Front Immunol. 2022 Sep 2;13:935321. doi: 10.3389/fimmu.2022.935321. eCollection 2022.

ABSTRACT

In this article, we will share lessons that patients with gain-of-function defects in Toll-like receptor 8 (TLR8-GOF) can teach us about the interface between bone marrow failure (BMF) disorders and inborn errors of immunity (IEI), subsequently referred to as "Interface Disorders". TLR8-GOF is a relatively young entity (from a discovery standpoint) that-through both similar and dissimilar disease characteristics-can increase our understanding of interface disorders, for example, as it pertains to pathophysiology, the genetic mechanism of disease, and related diagnostics and therapeutics. From a genetics point of view, TLR8-GOF joins a growing list of (interface) disorders that can cause disease both with germline and somatic (mosaic) genetic variants. This not only has repercussions for the diagnostic workup of these disorders, inasmuch that routine genetic testing may miss somatic variants, but has therapeutic implications as well, for example, with the approach to curative treatment, such as hematopoietic stem cell transplantation. Following an introduction and schematic rendering of the interface, we will review the salient features of TLR8-GOF, with the understanding that the phenotype of this new disorder is likely not written in stone yet. In keeping with the principle of "Form Follows Function", we will discuss specific immunological biomarkers that can be measured in clinical laboratories and highlight key disease features that pertain to TLR8-GOF, and can be found in several interface disorders. As can be seen from a schematic representation, the interface provides not only opportunities for learning and collaboration with respect to shared diagnostics but also the potential for drug repurposing and precision therapeutics. Ideally, collaboration also focuses on education and teaching, such that cross-fertilization and collaboration across these disciplines can create a framework for complementary research.

PMID:36119097 | PMC:PMC9479092 | DOI:10.3389/fimmu.2022.935321

Seizure. 2022 Sep 5;101:253-261. doi: 10.1016/j.seizure.2022.09.003. Online ahead of print.

ABSTRACT

BACKGROUND: Available anti-seizure medications (ASMs) target the symptomatology of the disease rather than any significant disease/epileptogenesis modifying actions. There are critical concerns of drug resistance and seizure recurrence during epilepsy management. So, drug repurposing is evolving as a paradigm change in the quest for novel epilepsy treatment strategies. Metformin, a well-known anti-diabetic drug has shown multiple pieces of evidence of its potential antiepileptic action.

OBJECTIVE: This review elucidates various mechanisms underlying the beneficial role of metformin in seizure control and modulation of the epileptogenesis process.

METHODS: Preclinical and clinical evidence involving metformin's role in epilepsy and special conditions like tuberous sclerosis have been reviewed in this paper. The putative mechanisms of epileptogenesis modulation through the use of metformin are also summarised.

RESULTS: This review found the efficacy of metformin in different seizure models including genetic knockout model, chemical induced, and kindling models. Only one clinical study of metformin in tuberous sclerosis has shown a reduction in seizure frequency and tumor volume compared to placebo. The suggested mechanisms of metformin relevant to epileptogenesis modulation mainly encompass AMPK activation, mTOR inhibition, protection against blood-brain-barrier disruption, inhibition of neuronal apoptosis, and reduction of oxidative stress. In addition to seizure protection, metformin has a potential role in attenuating adverse effects associated with epilepsy and ASMs such as cognition and memory impairment.

CONCLUSION: Metformin has shown promising utility in epilepsy management and epileptogenesis modulation. The evidence in this review substantiates the need for a robust clinical trial to explore the efficacy and safety of metformin in persons with epilepsy.

PMID:36116284 | DOI:10.1016/j.seizure.2022.09.003

Neuropsychopharmacology. 2022 Sep 16. doi: 10.1038/s41386-022-01456-5. Online ahead of print.

ABSTRACT

Psychiatric disorders impose tremendous economic burden on society and are leading causes of disability worldwide. However, only limited drugs are available for psychiatric disorders and the efficacy of most currently used drugs is poor for many patients. To identify novel therapeutic targets for psychiatric disorders, we performed genome-wide Mendelian randomization analyses by integrating brain-derived molecular quantitative trait loci (mRNA expression and protein abundance quantitative trait loci) of 1263 actionable proteins (targeted by approved drugs or drugs in clinical phase of development) and genetic findings from large-scale genome-wide association studies (GWASs). Using transcriptome data, we identified 25 potential drug targets for psychiatric disorders, including 12 genes for schizophrenia, 7 for bipolar disorder, 7 for depression, and 1 (TIE1) for attention deficit and hyperactivity. We also identified 10 actionable drug targets by using brain proteome data, including 4 (HLA-DRB1, CAMKK2, P2RX7, and MAPK3) for schizophrenia, 1 (PRKCB) for bipolar disorder, 6 (PSMB4, IMPDH2, SERPINC1, GRIA1, P2RX7 and TAOK3) for depression. Of note, MAPK3 and HLA-DRB1 were supported by both transcriptome and proteome-wide MR analyses, suggesting that these two proteins are promising therapeutic targets for schizophrenia. Our study shows the power of integrating large-scale GWAS findings and transcriptomic and proteomic data in identifying actionable drug targets. Besides, our findings prioritize actionable novel drug targets for development of new therapeutics and provide critical drug-repurposing opportunities for psychiatric disorders.

PMID:36114287 | DOI:10.1038/s41386-022-01456-5

Biochem Pharmacol. 2022 Sep 13:115248. doi: 10.1016/j.bcp.2022.115248. Online ahead of print.

ABSTRACT

Tubocurarine (d-TC), a non-depolarizing competitive blocker of nicotinic acetylcholine receptors is extensively utilized for the relaxation of skeletal muscles. Drug repositioning is a forthright approach to reduce the cost and speed up drug development process. Herein, we have attempted to evaluate the analgesic and anti-inflammatory activity of d-TC for its possible repurposing in pain and inflammation-related issues. Experimental Approach We examined the soluble epoxide hydrolase inhibitory (sEHI) activity of d-TC employing in silico high throughput screening protocols, in vitro cell-free sEH inhibitory assay, and in in vivo rodent models for its repositioning in pain and inflammation-related disorders. Key Results In molecular docking study, d-TC displayed impressive hydrogen bonding interactions within the cavity of sEH enzyme with good docking score. d-TC also exhibited notable sEH inhibitory activity (IC50 3.72nm) at the in vitro assay. Oral absorption capability of d-TC (0.1 and 0.2 mg/mL) was determined using an in vitro everted intestinal sac model employing rat ileum tissue that revealed significant oral absorption of d-TC. Besides, in vivo studies revealed that oral administration of d-TC (0.1 and 0.2 mg/kg) in rodents significantly attenuated hyperalgesia (cold plate test, tail immersion test and formalin test) and inflammation (estimation of rectal temperature, acetic acid induced pleurisy test and cotton pellet-induced granuloma test) induced in robust preclinical models. Conclusion and Implications These findings are novel and warrant immediate efforts to reposition d-TC as a new therapeutic candidate in the management of hyperalgesia, inflammation, and associated conditions.

PMID:36113566 | DOI:10.1016/j.bcp.2022.115248

Curr Comput Aided Drug Des. 2022 Sep 14. doi: 10.2174/1573409918666220914092145. Online ahead of print.

ABSTRACT

BACKGROUND: Network pharmacology based identification of phytochemicals in the form of cocktails against off-targets can play a significant role in inhibition of SARS_CoV2 viral entry and its propagation. This study includes network pharmacology, virtual screening, docking and molecular dynamics to investigate the distinct antiviral mechanisms of effective phytochemicals against SARS_CoV2.

METHODS: SARS_CoV2 human-protein interaction network was explored from the BioGRID database and analysed using Cytoscape. Further analysis was performed to explore biological function, protein-phytochemical/drugs network and up-down regulation of pathological host target proteins. This lead to understand the antiviral mechanism of phytochemicals against SARS_CoV2. The network was explored through g:Profiler, EnrichR, CTD, SwissTarget, STITCH, DrugBank, BindingDB, STRING and SuperPred. Virtual screening of phytochemicals against potential antiviral targets such as M-Pro, NSP1, Receptor binding domain, RNA binding domain, and ACE2 discloses the effective interaction between them. Further, the binding energy calculations through simulation of the docked complex explains the efficiency and stability of the interactions.

RESULTS: The network analysis identified quercetin, genistein, luteolin, eugenol, berberine, isorhamnetin and cinnamaldehyde to be interacting with host proteins ACE2, DPP4, COMT, TUBGCP3, CENPF, BRD2 and HMOX1 which are involved in antiviral mechanisms such as viral entry, viral replication, host immune response, and antioxidant activity. Thus indicating that herbal cocktails can effectively tackle the viral hijacking of the crucial biological functions of human host. Further exploration through Virtual screening, docking and molecular dynamics recognizes the effective interaction of phytochemicals such as punicalagin, scutellarin, and solamargine with their respective potential targets.

CONCLUSION: This work illustrates probable strategy for identification of phytochemical based cocktails and off-targets which are effective against SARS_CoV 2.

PMID:36111763 | DOI:10.2174/1573409918666220914092145

Stroke. 2022 Sep 16:101161STROKEAHA122039305. doi: 10.1161/STROKEAHA.122.039305. Online ahead of print.

NO ABSTRACT

PMID:36111545 | DOI:10.1161/STROKEAHA.122.039305

F1000Res. 2022 Apr 7;11:Chem Inf Sci-400. doi: 10.12688/f1000research.109586.1. eCollection 2022.

ABSTRACT

Background: COVID-19 has become a global threat. Since its first outbreak from Wuhan, China in December 2019, the SARS-CoV-2 virus has gone through structural changes arising due to mutations in its surface glycoprotein. These mutations have led to the emergence of different genetic variants threatening public health due to increased transmission and virulence. As new drug development is a long process, repurposing existing antiviral drugs with potential activity against SARS-CoV-2 might be a possible solution to mitigate the current situation. Methods: This study focused on utilizing molecular docking to determine the effect of potential drugs on several variants of concern (VOCs). The effect of various drugs such as baricitinib, favipiravir, lopinavir, remdesivir and dexamethasone, which might have the potential to treat SARS-CoV-2 infections as evident from previous studies, was investigated for different VOCs. Results: Remdesivir showed promising results for B.1.351 variant (binding energy: -7.3 kcal/mol) with residues Gln319 and Val503 facilitating strong binding. Favipiravir showed favorable results against B.1.1.7 (binding energy: -5.6 kcal/mol), B.1.351 (binding energy: -5.1 kcal/mol) and B.1.617.2 (binding energy: -5 kcal/mol). Molecular dynamics simulation for favipiravir/B.1.1.7 was conducted and showed significant results in agreement with our findings. Conclusions: From structural modeling and molecular docking experiments, it is evident that mutations outside the receptor binding domain of surface glycoprotein do not have a sharp impact on drug binding affinity. Thus, the potential use of these drugs should be explored further for their antiviral effect against SARS-CoV-2 VOCs.

PMID:36111219 | PMC:PMC9445560 | DOI:10.12688/f1000research.109586.1

Wellcome Open Res. 2022 May 12;7:150. doi: 10.12688/wellcomeopenres.17845.1. eCollection 2022.

ABSTRACT

Drug repositioning and the relevance of orphan drug designation for β-thalassemia is reviewed. Drug repositioning and similar terms ('drug repurposing', 'drug reprofiling', 'drug redirecting', 'drug rescue', 'drug re-tasking' and/or 'drug rediscovery') have gained great attention, especially in the field or rare diseases (RDs), and represent relevant novel drug development strategies to be considered together with the "off-label" use of pharmaceutical products under clinical trial regimen. The most significant advantage of drug repositioning over traditional drug development is that the repositioned drug has already passed a significant number of short- and long-term toxicity tests, as well as it has already undergone pharmacokinetic and pharmacodynamic (PK/PD) studies. The established safety of repositioned drugs is known to significantly reduce the probability of project failure. Furthermore, development of repurposed drugs can shorten much of the time needed to bring a drug to market. Finally, patent filing of repurposed drugs is expected to catch the attention of pharmaceutical industries interested in the development of therapeutic protocols for RDs. Repurposed molecules that could be proposed as potential drugs for β-thalassemia, will be reported, with some of the most solid examples, including sirolimus (rapamycin) that recently has been tested in a pilot clinical trial.

PMID:36110836 | PMC:PMC9453112 | DOI:10.12688/wellcomeopenres.17845.1

Drug Des Devel Ther. 2022 Sep 9;16:2995-3013. doi: 10.2147/DDDT.S366423. eCollection 2022.

ABSTRACT

PURPOSE: The development of effective treatments for coronavirus infectious disease 19 (COVID-19) caused by SARS-Coronavirus-2 was hindered by the little data available about this virus at the start of the pandemic. Drug repurposing provides a good strategy to explore approved drugs' possible SARS-CoV-2 antiviral activity. Moreover, drug synergism is essential in antiviral treatment due to improved efficacy and reduced toxicity. In this work, we studied the effect of approved and investigational drugs on one of SARS-CoV-2 essential proteins, the main protease (Mpro), in search of antiviral treatments and/or drug combinations.

METHODS: Different possible druggable sites of Mpro were identified and screened against an in-house library of more than 4000 chemical compounds. Molecular dynamics simulations were carried out to explore conformational changes induced by different ligands' binding. Subsequently, the inhibitory effect of the identified compounds and the suggested drug combinations on the Mpro were established using a 3CL protease (SARS-CoV-2) assay kit.

RESULTS: Three potential inhibitors in three different binding sites were identified; favipiravir, cefixime, and carvedilol. Molecular dynamics simulations predicted the synergistic effect of two drug combinations: favipiravir/cefixime, and favipiravir/carvedilol. The in vitro inhibitory effect of the predicted drug combinations was established on this enzyme.

CONCLUSION: In this work, we could study one of the promising SARS-CoV-2 viral protein targets in searching for treatments for COVID-19. The inhibitory effect of several drugs on Mpro was established in silico and in vitro assays. Molecular dynamics simulations showed promising results in predicting the synergistic effect of drug combinations.

PMID:36110398 | PMC:PMC9469804 | DOI:10.2147/DDDT.S366423

ACS Pharmacol Transl Sci. 2022 Aug 10;5(9):811-818. doi: 10.1021/acsptsci.2c00126. eCollection 2022 Sep 9.

ABSTRACT

Bexarotene, a retinoid X receptor (RXR) agonist, is used to treat cutaneous T-cell lymphoma, and drug repositioning research has also been reported, despite warnings of teratogenicity. However, fetal transfer of bexarotene and its effect on rat fetal bone formation have not been examined. In this study, we conducted a detailed teratogenicity and fetal transferability assessment of bexarotene in rats. Repeated administration of bexarotene during pregnancy caused marked fetal atrophy and bone dysplasia. Although fetal transfer was not detectable by dynamic imaging of [11C]bexarotene by means of positron emission tomography, transfer to the fetus was confirmed by using a gamma counter. Similar levels were found in mother and fetus. In addition, we found that bexarotene was accumulated in the placenta. These findings will be useful for the toxicity assessment of bexarotene as well as for drug discovery research targeting RXR agonists, which are expected to have therapeutic effects in various diseases.

PMID:36110376 | PMC:PMC9469495 | DOI:10.1021/acsptsci.2c00126

Trials. 2022 Sep 15;23(1):783. doi: 10.1186/s13063-022-06713-y.

ABSTRACT

BACKGROUND: Academic-sponsored trials for rare diseases face many challenges; the present paper identifies hurdles in the set-up of six multinational clinical trials for drug repurposing, as use cases.

METHODS: Six academic-sponsored multinational trials aiming to generate knowledge on rare diseases drug repurposing were used as examples to identify problems in their set-up. Coordinating investigators leading these trials provided feedback on hurdles linked to study, country, and site set up, on the basis of pre-identified categories established through the analysis of previous peer-reviewed publications.

RESULTS: Administrative burden and lack of harmonization for trial-site agreements were deemed as a major hurdle. Other main identified obstacles included the following: (1) complexity and restriction on the use of public funding, especially in a multinational set up, (2) drug supply, including procurement tendering rules and country-specific requirements for drug stability, and (3) lack of harmonization on regulatory requirements to get trial approvals.

CONCLUSION: A better knowledge of the non-commercial clinical research landscape and its challenges and requirements is needed to make drugs-especially those with less commercial gain-accessible to rare diseases patients. Better information about existing resources like research infrastructures, clinical research programs, and counseling mechanisms is needed to support and guide clinicians through the many challenges associated to the set-up of academic-sponsored multinational trials.

PMID:36109818 | DOI:10.1186/s13063-022-06713-y

J Nanobiotechnology. 2022 Sep 15;20(1):413. doi: 10.1186/s12951-022-01612-5.

ABSTRACT

Parkinson's disease (PD) significantly affects patients' quality of life and represents a high economic burden for health systems. Given the lack of safe and effective treatments for PD, drug repositioning seeks to offer new medication alternatives, reducing research time and costs compared to the traditional drug development strategy. This review aimed to collect evidence of drugs proposed as candidates to be reused in PD and identify those with the potential to be reformulated into nanocarriers to optimize future repositioning trials. We conducted a detailed search in PubMed, Web of Science, and Scopus from January 2015 at the end of 2021, with the descriptors "Parkinson's disease" and "drug repositioning" or "drug repurposing". We identified 28 drugs as potential candidates, and six of them were found in repositioning clinical trials for PD. However, a limitation of many of these drugs to achieve therapeutic success is their inability to cross the blood-brain barrier (BBB), as is the case with nilotinib, which has shown promising outcomes in clinical trials. We suggest reformulating these drugs in biodegradable nanoparticles (NPs) based on lipids and polymers to perform future trials. As a complementary strategy, we propose functionalizing the NPs surface by adding materials to the surface layer. Among other advantages, functionalization can promote efficient crossing through the BBB and improve the affinity of NPs towards certain brain regions. The main parameters to consider for the design of NPs targeting the central nervous system are highlighted, such as size, PDI, morphology, drug load, and Z potential. Finally, current advances in the use of NPs for Parkinson's disease are cited.

PMID:36109747 | DOI:10.1186/s12951-022-01612-5

Pharm Res. 2022 Sep 15. doi: 10.1007/s11095-022-03392-x. Online ahead of print.

ABSTRACT

Most lung cancer instances are non-small cell lung cancers (NSCLC). As stated by recent literature, cycloxygenase-2 (COX-2) is upregulated in lung adenocarcinomas. COX-2 relates to enhanced cell proliferation and reduced apoptosis; both of which are essential for an invasive tumor growth and metastasis. Thus, COX-2 inhibition forms an important checkpoint. Drug repurposing and nano drug delivery systems will enable the faster and more efficacious drug development. This study was designed to prepare, characterize, and establish superior effectiveness of indomethacin (IND), (a nonselective COX-2 inhibitor) as liposomes (IND-Lip). IND-Lip were made using thin film hydration method and physicochemical properties were characterized. Cell viability was performed on NSCLC cell lines (A549, H1299 and H460) Clonogenic, spheroidal, caspase and COX-2 assays were then carried out. IND-Lip were found to have optimum physicochemical properties. Based on IC50 value of 38.4 ± 4.9 µM, A549 cells were used for further assays. From clonogenic assay, % colonies were found to be 25.5 ± 9.5% at 200 µM of IND-Lip. IND-Lip performed significantly better in ex-vivo tumor reduction in 3D spheroid assay at 200 μM concentration, compared to plain IND by Day 15. Finally, a significant inhibition of COX-2 as well as induction of caspase in all IND treated groups was observed. It is of note that liposomes demonstrated a superior efficacy in all studies compared to the plain drug. IND through liposomal delivery system can be a potentially beneficial strategy for lung carcinoma. However, further clinical studies and in-vivo research are essential to comprehend the complete view of this approach.

PMID:36109463 | DOI:10.1007/s11095-022-03392-x

Cancer Med. 2022 Sep 15. doi: 10.1002/cam4.5243. Online ahead of print.

ABSTRACT

BACKGROUND: Choriocarcinoma is a rare and aggressive gynecological malignancy. The standard treatment is systemic chemotherapy as choriocarcinoma exhibits high chemosensitivity. However, refractory choriocarcinoma exhibits chemoresistance; thus, the prognosis remains very poor. This study aimed to identify novel therapeutic agents for choriocarcinoma by utilizing a drug repositioning strategy.

METHODS: Three choriocarcinoma cell lines (JAR, JEG-3, and BeWo) and a human extravillous trophoblast cell line (HTR-8/SVneo) were used for the analyses. The growth inhibitory effects of 1,271 FDA-approved compounds were evaluated in vitro screening assays and selected drugs were tested in tumor-bearing mice. Functional analyses of drug effects were performed based on RNA sequencing.

RESULTS: Muti-step screening identified vorinostat, camptothecin (S, +), topotecan, proscillaridin A, and digoxin as exhibiting an anti-cancer effect in choriocarcinoma cells. Vorinostat, a histone deacetylase inhibitor, was selected as a promising candidate for validation and the IC50 values for choriocarcinoma cells were approximately 1 μM. RNA sequencing and subsequent pathway analysis revealed that the ferroptosis pathway was likely implicated, and key ferroptosis-related genes (i.e., GPX4, NRF2, and SLC3A2) were downregulated following vorinostat treatment. Furthermore, vorinostat repressed tumor growth and downregulated the expression of GPX4 and NRF2 in JAR cell-bearing mice model.

CONCLUSION: Vorinostat, a clinically approved drug for the treatment of advanced primary cutaneous T-cell lymphoma, showed a remarkable anticancer effect both in vitro and in vivo by regulating the expression of ferroptosis-related genes. Therefore, vorinostat may be an effective therapeutic candidate for patients with choriocarcinoma.

PMID:36106577 | DOI:10.1002/cam4.5243

Struct Chem. 2022 Sep 10:1-16. doi: 10.1007/s11224-022-02036-5. Online ahead of print.

ABSTRACT

The SARS-CoV-2 proteases Mpro and PLpro are important targets for the development of antivirals against COVID-19. The functional group 1,2,4-thiadiazole has been indicated to inhibit cysteinyl proteases, such as papain and cathepsins. Of note, the 1,2,4-thiadiazole moiety is found in a new class of cephalosporin FDA-approved antibiotics: ceftaroline fosamil, ceftobiprole, and ceftobiprole medocaril. Here we investigated the interaction of these new antibiotics and their main metabolites with the SARS-CoV-2 proteases by molecular docking, molecular dynamics (MD), and density functional theory (DFT) calculations. Our results indicated the PLpro enzyme as a better in silico target for the new antibacterial cephalosporins. The results with ceftaroline fosamil and the dephosphorylate metabolite compounds should be tested as potential inhibitor of PLpro, Mpro, and SARS-CoV-2 replication in vitro. In addition, the data here reported can help in the design of new potential drugs against COVID-19 by exploiting the S atom reactivity in the 1,2,4-thiadiazole moiety.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11224-022-02036-5.

PMID:36106095 | PMC:PMC9463509 | DOI:10.1007/s11224-022-02036-5

Biochem Biophys Rep. 2022 Sep 5;32:101337. doi: 10.1016/j.bbrep.2022.101337. eCollection 2022 Dec.

ABSTRACT

Multiple sclerosis (MS) is a chronic autoimmune disease in the central nervous system (CNS) marked by inflammation, demyelination, and axonal loss. Currently available MS medication is limited, thereby calling for a strategy to accelerate new drug discovery. One of the strategies to discover new drugs is to utilize old drugs for new indications, an approach known as drug repurposing. Herein, we first identified 421 MS-associated SNPs from the Genome-Wide Association Study (GWAS) catalog (p-value < 5 × 10-8), and a total of 427 risk genes associated with MS using HaploReg version 4.1 under the criterion r 2 > 0.8. MS risk genes were then prioritized using bioinformatics analysis to identify biological MS risk genes. The prioritization was performed based on six defined categories of functional annotations, namely missense mutation, cis-expression quantitative trait locus (cis-eQTL), molecular pathway analysis, protein-protein interaction (PPI), genes overlap with knockout mouse phenotype, and primary immunodeficiency (PID). A total of 144 biological MS risk genes were found and mapped into 194 genes within an expanded PPI network. According to the DrugBank and the Therapeutic Target Database, 27 genes within the list targeted by 68 new candidate drugs were identified. Importantly, the power of our approach is confirmed with the identification of a known approved drug (dimethyl fumarate) for MS. Based on additional data from ClinicalTrials.gov, eight drugs targeting eight distinct genes are prioritized with clinical evidence for MS disease treatment. Notably, CD80 and CD86 pathways are promising targets for MS drug repurposing. Using in silico drug repurposing, we identified belatacept as a promising MS drug candidate. Overall, this study emphasized the integration of functional genomic variants and bioinformatic-based approach that reveal important biological insights for MS and drive drug repurposing efforts for the treatment of this devastating disease.

PMID:36105612 | PMC:PMC9464879 | DOI:10.1016/j.bbrep.2022.101337

Front Pharmacol. 2022 Aug 29;13:997618. doi: 10.3389/fphar.2022.997618. eCollection 2022.

NO ABSTRACT

PMID:36105235 | PMC:PMC9465373 | DOI:10.3389/fphar.2022.997618

Front Pharmacol. 2022 Aug 29;13:990665. doi: 10.3389/fphar.2022.990665. eCollection 2022.

ABSTRACT

Based on the bidirectional interactions between neurology and cancer science, the burgeoning field "cancer neuroscience" has been proposed. An important node in the communications between nerves and cancer is the innervated niche, which has physical contact with the cancer parenchyma or nerve located in the proximity of the tumor. In the innervated niche, autophagy has recently been reported to be a double-edged sword that plays a significant role in maintaining homeostasis. Therefore, regulating the innervated niche by targeting the autophagy pathway may represent a novel therapeutic strategy for cancer treatment. Drug repurposing has received considerable attention for its advantages in cost-effectiveness and safety. The utilization of existing drugs that potentially regulate the innervated niche via the autophagy pathway is therefore a promising pharmacological approach for clinical practice and treatment selection in cancer neuroscience. Herein, we present the cancer neuroscience landscape with an emphasis on the crosstalk between the innervated niche and autophagy, while also summarizing the underlying mechanisms of candidate drugs in modulating the autophagy pathway. This review provides a strong rationale for drug repurposing in cancer treatment from the viewpoint of the autophagy-mediated innervated niche.

PMID:36105204 | PMC:PMC9464986 | DOI:10.3389/fphar.2022.990665

Sci Adv. 2022 Sep 16;8(37):eabo5400. doi: 10.1126/sciadv.abo5400. Epub 2022 Sep 14.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces mild or asymptomatic COVID-19 in most cases, but some patients develop an excessive inflammatory process that can be fatal. As the NLRP3 inflammasome and additional inflammasomes are implicated in disease aggravation, drug repositioning to target inflammasomes emerges as a strategy to treat COVID-19. Here, we performed a high-throughput screening using a 2560 small-molecule compound library and identified FDA-approved drugs that function as pan-inflammasome inhibitors. Our best hit, niclosamide (NIC), effectively inhibits both inflammasome activation and SARS-CoV-2 replication. Mechanistically, induction of autophagy by NIC partially accounts for inhibition of NLRP3 and AIM2 inflammasomes, but NIC-mediated inhibition of NAIP/NLRC4 inflammasome are autophagy independent. NIC potently inhibited inflammasome activation in human monocytes infected in vitro, in PBMCs from patients with COVID-19, and in vivo in a mouse model of SARS-CoV-2 infection. This study provides relevant information regarding the immunomodulatory functions of this promising drug for COVID-19 treatment.

PMID:36103544 | DOI:10.1126/sciadv.abo5400

Biofactors. 2022 Sep 14. doi: 10.1002/biof.1886. Online ahead of print.

ABSTRACT

Metabolic syndrome (MetS) is a common feature in obesity, comprising a cluster of abnormalities including abdominal fat accumulation, hyperglycemia, hyperinsulinemia, dyslipidemia, and hypertension, leading to diabetes and cardiovascular diseases (CVD). Intake of carbohydrates (CHO), particularly a sugary diet that rapidly increases blood glucose, triglycerides, and blood pressure levels is the predominant determining factor of MetS. Complex CHO, on the other hand, are a stable source of energy taking a longer time to digest. In particular, resistant starch (RS) or soluble fiber is an excellent source of prebiotics, which alter the gut microbial composition, which in turn improves metabolic control. Altering maternal CHO intake during pregnancy may result in the child developing MetS. Furthermore, lifestyle factors such as physical inactivity in combination with dietary habits may synergistically influence gene expression by modulating genetic and epigenetic regulators transforming childhood obesity into adolescent metabolic disorders. This review summarizes the common pathophysiology of MetS in connection with the nature of CHO, intrauterine nutrition, genetic predisposition, lifestyle factors, and advanced treatment approaches; it also emphasizes how dietary CHO may act as a key element in the pathogenesis and future therapeutic targets of obesity and MetS.

PMID:36102254 | DOI:10.1002/biof.1886