively common, affecting 3% of the population, and often manifest with complex multiorgan comorbidity. With advances in genetic, -omics, and computational analysis, more children can be diagnosed and at an earlier age. Innovations in translational research facilitate the identification of treatment targets and development of disease-modifying drugs such as gene therapy, nutraceuticals, and drug repurposing. This increasingly allows targeted therapy to prevent the often devastating manifestations of rare neurogenetic disorders. In this perspective, successes in diagnosis, prevention, and treatment are discussed with a focus on inherited disorders of metabolism. Barriers for the identification, development, and implementation of rare disease-specific therapies are discussed. New methodologies, care networks, and collaborative frameworks are proposed to optimize the potential of personalized genomic medicine to decrease morbidity and improve lives of these vulnerable patients.

PMID:35332073 | DOI:10.1101/mcs.a006200

Int J Mol Sci. 2022 Mar 18;23(6):3283. doi: 10.3390/ijms23063283.

ABSTRACT

BACKGROUND: Local anesthetics (LAs) have potent anti-inflammatory properties. Inflammatory down-regulation is crucial in diseases with overactive immune reactions, such as acute respiratory distress syndrome (ARDS) and chronic inflammation. We investigated the influence of four LAs, procaine, lidocaine, mepivacaine, and bupivacaine, on the reduction of tumor necrosis factor-alpha (TNF-α) secretion in lipopolysaccharide (LPS)-activated human leucocytes.

METHODS: Blood samples of 28 individuals were stimulated with LPS. The reduction of TNF-α production by each of the four LAs added (0.5 mg/mL) was measured and correlated with biometric variables. A response was defined as reduction to <85% of initial levels.

RESULTS: All four LAs down-regulated the TNF-α secretion in 44-61%: Bupivacaine (44.4%), lidocaine (61.5%), mepivacaine (44.4%), and procaine (50% of the individuals, "responders"). The TNF-α secretion was reduced to 67.4, 68.0, 63.6, and 67.1% of the initial values in responders. The effects in both patients and healthy persons were the same. Interindividual responses to LAs were not correlated with the duration or type of complaints, basal TNF-α serum level, sex, BMI, or age of responders.

CONCLUSIONS: Four clinically relevant LAs (amid-LA and ester-LA) attenuate the inflammatory response provoked by LPS. They are potential candidates for drug repositioning in treating overactive immune reactions and chronic inflammation.

PMID:35328706 | DOI:10.3390/ijms23063283

Genes (Basel). 2022 Mar 8;13(3):473. doi: 10.3390/genes13030473.

ABSTRACT

Skeletal muscle atrophy is a common condition in aging, diabetes, and in long duration spaceflights due to microgravity. This article investigates multi-modal gene disease and disease drug networks via link prediction algorithms to select drugs for repurposing to treat skeletal muscle atrophy. Key target genes that cause muscle atrophy in the left and right extensor digitorum longus muscle tissue, gastrocnemius, quadriceps, and the left and right soleus muscles are detected using graph theoretic network analysis, by mining the transcriptomic datasets collected from mice flown in spaceflight made available by GeneLab. We identified the top muscle atrophy gene regulators by the Pearson correlation and Bayesian Markov blanket method. The gene disease knowledge graph was constructed using the scalable precision medicine knowledge engine. We computed node embeddings, random walk measures from the networks. Graph convolutional networks, graph neural networks, random forest, and gradient boosting methods were trained using the embeddings, network features for predicting links and ranking top gene-disease associations for skeletal muscle atrophy. Drugs were selected and a disease drug knowledge graph was constructed. Link prediction methods were applied to the disease drug networks to identify top ranked drugs for therapeutic treatment of skeletal muscle atrophy. The graph convolution network performs best in link prediction based on receiver operating characteristic curves and prediction accuracies. The key genes involved in skeletal muscle atrophy are associated with metabolic and neurodegenerative diseases. The drugs selected for repurposing using the graph convolution network method were nutrients, corticosteroids, anti-inflammatory medications, and others related to insulin.

PMID:35328027 | DOI:10.3390/genes13030473

Biomedicines. 2022 Mar 10;10(3):641. doi: 10.3390/biomedicines10030641.

ABSTRACT

Genus Flavivirus contains several important human pathogens. Among these, the Zika virus is an emerging etiological agent that merits concern. One of its structural proteins, prM, plays an essential role in viral maturation and assembly, making it an attractive drug and vaccine development target. Herein, we have characterized ZikV-M as a potential viroporin candidate using three different bacteria-based assays. These assays were subsequently employed to screen a library of repurposed drugs from which ten compounds were identified as ZikV-M blockers. Mutational analyses of conserved amino acids in the transmembrane domain of other flaviviruses, including West Nile and Dengue virus, were performed to study their role in ion channel activity. In conclusion, our data show that ZikV-M is a potential ion channel that can be used as a drug target for high throughput screening and drug repurposing.

PMID:35327443 | DOI:10.3390/biomedicines10030641

Biomedicines. 2022 Mar 10;10(3):638. doi: 10.3390/biomedicines10030638.

ABSTRACT

KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year of age) represents an aggressive type of childhood leukemia characterized by a poor clinical outcome with a survival chance of <50%. Implementing novel therapeutic approaches for these patients is a slow-paced and costly process. Here, we utilized a drug-repurposing strategy to identify potent drugs that could expeditiously be translated into clinical applications. We performed high-throughput screens of various drug libraries, comprising 4191 different (mostly FDA-approved) compounds in primary KMT2A-rearranged infant ALL patient samples (n = 2). The most effective drugs were then tested on non-leukemic whole bone marrow samples (n = 2) to select drugs with a favorable therapeutic index for bone marrow toxicity. The identified agents frequently belonged to several recurrent drug classes, including BCL-2, histone deacetylase, topoisomerase, microtubule, and MDM2/p53 inhibitors, as well as cardiac glycosides and corticosteroids. The in vitro efficacy of these drug classes was successfully validated in additional primary KMT2A-rearranged infant ALL samples (n = 7) and KMT2A-rearranged ALL cell line models (n = 5). Based on literature studies, most of the identified drugs remarkably appeared to lead to activation of p53 signaling. In line with this notion, subsequent experiments showed that forced expression of wild-type p53 in KMT2A-rearranged ALL cells rapidly led to apoptosis induction. We conclude that KMT2A-rearranged infant ALL cells are vulnerable to p53 activation, and that drug-induced p53 activation may represent an essential condition for successful treatment results. Moreover, the present study provides an attractive collection of approved drugs that are highly effective against KMT2A-rearranged infant ALL cells while showing far less toxicity towards non-leukemic bone marrow, urging further (pre)clinical testing.

PMID:35327440 | DOI:10.3390/biomedicines10030638

Antibiotics (Basel). 2022 Feb 22;11(3):291. doi: 10.3390/antibiotics11030291.

ABSTRACT

Alternative strategies against multidrug-resistant (MDR) bacterial infections are suggested to clinicians, such as drug repurposing, which uses rapidly available and marketed drugs. We gathered a collection of MDR bacteria from our hospital and performed a phenotypic high-throughput screening with a 1280 FDA-approved drug library. We used two Gram positive (Enterococcus faecium P5014 and Staphylococcus aureus P1943) and six Gram negative (Acinetobacter baumannii P1887, Klebsiella pneumoniae P9495, Pseudomonas aeruginosa P6540, Burkholderia multivorans P6539, Pandoraea nosoerga P8103, and Escherichia coli DSM105182 as the reference and control strain). The selected MDR strain panel carried resistance genes or displayed phenotypic resistance to last-line therapies such as carbapenems, vancomycin, or colistin. A total of 107 compounds from nine therapeutic classes inhibited >90% of the growth of the selected Gram negative and Gram positive bacteria at a drug concentration set at 10 µmol/L, and 7.5% were anticancer drugs. The common hit was the antiseptic chlorhexidine. The activity of niclosamide, carmofur, and auranofin was found against the selected methicillin-resistant S. aureus. Zidovudine was effective against colistin-resistant E. coli and carbapenem-resistant K. pneumoniae. Trifluridine, an antiviral, was effective against E. faecium. Deferoxamine mesylate inhibited the growth of XDR P. nosoerga. Drug repurposing by an in vitro screening of a drug library is a promising approach to identify effective drugs for specific bacteria.

PMID:35326755 | DOI:10.3390/antibiotics11030291

Cancers (Basel). 2022 Mar 19;14(6):1573. doi: 10.3390/cancers14061573.

ABSTRACT

Hepatocellular carcinoma (HCC) is a malignant liver cancer that continues to increase deaths worldwide owing to limited therapies and treatments. Computational drug repurposing is a promising strategy to discover potential indications of existing drugs. In this study, we present a systematic drug repositioning method based on comprehensive integration of molecular signatures in liver cancer tissue and cell lines. First, we identify robust prognostic genes and two gene co-expression modules enriched in unfavorable prognostic genes based on two independent HCC cohorts, which showed great consistency in functional and network topology. Then, we screen 10 genes as potential target genes for HCC on the bias of network topology analysis in these two modules. Further, we perform a drug repositioning method by integrating the shRNA and drug perturbation of liver cancer cell lines and identifying potential drugs for every target gene. Finally, we evaluate the effects of the candidate drugs through an in vitro model and observe that two identified drugs inhibited the protein levels of their corresponding target genes and cell migration, also showing great binding affinity in protein docking analysis. Our study demonstrates the usefulness and efficiency of network-based drug repositioning approach to discover potential drugs for cancer treatment and precision medicine approach.

PMID:35326724 | DOI:10.3390/cancers14061573

Cancers (Basel). 2022 Mar 8;14(6):1374. doi: 10.3390/cancers14061374.

ABSTRACT

Resistance to chemotherapeutics and high metastatic rates contribute to the abysmal survival rate in patients with pancreatic cancer. An alternate approach for treating human pancreatic cancer involves repurposing the anti-inflammatory drug, aspirin (ASA), with oseltamivir phosphate (OP) in combination with the standard chemotherapeutic agent, gemcitabine (GEM). The question is whether treatment with ASA and OP can sensitize cancer cells to the cytotoxicity induced by GEM and limit the development of chemoresistance. To assess the key survival pathways critical for pancreatic cancer progression, we used the AlamarBlue cytotoxicity assay to determine the cell viability and combination index for the drug combinations, flow cytometric analysis of annexin V apoptosis assay to detect apoptotic and necrotic cells, fluorometric QCM™ chemotaxis migration assay to assess cellular migration, fluorometric extracellular matrix (ECM) cell adhesion array kit to assess the expression of the ECM proteins, scratch wound assay using the 96-well WoundMaker™, and the methylcellulose clonogenic assay to assess clonogenic potential. The combination of ASA and OP with GEM significantly upended MiaPaCa-2 and PANC-1 pancreatic cancer cell viability, clonogenic potential, expression of critical extracellular matrix proteins, migration, and promoted apoptosis. ASA in combination with OP significantly improves the effectiveness of GEM in the treatment of pancreatic cancer and disables key survival pathways critical to disease progression.

PMID:35326525 | DOI:10.3390/cancers14061374

Drug Des Devel Ther. 2022 Mar 15;16:685-715. doi: 10.2147/DDDT.S354841. eCollection 2022.

ABSTRACT

The rising outbreak of SARS-CoV-2 continues to unfold all over the world. The development of novel effective antiviral drugs to fight against SARS-CoV-2 is a time cost. As a result, some specific FDA-approved drugs have already been repurposed and authorized for COVID-19 treatment. The repurposed drugs used were either antiviral or non-antiviral drugs. Accordingly, the present review thoroughly focuses on the repurposing efficacy of these drugs including clinical trials experienced, the combination therapies used, the novel methods followed for treatment, and their future perspective. Therefore, drug repurposing was regarded as an effective avenue for COVID-19 treatment. Recently, molnupiravir is a prodrug antiviral medication that was approved in the United Kingdom in November 2021 for the treatment of COVID-19. On the other hand, PF-07321332 is an oral antiviral drug developed by Pfizer. For the treatment of COVID-19, the PF-07321332/ritonavir combination medication is used in Phase III studies and was marketed as Paxlovid. Herein, we represented the almost history of combating COVID-19 from repurposing to the recently available oral anti-SARS-CoV-2 candidates, as a new hope to end the current pandemic.

PMID:35321497 | PMC:PMC8935998 | DOI:10.2147/DDDT.S354841

Front Oncol. 2022 Mar 7;12:791365. doi: 10.3389/fonc.2022.791365. eCollection 2022.

ABSTRACT

BK002 consists of Achyranthes japonica Nakai (AJN) and Melandrium firmum Rohrbach (MFR) that have been used as herbal medicines in China and Korea. AJN and MFR have been reported to have anti-inflammatory, anti-oxidative, and anti-cancer activities, although the synergistic targeting multiple anti-cancer mechanism in castration-resistant prostate cancer (CRPC) has not been well reported. However, the drug resistance and transition to the androgen-independent state of prostate cancer contributing to CRPC is not well studied. Here, we reported that BK002 exerted cytotoxicity and apoptosis in CRPC PC3 cell lines and prostate cancer DU145 cell lines examined by cytotoxicity, western blot, a LIVE/DEAD cell imaging assay, reactive oxygen species (ROS) detection, quantitative real-time polymerase chain reaction (RT-PCR), and transfection assays. The results from our investigation found that BK002 showed more cellular cytotoxicity than AJN and MFR alone, suggesting that BK002 exhibited potential cytotoxic properties. Consistently, BK002 increased DNA damage, and activated p-γH2A.X and depletion of survivin-activated ubiquitination of pro-PARP, caspase9, and caspase3. Notably, live cell imaging using confocal microscopy found that BK002 effectively increased DNA-binding red fluorescent intensity in PC3 and DU145 cells. Also, BK002 increased the anti-proliferative effect with activation of the C/EBP homologous protein (CHOP) and significantly attenuated PI3K/AKT expression. Notably, BK002-treated cells increased ROS generation and co-treatment of N-Acetyl-L-cysteine (NAC), an ROS inhibitor, significantly preventing ROS production and cellular cytotoxicity, suggesting that ROS production is essential for initiating apoptosis in PC3 and DU145 cells. In addition, we found that BK002 significantly enhanced miR-192-5p expression, and co-treatment with BK002 and miR-192-5p inhibitor significantly reduced miR-192-5p expression and cellular viability in PC3 and DU145 cells, indicating modulation of miR-192-5p mediated apoptosis. Finally, we found that BK002-mediated CHOP upregulation and PI3K downregulation were significantly reduced and restrained by miR-192-5p inhibitor respectively, suggesting that the anti-cancer effect of BK002 is associated with the miR-192-5p/PI3K/CHOP pathway. Therefore, our study reveals that a combination of AJN and MFR might be more effective than single treatment against apoptotic activities of both CRPC cells and prostate cancer cells.

PMID:35321434 | PMC:PMC8936126 | DOI:10.3389/fonc.2022.791365

Mem Inst Oswaldo Cruz. 2022 Mar 23;117:e210403. doi: 10.1590/0074-02760220403. eCollection 2022.

ABSTRACT

Despite the increasing number of manuscripts describing potential alternative antileishmanial compounds, little is advancing on translating these knowledges to new products to treat leishmaniasis. This is in part due to the lack of standardisations during pre-clinical drug discovery stage and also depends on the alignment of goals among universities/research centers, government and pharmaceutical industry. Inspired or not by drug repurposing, metal-based antileishmanial drugs represent a class that deserves more attention on its use for leishmaniasis chemotherapy. Together with new chemical entities, progresses have been made on the knowledge of parasite-specific drug targets specially after using CRISPR/Cas system for functional studies. In this regard, Leishmania parasites undergoe post-translational modification as key regulators in several cellular processes, which represents an entire new field for drug target elucidation, once this is poorly explored. This perspective review describes the advances on antileishmanial metallodrugs and the elucidation of drug targets based on post-translational modifications, highlighting the limitations on the drug discovery/development process and suggesting standardisations focused on products addressed to who need it most.

PMID:35320824 | DOI:10.1590/0074-02760220403

Indian J Gastroenterol. 2022 Mar 22. doi: 10.1007/s12664-021-01230-3. Online ahead of print.

ABSTRACT

Despite the growing disease burden of non-alcoholic fatty liver disease (NAFLD), approved medical treatments to improve or prevent liver fibrosis are effective only in a small number of patients. Recent studies have found the new use of antiplatelet agents for antifibrotic benefits in NAFLD, but human studies are still limited. The goal of this meta-analysis was to combine the findings of existing relevant studies to investigate the effects of antiplatelet therapy in reducing or preventing advanced liver fibrosis in patients with NAFLD. We conducted a systematic literature search in PubMed, EMBASE, and Web of Science databases from inception to January 2021 to identify all original studies that investigated the use of antiplatelet agents in patients with NAFLD. We used the National Institutes of Health's quality assessment tool for observational cohort and cross-sectional studies to assess study quality and risk of bias. The primary outcome was the prevalence of advanced liver fibrosis stage 3-4. Data from each study was combined using the random-effects, generic inverse variance method of DerSimonian and Laird to calculate pooled odds ratio (OR) and 95% confidence intervals (CIs). Of the 2,498 studies identified, 4 studies involving 2,593 patients with NAFLD were included in this study (949 antiplatelet agent users and 1,644 non-antiplatelet agent users). The use of aspirin and/or P2Y12 receptor inhibitors was associated with a lower pooled OR of advanced liver fibrosis in patients with NAFLD (pooled OR = 0.66; 95% CI: 0.53-0.81, I2 = 0.0%; p < 0.001). This study focuses on the outcome of advanced liver fibrosis in patients with NAFLD. Our study is limited by the small number of studies that were included. Preliminary evidence from this meta-analysis suggests a protective association between antiplatelet therapy and the prevalence of advanced liver fibrosis in patients with NAFLD. Our findings support future research into repositioning an antiplatelet agent as a novel NAFLD treatment.

PMID:35318571 | DOI:10.1007/s12664-021-01230-3

Clin Proteomics. 2022 Mar 22;19(1):7. doi: 10.1186/s12014-022-09345-1.

ABSTRACT

BACKGROUND: Rheumatic heart disease (RHD) remains a major source of morbidity and mortality in developing countries. A deeper insight into the pathogenetic mechanisms underlying RHD could provide opportunities for drug repurposing, guide recommendations for secondary penicillin prophylaxis, and/or inform development of near-patient diagnostics.

METHODS: We performed quantitative proteomics using Sequential Windowed Acquisition of All Theoretical Fragment Ion Mass Spectrometry (SWATH-MS) to screen protein expression in 215 African patients with severe RHD, and 230 controls. We applied a machine learning (ML) approach to feature selection among the 366 proteins quantifiable in at least 40% of samples, using the Boruta wrapper algorithm. The case-control differences and contribution to Area Under the Receiver Operating Curve (AUC) for each of the 56 proteins identified by the Boruta algorithm were calculated by Logistic Regression adjusted for age, sex and BMI. Biological pathways and functions enriched for proteins were identified using ClueGo pathway analyses.

RESULTS: Adiponectin, complement component C7 and fibulin-1, a component of heart valve matrix, were significantly higher in cases when compared with controls. Ficolin-3, a protein with calcium-independent lectin activity that activates the complement pathway, was lower in cases than controls. The top six biomarkers from the Boruta analyses conferred an AUC of 0.90 indicating excellent discriminatory capacity between RHD cases and controls.

CONCLUSIONS: These results support the presence of an ongoing inflammatory response in RHD, at a time when severe valve disease has developed, and distant from previous episodes of acute rheumatic fever. This biomarker signature could have potential utility in recognizing different degrees of ongoing inflammation in RHD patients, which may, in turn, be related to prognostic severity.

PMID:35317720 | DOI:10.1186/s12014-022-09345-1

Drug Dev Res. 2022 Mar 21. doi: 10.1002/ddr.21935. Online ahead of print.

ABSTRACT

In recent years, the drug repositioning strategy has gained considerable attention in the drug discovery process that involves establishing new therapeutic uses of already known drugs. In line with this, we have identified digoxin a cardiac glycoside, as a potent inhibitor of soluble epoxide hydrolase (sEH) enzyme employing in silico high throughput screening protocols and further confirmed using in vitro cell-free sEH inhibitory assay and in vivo preclinical studies in rodents for its repurposing in hyperalgesia, inflammation, and related disorders. Oral administration of digoxin at dose 0.2 mg/kg significantly reduced (p < .0001) the allodynia in mice induced by using hot plate (3.6 ± 1.9) and tail-flick test (7.58 ± 0.9). In addition, digoxin at a dose of 0.2 mg/kg showed marked reduction (94%, p < .0001) in acetic acid-induced abdominal contraction in rats. Further, digoxin also demonstrated antipyretic activity (37.04 ± 0.2, p < .0001) and showed notable reduction (0.60 ± 0.06) in carrageenan-induced paw edema in rats. Also, the histopathological evaluation revealed that digoxin treatment attenuated the edema, neutrophil infiltration, and alveolar septal thickening in lung tissue. These findings are novel and highlight the newer insights towards repurposing digoxin as a new lead in the treatment of hyperalgesia, inflammation, and related disorders.

PMID:35315525 | DOI:10.1002/ddr.21935

Pharm Res. 2022 Mar 21. doi: 10.1007/s11095-022-03231-z. Online ahead of print.

ABSTRACT

PURPOSE: Dysregulations of key signaling pathways in metabolic syndrome are multifactorial, eventually leading to cardiovascular events. Hyperglycemia in conjunction with dyslipidemia induces insulin resistance and provokes release of proinflammatory cytokines resulting in chronic inflammation, accelerated lipid peroxidation with further development of atherosclerotic alterations and diabetes. We have proposed a novel combinatorial approach using FDA approved compounds targeting IL-17a and DPP4 to ameliorate a significant portion of the clustered clinical risks in patients with metabolic syndrome. In our current research we have modeled the outcomes of metabolic syndrome treatment using two distinct drug classes.

METHODS: Targets were chosen based on the clustered clinical risks in metabolic syndrome: dyslipidemia, insulin resistance, impaired glucose control, and chronic inflammation. Drug development platform, BIOiSIM™, was used to narrow down two different drug classes with distinct modes of action and modalities. Pharmacokinetic and pharmacodynamic profiles of the most promising drugs were modeling showing predicted outcomes of combinatorial therapeutic interventions.

RESULTS: Preliminary studies demonstrated that the most promising drugs belong to DPP-4 inhibitors and IL-17A inhibitors. Evogliptin was chosen to be a candidate for regulating glucose control with long term collateral benefit of weight loss and improved lipid profiles. Secukinumab, an IL-17A sequestering agent used in treating psoriasis, was selected as a repurposed candidate to address the sequential inflammatory disorders that follow the first metabolic insult.

CONCLUSIONS: Our analysis suggests this novel combinatorial therapeutic approach inducing DPP4 and Il-17a suppression has a high likelihood of ameliorating a significant portion of the clustered clinical risk in metabolic syndrome.

PMID:35313359 | DOI:10.1007/s11095-022-03231-z

Expert Rev Mol Med. 2022 Mar 15;24:e13. doi: 10.1017/erm.2022.10.

ABSTRACT

Coronavirus disease 2019 (COVID-19) is associated with autoimmunity and systemic inflammation. Patients with autoimmune rheumatic and musculoskeletal disease (RMD) may be at high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this review, based on evidence from the literature, as well as international scientific recommendations, we review the relationships between COVID-19, autoimmunity and patients with autoimmune RMDs, as well as the basics of a multisystemic inflammatory syndrome associated with COVID-19. We discuss the repurposing of pharmaceutics used to treat RMDs, the principles for the treatment of patients with autoimmune RMDs during the pandemic and the main aspects of vaccination against SARS-CoV-2 in autoimmune RMD patients.

PMID:35311631 | DOI:10.1017/erm.2022.10

ACS Omega. 2022 Mar 2;7(10):9015-9023. doi: 10.1021/acsomega.2c00182. eCollection 2022 Mar 15.

ABSTRACT

Neurodegenerative complexities, such as dementia, Alzheimer's disease (AD), and so forth, have been a crucial health concern for ages. Transferrin (Tf) is a chief target to explore in AD management. Fluoxetine (FXT) presents itself as a potent anti-AD drug-like compound and has been explored against several diseases based on the drug repurposing readings. The present study delineates the binding of FXT to Tf employing structure-based docking, molecular dynamics (MD) simulations, and principal component analysis (PCA). Docking results showed the binding of FXT with Tf with an appreciable binding affinity, making various close interactions. MD simulation of FXT with Tf for 100 ns suggested their stable binding without any significant structural alteration. Furthermore, fluorescence-based binding revealed a significant interaction between FXT and Tf. FXT binds to Tf with a binding constant of 5.5 × 105 M-1. Isothermal titration calorimetry (ITC) advocated the binding of FXT to Tf as spontaneous in nature, affirming earlier observations. This work indicated plausible interactions between FXT and Tf, which are worth considering for further studies in the clinical management of neurological disorders, including AD.

PMID:35309456 | PMC:PMC8928501 | DOI:10.1021/acsomega.2c00182