J Biomol Struct Dyn. 2023 May 22:1-15. doi: 10.1080/07391102.2023.2214232. Online ahead of print.

ABSTRACT

The Small Multidrug Resistance efflux pump protein KpnE, plays a pivotal role in multi-drug resistance in Klebsiella pneumoniae. Despite well-documented study of its close homolog, EmrE, from Escherichia coli, the mechanism of drug binding to KpnE remains obscure due to the absence of a high-resolution experimental structure. Herein, we exclusively elucidate its structure-function mechanism and report some of the potent inhibitors through drug repurposing. We used molecular dynamics simulation to develop a dimeric structure of KpnE and explore its dynamics in lipid-mimetic bilayers. Our study identified both semi-open and open conformations of KpnE, highlighting its importance in transport process. Electrostatic surface potential map suggests a considerable degree of similarity between KpnE and EmrE at the binding cleft, mostly occupied by negatively charged residues. We identify key amino acids Glu14, Trp63 and Tyr44, indispensable for ligand recognition. Molecular docking and binding free energy calculations recognizes potential inhibitors like acarbose, rutin and labetalol. Further validations are needed to confirm the therapeutic role of these compounds. Altogether, our membrane dynamics study uncovers the crucial charged patches, lipid-binding sites and flexible loop that could potentiate substrate recognition, transport mechanism and pave the way for development of novel inhibitors against K. pneumoniae.Communicated by Ramaswamy H. Sarma.

PMID:37218086 | DOI:10.1080/07391102.2023.2214232

Mol Med. 2023 May 22;29(1):67. doi: 10.1186/s10020-023-00664-z.

ABSTRACT

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed.

METHODS: As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available Pkd2 kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates' target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis.

RESULTS: With this in-silico approach, we prioritized 29 unique drug targets differentially expressed in Pkd2 ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo.

CONCLUSION: Collectively, these results indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD.

PMID:37217845 | DOI:10.1186/s10020-023-00664-z

Drug Dev Ind Pharm. 2023 May 22:1-21. doi: 10.1080/03639045.2023.2216785. Online ahead of print.

ABSTRACT

OBJECTIVE: Present study aimed to identify a safe and effective non-oncology drug cocktail as an alternative to toxic chemotherapeutics for hepatocellular carcinoma treatment. The assessment of cytotoxicity of cocktail (as co-adjuvant) in combination with chemotherapeutic docetaxel (DTX) is also aimed. Further, we aimed to develop an oral solid self-emulsifying drug delivery system (S-SEDDS) for the simultaneous delivery of identified drugs.

SIGNIFICANCE: The identified non-oncology drug cocktail could overcome the shortage of anticancer therapeutics and help to reduce cancer-related mortality. Moreover, the developed S-SEDDS could be an ideal system for concurrent oral delivery of non-oncology drug combinations.

METHODS: The non-oncology drugs (alone and in combinations) were screened in vitro for anticancer effect (against HepG2 cells) using (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide; MTT) dye assay, and cell cycle arresting and apoptotic behaviors using the fluorescence-activated cell sorting (FACS) technique. The S-SEDDS is composed of drugs such as Ketoconazole (KCZ), Disulfiram (DSR), Tadalafil (TLF), and excipients like span-80, tween-80, soybean oil, Leciva S-95, Poloxamer F108 (PF-108), and Neusilin® US2 (adsorbent carrier) was developed and characterized.

RESULTS: The cocktail composed of KCZ, DSR, and TLF has showed substantial cytotoxicity (at the lowest concentration of 3.3 picomoles), HepG2 cell arrest at G0/G1 and S phases, and substantial cell death via apoptosis. The Docetaxel (DTX) inclusion into this cocktail has further resulted in increased cytotoxicity, cell arrest at the G2/M phase, and cell necrosis. The optimized blank liquid SEDDS that remains transparent without phase separation for more than 6 months is used for the preparation of drug-loaded liquid SEDDS (DL-SEDDS). The optimized DL-SEDDS with low viscosity, good dispersibility, considerable drug retention upon dilution, and smaller particle size is further converted into drug-loaded solid SEDDS (DS-SEDDS). The final DS-SEDDS demonstrated acceptable flowability and compression characteristics, significant drug retention (more than 93%), particle size in nano range (less than 500 nm) and nearly spherical morphology following dilutions. The DS-SEDDS showed substantially increased cytotoxicity and Caco-2 cell permeability than plain drugs. Furthermore, DS-SEDDS containing only non-oncology drugs caused lower in vivo toxicity (only 6% body weight loss) than DS-SEDDS containing non-oncology drugs with DTX (about 10% weight loss).

CONCLUSION: The current study revealed a non-oncology drug combination effective against hepatocellular carcinoma. Further, it is concluded that the developed S-SEDDS containing non-oncology drug combination alone and in combination with DTX could be a promising alternative to toxic chemotherapeutics for the effective oral treatment of hepatic cancer.

PMID:37216496 | DOI:10.1080/03639045.2023.2216785

Health Sci Rep. 2023 May 20;6(5):e1276. doi: 10.1002/hsr2.1276. eCollection 2023 May.

ABSTRACT

Amidst, the global pandemic of antimicrobial resistance (AMR), the rate at which AMR increases overwhelms the increased efforts to discover new effective antimicrobials. There is a persistent need for alternative treatment modalities so as to keep up with the pace. AMR is the leading cause of death in the world and its health and economic consequences suggest the urgent need for sustainable interventions. Vitamins have consistently proven to have antimicrobial activity as well as slowing down the AMR rate by influencing the AMR genes even towards extensive multidrug resistant strains. Evidences suggest that the use of some vitamins on their own or in combination with existing antimicrobial agents could be a breakthrough towards combating AMR. This will widen the antimicrobial agents' options in the treatment arena, preserve the antimicrobial agents susceptible to develop resistant so that they can be used in severe infections only, reduce the tension and burden of the AMR crisis significantly and give enough room for development of new antimicrobial agents. Moreover, almost all viral, fungal, parasitic and bacterial resistant strains of concern as listed by World Health Organization have been found to be sensitive to several vitamins either synergistically with other antimicrobials or independently. Considering their widened spectrum of immunomodulatory and antimicrobial effect, some vitamins can further be repositioned as prophylactic antimicrobial agents in clinical situations like in presurgeries prophylaxis so as to avoid unnecessary use of antimicrobials especially antibiotics. Various relevant AMR stakeholders should invest in clinical trials and systematic reviews with available data to enable quick repositioning of some potential vitamins as antimicrobial agents as an emergency rapid response towards AMR Crisis. This includes the preparation of guidelines containing specificity of which vitamin to be used for treatment of which type of infection.

PMID:37216052 | PMC:PMC10199457 | DOI:10.1002/hsr2.1276

IIC Int Rev Ind Prop Copyr Law. 2023;54(5):732-763. doi: 10.1007/s40319-023-01329-4. Epub 2023 May 4.

ABSTRACT

The benefits of access to clinical trial data are related to their inestimable value from the perspective of clinical trial participants, society as a whole, public health systems and scientific progress. In light of the development of innovative data analysis technologies, access to raw clinical trial data opens up an ever-widening array of possibilities: it can profoundly facilitate machine data analysis for, inter alia, hypothesis generation, risk modelling, counterfactual simulation and - finally - drug repurposing and development. The enactment of the new Clinical Trials Regulation (EU) No. 536/2014 (CTR) and introduction of the Clinical Trials Information System (CTIS) were heralded as ensuring a level of transparency in clinical trials that is sufficient to contribute to protecting public health and fostering the innovation capacity of European medical research, while recognizing the legitimate economic interests of sponsors. This paper presents the hitherto binding rules for the disclosure of clinical trial data and, against this background, their new framework, introduced by the CTR. In addition to assessing whether the CTR's objectives are fulfilled, this paper examines whether the latest changes impact the hitherto existing rules on protection of regulatory data via regulatory exclusivities. Finally, it points out concerns regarding whether data gathered in the CTIS can be efficiently used by innovative data analysis technologies for further processing for both commercial and non-commercial purposes.

PMID:37215361 | PMC:PMC10158712 | DOI:10.1007/s40319-023-01329-4

World J Gastroenterol. 2023 May 7;29(17):2571-2599. doi: 10.3748/wjg.v29.i17.2571.

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.

PMID:37213397 | PMC:PMC10198058 | DOI:10.3748/wjg.v29.i17.2571

Future Microbiol. 2023 May 22. doi: 10.2217/fmb-2022-0232. Online ahead of print.

ABSTRACT

Aim: To evaluate the antibacterial activity of paroxetine alone and associated with oxacillin against isolates of methicillin-sensitive and -resistant Staphylococcus aureus. Materials & methods: The broth microdilution and checkerboard techniques were used, with investigation of possible mechanisms of action through flow cytometry, fluorescence microscopy and molecular docking, in addition to scanning electron microscopy for morphological analysis. Results: Paroxetine showed a MIC of 64 μg/ml and bactericidal activity, mostly additive interactions in combination with oxacillin, evidence of action on genetic material and membrane, morphological changes in microbial cells and influence on virulence factors. Conclusion: Paroxetine has antibacterial potential from the perspective of drug repositioning.

PMID:37213136 | DOI:10.2217/fmb-2022-0232

Int Immunopharmacol. 2023 May 19;120:110331. doi: 10.1016/j.intimp.2023.110331. Online ahead of print.

ABSTRACT

Psoriasis is an autoimmune chronic disorder that causes inflammation and a scaly epidermis. The exact pathogenesis of the disease is not known yet. According to the studies, psoriasis is considered an immune-mediated disease. Until now it is believed that genetic and environmental factors are responsible for the disease. There are many comorbidities associated with psoriasis which increases difficulties as patients in some cases get addicted to drugs, alcohol, and smoking which reduces their quality of life. The patient may face social ignorance or suicidal thoughts which may arise in the patient's mind. Due to the undefined trigger of the disease, the treatment is not fully established but by considering the severe impact of the disease researchers are focusing on novel approaches for successful treatment. which has succeeded to a large extent. Here we review pathogenesis, problems faced by psoriatic patients, the need for the development of new treatments over conventional therapies, and the history of psoriatic treatments. We thoroughly focus on emerging treatments like biologics, biosimilars, and small molecules which are now showing more efficacy and safety than conventional treatments. Also, this review article discusses novel approaches which are now in research such as drug repurposing, treatment by stimulation of the vagus nerve, regulation of microbiota, and autophagy for improving disease conditions.

PMID:37210912 | DOI:10.1016/j.intimp.2023.110331

Arch Toxicol. 2023 May 21. doi: 10.1007/s00204-023-03516-1. Online ahead of print.

ABSTRACT

Cutaneous basal and squamous cell carcinoma reflect the first and second most common type of non-melanoma skin cancer, respectively. Especially cutaneous squamous cell carcinoma has the tendency to metastasize, finally resulting in a rather poor prognosis. Therapeutic options comprise surgery, radiation therapy, and a systemic or targeted chemotherapy. There are some good treatment results, but overall, the response rate of newly developed drugs is still modest. Drug repurposing represents an alternative approach where already available and clinically approved substances are used, which originally intended for other clinical benefits. In this context, we tested the effect of the naturally occurring polyphenolic aldehyde (±) gossypol with concentrations between 1 and 5 µM on the invasive squamous cell carcinoma cell line SCL-1 and normal human epidermal keratinocytes. Gossypol treatment up to 96 h resulted in a selective cytotoxicity of SCL-1 cells (IC50: 1.7 µM, 96 h) compared with normal keratinocytes (IC50: ≥ 5.4 µM, 96 h) which is mediated by mitochondrial dysfunction and finally leading to necroptotic cell death. Taken together, gossypol shows a high potential as an alternative anticancer drug for the treatment of cutaneous squamous cell carcinoma.

PMID:37210688 | DOI:10.1007/s00204-023-03516-1

J Transl Med. 2023 May 20;21(1):332. doi: 10.1186/s12967-023-04192-6.

ABSTRACT

BACKGROUND: Despite numerous clinical trials and decades of endeavour, there is still no effective cure for Alzheimer's disease. Computational drug repositioning approaches may be employed for the development of new treatment strategies for Alzheimer's patients since an extensive amount of omics data has been generated during pre-clinical and clinical studies. However, targeting the most critical pathophysiological mechanisms and determining drugs with proper pharmacodynamics and good efficacy are equally crucial in drug repurposing and often imbalanced in Alzheimer's studies.

METHODS: Here, we investigated central co-expressed genes upregulated in Alzheimer's disease to determine a proper therapeutic target. We backed our reasoning by checking the target gene's estimated non-essentiality for survival in multiple human tissues. We screened transcriptome profiles of various human cell lines perturbed by drug induction (for 6798 compounds) and gene knockout using data available in the Connectivity Map database. Then, we applied a profile-based drug repositioning approach to discover drugs targeting the target gene based on the correlations between these transcriptome profiles. We evaluated the bioavailability, functional enrichment profiles and drug-protein interactions of these repurposed agents and evidenced their cellular viability and efficacy in glial cell culture by experimental assays and Western blotting. Finally, we evaluated their pharmacokinetics to anticipate to which degree their efficacy can be improved.

RESULTS: We identified glutaminase as a promising drug target. Glutaminase overexpression may fuel the glutamate excitotoxicity in neurons, leading to mitochondrial dysfunction and other neurodegeneration hallmark processes. The computational drug repurposing revealed eight drugs: mitoxantrone, bortezomib, parbendazole, crizotinib, withaferin-a, SA-25547 and two unstudied compounds. We demonstrated that the proposed drugs could effectively suppress glutaminase and reduce glutamate production in the diseased brain through multiple neurodegeneration-associated mechanisms, including cytoskeleton and proteostasis. We also estimated the human blood-brain barrier permeability of parbendazole and SA-25547 using the SwissADME tool.

CONCLUSIONS: This study method effectively identified an Alzheimer's disease marker and compounds targeting the marker and interconnected biological processes by use of multiple computational approaches. Our results highlight the importance of synaptic glutamate signalling in Alzheimer's disease progression. We suggest repurposable drugs (like parbendazole) with well-evidenced activities that we linked to glutamate synthesis hereby and novel molecules (SA-25547) with estimated mechanisms for the treatment of Alzheimer's patients.

PMID:37210557 | DOI:10.1186/s12967-023-04192-6

Mol Cancer. 2023 May 20;22(1):86. doi: 10.1186/s12943-023-01788-w.

ABSTRACT

BACKGROUND: The discovery of functionally relevant KRAS effectors in lung and pancreatic ductal adenocarcinoma (LUAD and PDAC) may yield novel molecular targets or mechanisms amenable to inhibition strategies. Phospholipids availability has been appreciated as a mechanism to modulate KRAS oncogenic potential. Thus, phospholipid transporters may play a functional role in KRAS-driven oncogenesis. Here, we identified and systematically studied the phospholipid transporter PITPNC1 and its controlled network in LUAD and PDAC.

METHODS: Genetic modulation of KRAS expression as well as pharmacological inhibition of canonical effectors was completed. PITPNC1 genetic depletion was performed in in vitro and in vivo LUAD and PDAC models. PITPNC1-deficient cells were RNA sequenced, and Gene Ontology and enrichment analyses were applied to the output data. Protein-based biochemical and subcellular localization assays were run to investigate PITPNC1-regulated pathways. A drug repurposing approach was used to predict surrogate PITPNC1 inhibitors that were tested in combination with KRASG12C inhibitors in 2D, 3D, and in vivo models.

RESULTS: PITPNC1 was increased in human LUAD and PDAC, and associated with poor patients' survival. PITPNC1 was regulated by KRAS through MEK1/2 and JNK1/2. Functional experiments showed PITPNC1 requirement for cell proliferation, cell cycle progression and tumour growth. Furthermore, PITPNC1 overexpression enhanced lung colonization and liver metastasis. PITPNC1 regulated a transcriptional signature which highly overlapped with that of KRAS, and controlled mTOR localization via enhanced MYC protein stability to prevent autophagy. JAK2 inhibitors were predicted as putative PITPNC1 inhibitors with antiproliferative effect and their combination with KRASG12C inhibitors elicited a substantial anti-tumour effect in LUAD and PDAC.

CONCLUSIONS: Our data highlight the functional and clinical relevance of PITPNC1 in LUAD and PDAC. Moreover, PITPNC1 constitutes a new mechanism linking KRAS to MYC, and controls a druggable transcriptional network for combinatorial treatments.

PMID:37210549 | DOI:10.1186/s12943-023-01788-w

Br J Anaesth. 2023 May 18:S0007-0912(23)00197-6. doi: 10.1016/j.bja.2023.04.021. Online ahead of print.

ABSTRACT

Over the past few decades, substantial advances have been made in neuropathic pain clinical research. An updated definition and classification have been agreed. Validated questionnaires have improved the detection and assessment of acute and chronic neuropathic pain; and newer neuropathic pain syndromes associated with COVID-19 have been described. The management of neuropathic pain has moved from empirical to evidence-based medicine. However, appropriately targeting current medications and the successful clinical development of drugs acting on new targets remain challenging. Innovative approaches to improving therapeutic strategies are required. These mainly encompass rational combination therapy, drug repurposing, non-pharmacological approaches (such as neurostimulation techniques), and personalised therapeutic management. This narrative review reports historical and current perspectives regarding the definitions, classification, assessment, and management of neuropathic pain and explores potential avenues for future research.

PMID:37210279 | DOI:10.1016/j.bja.2023.04.021

Comput Struct Biotechnol J. 2023 Apr 20;21:2809-2823. doi: 10.1016/j.csbj.2023.04.018. eCollection 2023.

ABSTRACT

Stroke is the leading cause of death and disability worldwide, with a growing number of incidences in developing countries. However, there are currently few medical therapies for this disease. Emerged as an effective drug discovery strategy, drug repurposing which owns lower cost and shorter time, is able to identify new indications from existing drugs. In this study, we aimed at identifying potential drug candidates for stroke via computationally repurposing approved drugs from Drugbank database. We first developed a drug-target network of approved drugs, employed network-based approach to repurpose these drugs, and altogether identified 185 drug candidates for stroke. To validate the prediction accuracy of our network-based approach, we next systematically searched for previous literature, and found 68 out of 185 drug candidates (36.8 %) exerted therapeutic effects on stroke. We further selected several potential drug candidates with confirmed neuroprotective effects for testing their anti-stroke activity. Six drugs, including cinnarizine, orphenadrine, phenelzine, ketotifen, diclofenac and omeprazole, have exhibited good activity on oxygen-glucose deprivation/reoxygenation (OGD/R) induced BV2 cells. Finally, we showcased the anti-stroke mechanism of actions of cinnarizine and phenelzine via western blot and Olink inflammation panel. Experimental results revealed that they both played anti-stroke effects in the OGD/R induced BV2 cells via inhibiting the expressions of IL-6 and COX-2. In summary, this study provides efficient network-based methodologies for in silico identification of drug candidates toward stroke.

PMID:37206617 | PMC:PMC10189095 | DOI:10.1016/j.csbj.2023.04.018

bioRxiv. 2023 May 3:2023.05.01.538993. doi: 10.1101/2023.05.01.538993. Preprint.

ABSTRACT

Computational drug repositioning methods have emerged as an attractive and effective solution to find new candidates for existing therapies, reducing the time and cost of drug development. Repositioning methods based on biomedical knowledge graphs typically offer useful supporting biological evidence. This evidence is based on reasoning chains or subgraphs that connect a drug to disease predictions. However, there are no databases of drug mechanisms that can be used to train and evaluate such methods. Here, we introduce the Drug Mechanism Database (DrugMechDB), a manually curated database that describes drug mechanisms as paths through a knowledge graph. DrugMechDB integrates a diverse range of authoritative free-text resources to describe 4,583 drug indications with 32,249 relationships, representing 14 major biological scales. DrugMechDB can be employed as a benchmark dataset for assessing computational drug repurposing models or as a valuable resource for training such models.

PMID:37205439 | PMC:PMC10187194 | DOI:10.1101/2023.05.01.538993

Front Immunol. 2023 May 2;14:1145028. doi: 10.3389/fimmu.2023.1145028. eCollection 2023.

ABSTRACT

Immunotherapy has emerged as an effective therapeutic approach to several cancer types. The reinvigoration of tumor-infiltrating lymphocyte-mediated immune responses via the blockade of immune checkpoint markers, such as program cell death-1 (PD-1) or its cognate ligand PD-L1, has been the basis for developing clinically effective anticancer therapies. We identified pentamidine, an FDA-approved antimicrobial agent, as a small-molecule antagonist of PD-L1. Pentamidine enhanced T-cell-mediated cytotoxicity against various cancer cells in vitro by increasing the secretion of IFN-γ, TNF-α, perforin, and granzyme B in the culture medium. Pentamidine promoted T-cell activation by blocking the PD-1/PD-L1 interaction. In vivo administration of pentamidine attenuated the tumor growth and prolonged the survival of tumor-bearing mice in PD-L1 humanized murine tumor cell allograft models. Histological analysis of tumor tissues showed an increased number of tumor-infiltrating lymphocytes in tissues derived from pentamidine-treated mice. In summary, our study suggests that pentamidine holds the potential to be repurposed as a novel PD-L1 antagonist that may overcome the limitations of monoclonal antibody therapy and can emerge as a small molecule cancer immunotherapy.

PMID:37205112 | PMC:PMC10185823 | DOI:10.3389/fimmu.2023.1145028

J Clin Immunol. 2023 May 19. doi: 10.1007/s10875-023-01518-3. Online ahead of print.

ABSTRACT

Hidradenitis suppurativa (HS), also known as Verneuil's disease and acne inversa, is a prevalent, debilitating, and understudied inflammatory skin disease. It is marked by repeated bouts of pathological inflammation causing pain, hyperplasia, aberrant healing, and fibrosis. HS is difficult to manage and has many unmet medical needs. There is clinical and pharmacological evidence for extensive etiological heterogeneity with HS, suggesting that this clinical diagnosis is capturing a spectrum of disease entities. Human genetic studies provide robust insight into disease pathogenesis. They also can be used to resolve etiological heterogeneity and to identify drug targets. However, HS has not been extensively investigated with well-powered genetic studies. Here, we review what is known about its genetic architecture. We identify overlap in molecular, cellular, and clinical features between HS and inborn errors of immunity (IEI). This evidence indicates that HS may be an underrecognized component of IEI and suggests that undiagnosed IEI are present in HS cohorts. Inborn errors of immunity represent a salient opportunity for rapidly resolving the immunological landscape of HS pathogenesis, for prioritizing drug repurposing studies, and for improving the clinical management of HS.

PMID:37204644 | DOI:10.1007/s10875-023-01518-3

Epilepsia. 2023 May 18. doi: 10.1111/epi.17656. Online ahead of print.

ABSTRACT

Variable phenotypes, including developmental encephalopathy with (DEE) or without (DE) seizures and myoclonic epilepsy and ataxia due to potassium channel mutation (MEAK), are caused by pathogenetic variants in KCNC1, encoding for Kv3.1 channel subunits. In vitro, channels carrying most KCNC1 pathogenic variants display loss-of-function (LoF) features. Here we describe a child affected by DEE with fever-triggered seizures, caused by a novel de novo heterozygous missense KCNC1 variant (c.1273G>A; V425M). Patch-clamp recordings in transiently-transfected CHO cells revealed that, compared to wild-type, Kv3.1 V425M currents: i) were larger between -40 and +40 mV membrane potentials; ii) displayed a hyperpolarizing shift in activation gating; iii) failed to inactivate; iv) had slower activation and deactivation kinetics, consistent with a mixed functional pattern with prevalent gain-of-function (GoF) effects. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant Kv3.1 channels. Treatment of the proband with fluoxetine led to a rapid and prolonged clinical amelioration, with the disappearance of seizures and an improvement in balance, gross motor skills and oculomotor coordination. These results suggest that drug repurposing based on the specific genetic defect may provide an effective personalized treatment for KCNC1-related DEEs.

PMID:37203213 | DOI:10.1111/epi.17656

RSC Adv. 2023 May 16;13(22):14943-14957. doi: 10.1039/d3ra02244g. eCollection 2023 May 15.

ABSTRACT

The global state of antibiotic resistance highlights the necessity for new drugs that can treat a wide range of microbial infections. Drug repurposing has several advantages, including lower costs and improved safety compared to developing a new compound. The aim of the current study is to evaluate the repurposed antimicrobial activity of Brimonidine tartrate (BT), a well-known antiglaucoma drug, and to potentiate its antimicrobial effect by using electrospun nanofibrous scaffolds. BT-loaded nanofibers were fabricated in different drug concentrations (1.5, 3, 6, and 9%) via the electrospinning technique using two biopolymers (PCL and PVP). Then, the prepared nanofibers were characterized by SEM, XRD, FTIR, swelling ratio, and in vitro drug release. Afterward, the antimicrobial activities of the prepared nanofibers were investigated in vitro using different methods against several human pathogens and compared to the free BT. The results showed that all nanofibers were prepared successfully with a smooth surface. The diameters of nanofibers were reduced after loading of BT compared to the unloaded ones. In addition, scaffolds showed controlled-drug release profiles that were maintained for more than 7 days. The in vitro antimicrobial assessments revealed good activities for all scaffolds against most of the investigated human pathogens, particularly the one prepared with 9% BT which showed superiority in the antimicrobial effect over other scaffolds. To conclude, our findings proved the capability of nanofibers in loading BT and improving its repurposed antimicrobial efficacy. Therefore, it could be a promising carrier for BT to be used in combating numerous human pathogens.

PMID:37200698 | PMC:PMC10186146 | DOI:10.1039/d3ra02244g

Drug Des Devel Ther. 2023 May 11;17:1417-1432. doi: 10.2147/DDDT.S404055. eCollection 2023.

ABSTRACT

PURPOSE: The glucagon-like peptide-1 receptor (GLP-1R) is an effective therapeutic target for type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH). Research has focused on small-molecule GLP-1R agonists because of their ease of use in oral formulations and improved patient compliance. However, no small-molecule GLP-1R agonists are currently available in the market. We aimed to screen for a potential oral small-molecule GLP-1R agonist and evaluated its effect on blood glucose and NASH.

METHODS: The Connectivity map database was used to screen for candidate small-molecule compounds. Molecular docking was performed using SYBYL software. Rat pancreatic islets were incubated in different concentrations glucose solutions, with cinchonine or Exendin (9-39) added to determine insulin secretion levels. C57BL/6 mice, GLP-1R-/- mice and hGLP-1R mice were used to conduct oral glucose tolerance test. In addition, we fed ob/ob mice with the GAN diet to induce the NASH model. Cinchonine (50 mg/kg or 100 mg/kg) was administered orally twice daily to the mice. Serum liver enzymes were measured using biochemical analysis. Liver tissues were examined using Hematoxylin-eosin staining, Oil Red O staining and Sirius Red staining.

RESULTS: Based on the small intestinal transcriptome of geniposide, a recognized small-molecule GLP-1R agonist, we identified that cinchonine exerted GLP-1R agonist-like effects. Cinchonine had a good binding affinity for GLP-1R. Cinchonine promoted glucose-dependent insulin secretion, which could be attenuated significantly by Exendin (9-39), a specific GLP-1R antagonist. Moreover, cinchonine could reduce blood glucose in C57BL/6 and hGLP-1R mice, an effect that could be inhibited with GLP-1R knockout. In addition, cinchonine reduced body weight gain and food intake in ob/ob-GAN NASH mice dose-dependently. 100 mg/kg cinchonine significantly improved liver function by reducing the ALT, ALP and LDH levels. Importantly, 100 mg/kg cinchonine ameliorated hepatic steatosis and fibrosis in NASH mice.

CONCLUSION: Cinchonine, a potential oral small-molecule GLP-1R agonist, could reduce blood glucose and ameliorate NASH, providing a strategy for developing small-molecule GLP-1R agonists.

PMID:37197367 | PMC:PMC10184894 | DOI:10.2147/DDDT.S404055

Exp Parasitol. 2023 May 15:108547. doi: 10.1016/j.exppara.2023.108547. Online ahead of print.

ABSTRACT

The current scenario for cutaneous leishmaniasis treatment includes the use of first and second-choice drugs, both therapeutic strategies presenting several adverse effects and being related to an increment of treatment-refractory parasite strains. These facts encourage the search for new treatment approaches, including repositioning drugs, such as nystatin. Although some in vitro assays show that this polyene macrolide compound has leishmanicidal activity, no in vivo evidence for a similar activity has been shown so far for the commercial nystatin cream formulation (25,000 IU/g). This work assessed the effects of nystatin cream administered on mice in an amount to completely cover the paw surface of BALB/c mice infected with L. (L.) amazonensis once a day, until a total of up to 20 doses. The data presented herein points to unequivocal evidence that this formulation is related to a statistically significant reduction of swelling/edema in mice paws when compared to animal groups not submitted to this treatment regimen after the fourth week of infection: lesion sizes at the sixth (p = 0.0159), seventh (p = 0.0079) and eighth (p = 0.0079) week. Furthermore, infection reduction relates to a decrease in parasite load in the footpad (∼48%) and in draining lymph nodes (∼68%) at 8th weeks post-infection. This is the first report of the effectiveness of nystatin cream used as a topical treatment in BALB/c model for cutaneous leishmaniasis.

PMID:37196701 | DOI:10.1016/j.exppara.2023.108547