Int Rev Psychiatry. 2022 Nov-Dec;34(7-8):699-714. doi: 10.1080/09540261.2022.2113369. Epub 2022 Aug 23.

ABSTRACT

Depression has a large burden, but the development of new drugs for its treatment has proved difficult. Progresses in neuroscience have highlighted several physiopathological pathways, notably inflammatory and metabolic ones, likely involved in the genesis of depressive symptoms. A novel strategy proposes to repurpose established medical treatments of known safety and to investigate their potential antidepressant activity. Among numerous candidates, growing evidence suggests that statins may have a positive role in the treatment of depressive disorders, although some have raised concerns about possible depressogenic effects of these widely prescribed medications. This narrative review summarises relevant findings from translational studies implicating many interconnected neurobiological and neuropsychological, cardiovascular, endocrine-metabolic, and immunological mechanisms by which statins could influence mood. Also, the most recent clinical investigations on the effects of statins in depression are presented. Overall, the use of statins for the treatment of depressive symptoms cannot be recommended based on the available literature, though this might change as several larger, methodologically robust studies are being conducted. Nevertheless, statins can already be acknowledged as a driver of innovation in mental health, as they provide a novel perspective to the physical health of people with depression and for the development of more precise antidepressant treatments.

PMID:36786109 | DOI:10.1080/09540261.2022.2113369

Biophys J. 2023 Feb 10;122(3S1):472a-473a. doi: 10.1016/j.bpj.2022.11.2533.

NO ABSTRACT

PMID:36784427 | DOI:10.1016/j.bpj.2022.11.2533

Biophys J. 2023 Feb 10;122(3S1):144a. doi: 10.1016/j.bpj.2022.11.942.

NO ABSTRACT

PMID:36782662 | DOI:10.1016/j.bpj.2022.11.942

Biophys J. 2023 Feb 10;122(3S1):144a. doi: 10.1016/j.bpj.2022.11.941.

NO ABSTRACT

PMID:36782661 | DOI:10.1016/j.bpj.2022.11.941

Purinergic Signal. 2023 Feb 13. doi: 10.1007/s11302-023-09924-3. Online ahead of print.

ABSTRACT

Some non-adenosinergic drugs are reported to also act through adenosine receptors (ARs). We used mouse hypothermia, which can be induced by agonism at any of the four ARs, as an in vivo screen for adenosinergic effects. An AR contribution was identified when a drug caused hypothermia in wild type mice that was diminished in mice lacking all four ARs (quadruple knockout, QKO). Alternatively, an adenosinergic effect was identified if a drug potentiated adenosine-induced hypothermia. Four drugs (dipyridamole, nimodipine, cilostazol, cyclosporin A) increased the hypothermia caused by adenosine. Dipyridamole and nimodipine probably achieved this by inhibition of adenosine clearance via ENT1. Two drugs (cannabidiol, canrenoate) did not cause hypothermia in wild type mice. Four other drugs (nifedipine, ranolazine, ketamine, ethanol) caused hypothermia, but the hypothermia was unchanged in QKO mice indicating non-adenosinergic mechanisms. Zinc chloride caused hypothermia and hypoactivity; the hypoactivity was blunted in the QKO mice. Interestingly, the antidepressant amitriptyline caused hypothermia in wild type mice that was amplified in the QKO mice. Thus, we have identified adenosine-related effects for some drugs, while other candidates do not affect adenosine signaling by this in vivo assay. The adenosine-modulating drugs could be considered for repurposing based on predicted effects on AR activation.

PMID:36781825 | DOI:10.1007/s11302-023-09924-3

Biomater Sci. 2023 Feb 13. doi: 10.1039/d2bm01957d. Online ahead of print.

ABSTRACT

A simple but novel ophthalmic solution based on two approved drugs was developed to reposition existing drugs to treat new diseases. This nanoformulation was developed using the phytochemical drug glycyrrhizin as an amphiphilic nanocarrier to micellarly solubilize empagliflozin (EMP), an oral drug that is widely used to control high blood glucose but has poor water solubility. This novel nanoformulation, which we designated the EMP@glycymicelle ophthalmic solution, was obtained using a simple preparation process. The resulting solution was a clear solution with an EMP encapsulation efficiency of 97.91 ± 0.50%, a small glycymicelle size of 6.659 ± 0.196 nm, and a narrow polydispersity index of 0.226 ± 0.059. The optimized formulation demonstrated that EMP was soluble in water up to 18 mg ml-1 because of its encapsulation within glycymicelles. The EMP@glycymicelle ophthalmic solution exhibited excellent characteristics, including good storage stability, fast in vitro release profiles, improved in vitro antioxidant activity, and no ocular irritation. Ocular permeation evaluation showed that the EMP@glycymicelle ophthalmic solution had strong ocular permeation of EMP, and it reached the posterior segment of mouse eyes after ocular topical administration. The treatment efficacy evaluation showed that the EMP@glycymicelle ophthalmic solution had a significant effect against corneal alkali burns in mice, prompting corneal wound healing, recovering corneal sensitivity, reducing corneal haze, and relieving corneal NV invasion. The mechanism of inhibiting HMGB1 signaling was involved in this strong treatment effect. These results indicated that the EMP@glycymicelle ophthalmic solution provided a new concept of drug repurposing and a promising ocular system for the nano-delivery of EMP with significantly improved in vivo profiles.

PMID:36779571 | DOI:10.1039/d2bm01957d

Expert Rev Precis Med Drug Dev. 2022;7(1):4-16. doi: 10.1080/23808993.2022.2028548. Epub 2022 Jan 24.

ABSTRACT

INTRODUCTION: Cardiovascular disease persists as the leading cause of death worldwide despite continued advances in diagnostics and therapeutics. Our current approach to patients with cardiovascular disease is rooted in reductionism, which presupposes that all patients share a similar phenotype and will respond the same to therapy; however, this is unlikely as cardiovascular diseases exhibit complex heterogeneous phenotypes.

AREAS COVERED: With the advent of high-throughput platforms for omics testing, phenotyping cardiovascular diseases has advanced to incorporate large-scale molecular data with classical history, physical examination, and laboratory results. Findings from genomics, proteomics, and metabolomics profiling have been used to define more precise cardiovascular phenotypes and predict adverse outcomes in population-based and disease-specific patient cohorts. These molecular data have also been utilized to inform drug efficacy based on a patient's unique phenotype.

EXPERT OPINION: Multiscale phenotyping of cardiovascular disease has revealed diversity among patients that can be used to personalize pharmacotherapies and predict outcomes. Nonetheless, precision phenotyping for cardiovascular disease remains a nascent field that has not yet translated into widespread clinical practice despite its many potential advantages for patient care. Future endeavors that demonstrate improved pharmacotherapeutic responses and associated reduction in adverse events will facilitate mainstream adoption of precision cardiovascular phenotyping.

PMID:36778892 | PMC:PMC9913616 | DOI:10.1080/23808993.2022.2028548

Front Microbiol. 2023 Jan 26;14:1112491. doi: 10.3389/fmicb.2023.1112491. eCollection 2023.

ABSTRACT

Mycobacterium tuberculosis is a deadly pathogen, currently the leading cause of death worldwide from a single infectious agent through tuberculosis infections. If the End TB 2030 strategy is to be achieved, additional drugs need to be identified and made available to supplement the current treatment regimen. In addition, drug resistance is a growing issue, leading to significantly lower treatment success rates, necessitating further drug development. Vanoxerine (GBR12909), a dopamine re-uptake inhibitor, was recently identified as having anti-mycobacterial activity during a drug repurposing screening effort. However, its effects on mycobacteria were not well characterized. Herein, we report vanoxerine as a disruptor of the membrane electric potential, inhibiting mycobacterial efflux and growth. Vanoxerine had an undetectable level of resistance, highlighting the lack of a protein target. This study suggests a mechanism of action for vanoxerine, which will allow for its continued development or use as a tool compound.

PMID:36778873 | PMC:PMC9909702 | DOI:10.3389/fmicb.2023.1112491

Cell Genom. 2022 Feb 9;2(2):100100. doi: 10.1016/j.xgen.2022.100100. eCollection 2022 Feb 9.

ABSTRACT

Hirt et al.1 report an automated, high-throughput drug screening platform for organoid cultures to enable repurposing of previously approved drugs for pancreatic cancers harboring specific genetic alterations. The pancreatic cancer organoid biobank also represents a valuable tool to uncover new drug-gene interactions in pancreatic tumors.

PMID:36778660 | PMC:PMC9903715 | DOI:10.1016/j.xgen.2022.100100

bioRxiv. 2023 Jan 31:2023.01.31.526483. doi: 10.1101/2023.01.31.526483. Preprint.

ABSTRACT

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets, we screened the Repurposing, Focused Rescue, and Accelerated Medchem library against P. vivax liver stages and identified the DNA methyltransferase inhibitors hydralazine and cadralazine as active against hypnozoites. We then used bisulfite sequencing and immunostaining to identify cytosine modifications in the infectious stage (sporozoites) and liver stages, respectively. A subsequent screen of epigenetic inhibitors revealed hypnozoites are broadly sensitive to histone acetyltransferase and methyltransferase inhibitors, indicating that several epigenetic mechanisms are likely modulating hypnozoite persistence. Our data present an avenue for the discovery and development of improved radical cure antimalarials.

ONE-SENTENCE SUMMARY: A drug repurposing screen reveals antihypertension drugs are active against P. vivax hypnozoites and epigenetic mechanisms play a role in hypnozoite quiescence.

PMID:36778461 | PMC:PMC9915689 | DOI:10.1101/2023.01.31.526483

Lab Invest. 2022 Sep;102(9):1038-1049. doi: 10.1038/s41374-021-00704-4. Epub 2023 Jan 4.

ABSTRACT

Mesenchymal chondrosarcoma (MCS) is a high-grade malignancy that represents 2-9% of chondrosarcomas and mostly affects children and young adults. HEY1-NCoA2 gene fusion is considered to be a driver of tumorigenesis and it has been identified in 80% of MCS tumors. The shortage of MCS samples and biological models creates a challenge for the development of effective therapeutic strategies to improve the low survival rate of MCS patients. Previous molecular studies using immunohistochemical staining of patient samples suggest that activation of PDGFR signaling could be involved in MCS tumorigenesis. This work presents the development of two independent in vitro and in vivo models of HEY1-NCoA2-driven MCS and their application in a drug repurposing strategy. The in vitro model was characterized by RNA sequencing at the single-cell level and successfully recapitulated relevant MCS features. Imatinib, as well as specific inhibitors of ABL and PDGFR, demonstrated a highly selective cytotoxic effect targeting the HEY1-NCoA2 fusion-driven cellular model. In addition, patient-derived xenograft (PDX) models of MCS harboring the HEY1-NCoA2 fusion were developed from a primary tumor and its distant metastasis. In concordance with in vitro observations, imatinib was able to significantly reduce tumor growth in MCS-PDX models. The conclusions of this study serve as preclinical results to revisit the clinical efficacy of imatinib in the treatment of HEY1-NCoA2-driven MCS.

PMID:36775418 | DOI:10.1038/s41374-021-00704-4

Comput Biol Med. 2023 Feb 7;155:106630. doi: 10.1016/j.compbiomed.2023.106630. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is a severe health concern that results from a cocktail of genetic, epigenetic, and environmental abnormalities. Because it is the second most lethal malignancy in the world and the third-most common malignant tumor, but the treatment is unavailable. The goal of the current study was to use bioinformatics and systems biology techniques to determine the pharmacological mechanism underlying putative important genes and linked pathways in early-onset CRC. Computer-aided methods were used to uncover similar biological targets and signaling pathways associated with CRC, along with bioinformatics and network pharmacology techniques to assess the effects of enzastaurin on CRC. The KEGG and gene ontology (GO) pathway analysis revealed several significant pathways including in positive regulation of protein phosphorylation, negative regulation of the apoptotic process, nucleus, nucleoplasm, protein tyrosine kinase activity, PI3K-Akt signaling pathway, pathways in cancer, focal adhesion, HIF-1 signaling pathway, and Rap1 signaling pathway. Later, the hub protein module identified from the protein-protein interactions (PPIs) network, molecular docking and molecular dynamics simulation represented that enzastaurin showed strong binding interaction with two hub proteins including CASP3 (-8.6 kcal/mol), and MCL1 (-8.6 kcal/mol), which were strongly implicated in CRC management than other the five hub proteins. Moreover, the pharmacokinetic features of enzastaurin revealed that it is an effective therapeutic agent with minimal adverse effects. Enzastaurin may inhibit the potential biological targets that are thought to be responsible for the advancement of CRC and this study suggests a potential novel therapeutic target for CRC.

PMID:36774894 | DOI:10.1016/j.compbiomed.2023.106630

Cytokine. 2023 Feb 10;164:156143. doi: 10.1016/j.cyto.2023.156143. Online ahead of print.

ABSTRACT

Leishmania amazonensis can cause a wide spectrum of the clinical manifestations of leishmaniasis in humans. The development of new therapeutics is a long and expensive task; in this context, drug repositioning could be considered a strategy to identify new biological actions of known products. In the present study, ivermectin (IVE) was tested against distinct Leishmania species able to cause disease in humans. In vitro experiments showed that IVE was effective to reduce the infection degree and parasite load in Leishmania donovani- and L. amazonensis-infected macrophages that were treated with it. In addition, using the culture supernatant of treated macrophages, higher production of IFN-γ and IL-12 and lower levels of IL-4 and IL-10 were found. Then, IVE was used in a pure form or incorporated into Poloxamer 407-based polymeric micelles (IVE/M) for the treatment of L. amazonensis-infected BALB/c mice. Animals (n = 16 per group) were infected and later received saline, empty micelles, amphotericin B (AmpB), IVE, or IVE/M. They were euthanized at one (n = 8 per group) and 30 (n = 8 per group) days after treatment and, in both endpoints, immunological, parasitological, and biochemical evaluations were performed. Results showed that both IVE and IVE/M induced higher levels of IFN-γ, IL-12, GM-CSF, nitrite, and IgG2a antibodies, as well as higher IFN-γ expression evaluated by RT-qPCR in spleen cell cultures. Such animals showed low organic toxicity, as well as significant reductions in the lesion's average diameter and parasite load in their infected tissue, spleen, liver, and draining lymph node. The efficacy was maintained 30 days post-therapy, while control mice developed a polarized Th2-type response and high parasite load. In this context, IVE could be considered as a new candidate to be applied in future studies for the treatment against distinct Leishmania species.

PMID:36774730 | DOI:10.1016/j.cyto.2023.156143

Molecules. 2023 Jan 31;28(3):1365. doi: 10.3390/molecules28031365.

ABSTRACT

Marine algae have excellent bioresource properties with potential nutritional and bioactive therapeutic benefits, but studies regarding Caulerpa lentillifera are limited. This study aims to explore the metabolites profile and the antioxidant, anticancer, anti-obesity, and in vitro cytotoxicity properties of fractionated ethanolic extract of C. lentillifera using two maceration and soxhlet extraction methods. Dried simplicia of C. lentillifera was mashed and extracted in ethanol solvent, concentrated and evaporated, then sequentially partitioned with equal volumes of ethyl acetate and n-Hexane. Six samples were used in this study, consisting of ME (Maceration-Ethanol), MEA (Maceration-Ethyl Acetate), MH (Maceration-n-Hexane), SE (Soxhletation-Ethanol), SEA (Soxhletation-Ethyl Acetate), and SH (Soxhletation-n-Hexane). Non-targeted metabolomic profiling was determined using LC-HRMS, while antioxidant, anti-obesity, and anticancer cytotoxicity were determined using DPPH and ABTS, lipase inhibition, and MTT assay, respectively. This study demonstrates that C. lentillifera has several functional metabolites, antioxidant capacity (EC50 MH is very close to EC50 of Trolox), as well as anti-obesity properties (EC50 MH < EC50 orlistat, an inhibitor of lipid hydrolyzing enzymes), which are useful as precursors for new therapeutic approaches in improving obesity-related diseases. More interestingly, ME, MH, and SE are novel bioresource agents for anticancer drugs, especially for hepatoma, breast, colorectal, and leukemia cancers. Finally, C. lentillifera can be a nutraceutical with great therapeutic benefits.

PMID:36771032 | DOI:10.3390/molecules28031365

Molecules. 2023 Jan 23;28(3):1137. doi: 10.3390/molecules28031137.

ABSTRACT

Novel drugs are desperately needed in order to combat a significant challenge due to chemo-therapeutic resistance and bad prognosis. This research aimed to assess the anticancer activity of a newly synthesized ciprofloxacin Mannich base (CMB) on ovarian cancer (OVCAR-3) and lung cancer (A-549) cell lines and to investigate probable involved molecular mechanisms. The cytotoxic and pro-apoptotic impact of CMB on both cell lines was investigated using MTT assay, Annexin V assay, and cell cycle analysis, as well as caspase-3 activation. Western blotting was carried out to evaluate downstream targets of the MAPK pathway, while qRT PCR was used to evaluate the gene expression pattern of the p53/Bax/Bcl2 pathway. CMB treatment showed significantly reduced cell proliferation in both OVCAR-3 and A-549 cells with half maximum inhibitory concentration (IC50) = 11.60 and 16.22 µg/mL, respectively. CMB also induced apoptosis, S phase cell cycle arrest, and up-regulated expression of p53, p21, and Bax while down-regulated Bcl2 expression. CMB also halted cell proliferation by deactivating the MAPK pathway. In conclusion, CMB may be regarded as a potential antiproliferative agent for lung and ovarian cancers due to anti-proliferative and pro-apoptotic actions via inhibition of the MAPK pathway and p53/Bax/Bcl2.

PMID:36770806 | DOI:10.3390/molecules28031137

Int J Mol Sci. 2023 Feb 3;24(3):2974. doi: 10.3390/ijms24032974.

ABSTRACT

Coronavirus disease-19 (COVID-19) emerged in December 2019 and quickly spread, giving rise to a pandemic crisis. Therefore, it triggered tireless efforts to identify the mechanisms of the disease, how to prevent and treat it, and to limit and hamper its global dissemination. Considering the above, the search for prophylactic approaches has led to a revolution in the reglementary pharmaceutical pipeline, with the approval of vaccines against COVID-19 in an unprecedented way. Moreover, a drug repurposing scheme using regulatory-approved antiretroviral agents is also being pursued. However, their physicochemical characteristics or reported adverse events have sometimes limited their use. Hence, nanotechnology has been employed to potentially overcome some of these challenges, particularly cyclodextrins. Cyclodextrins are cyclic oligosaccharides that present hydrophobic cavities suitable for complexing several drugs. This review, besides presenting studies on the inclusion of antiviral drugs in cyclodextrins, aims to summarize some currently available prophylactic and therapeutic schemes against COVID-19, highlighting those that already make use of cyclodextrins for their complexation. In addition, some new therapeutic approaches are underscored, and the potential application of cyclodextrins to increase their promising application against COVID-19 will be addressed. This review describes the instances in which the use of cyclodextrins promotes increased bioavailability, antiviral action, and the solubility of the drugs under analysis. The potential use of cyclodextrins as an active ingredient is also covered. Finally, toxicity and regulatory issues as well as future perspectives regarding the use of cyclodextrins in COVID-19 therapy will be provided.

PMID:36769299 | DOI:10.3390/ijms24032974

Int J Mol Sci. 2023 Feb 2;24(3):2890. doi: 10.3390/ijms24032890.

ABSTRACT

Rilpivirine is an antiretroviral drug used to treat AIDS worldwide. The drug is a non-nucleoside reverse transcriptase inhibitor that halts the cDNA elongation process and, thus, the capacity of the HIV-1 virus to replicate. With the new wave of drug repurposing in recent years, rilpivirine has been studied in this regard. This drug is useful in Zika virus treatment, with in vivo results indicating regression in neuronal effects often associated with this infection. Several cancer types have also been researched, from breast to leukemia and pancreatic cancer, and rilpivirine has proved to have inhibitory effects in various cell lines with low concentrations, causing cellular death, apoptosis, and cell cycle arrest. The pathways are not yet established, but some works have hypothesized and demonstrated that rilpivirine causes inhibition of Aurora A kinase and has effects on the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway and the vascular endothelial growth factors-receptors (VEGFs-VEGFRs) pathway, which are known to be altered in cancer and tumors and can be targeted for cancer treatment. Further testing and clinical trials are needed, but this review demonstrates the potential of rilpivirine's repurposing for cancer treatment.

PMID:36769210 | DOI:10.3390/ijms24032890

Int J Mol Sci. 2023 Jan 23;24(3):2244. doi: 10.3390/ijms24032244.

ABSTRACT

Drug repositioning aims to discover novel clinical benefits of existing drugs, is an effective way to develop drugs for complex diseases such as cancer and may facilitate the process of traditional drug development. Meanwhile, network-based computational biology approaches, which allow the integration of information from different aspects to understand the relationships between biomolecules, has been successfully applied to drug repurposing. In this work, we developed a new strategy for network-based drug repositioning against cancer. Combining the mechanism of action and clinical efficacy of the drugs, a cancer-related drug similarity network was constructed, and the correlation score of each drug with a specific cancer was quantified. The top 5% of scoring drugs were reviewed for stability and druggable potential to identify potential repositionable drugs. Of the 11 potentially repurposable drugs for non-small cell lung cancer (NSCLC), 10 were confirmed by clinical trial articles and databases. The targets of these drugs were significantly enriched in cancer-related pathways and significantly associated with the prognosis of NSCLC. In light of the successful application of our approach to colorectal cancer as well, it provides an effective clue and valuable perspective for drug repurposing in cancer.

PMID:36768566 | DOI:10.3390/ijms24032244

Int J Mol Sci. 2023 Jan 19;24(3):1997. doi: 10.3390/ijms24031997.

ABSTRACT

Cardiovascular and renal diseases are among the leading causes of death worldwide, and regardless of current efforts, there is a demanding need for therapeutic alternatives to reduce their progression to advanced stages. The stress caused by diseases leads to the activation of protective mechanisms in the cell, including chaperone proteins. The Sigma-1 receptor (Sig-1R) is a ligand-operated chaperone protein that modulates signal transduction during cellular stress processes. Sig-1R interacts with various ligands and proteins to elicit distinct cellular responses, thus, making it a potential target for pharmacological modulation. Furthermore, Sig-1R ligands activate signaling pathways that promote cardioprotection, ameliorate ischemic injury, and drive myofibroblast activation and fibrosis. The role of Sig-1R in diseases has also made it a point of interest in developing clinical trials for pain, neurodegeneration, ischemic stroke, depression in patients with heart failure, and COVID-19. Sig-1R ligands in preclinical models have significantly beneficial effects associated with improved cardiac function, ventricular remodeling, hypertrophy reduction, and, in the kidney, reduced ischemic damage. These basic discoveries could inform clinical trials for heart failure (HF), myocardial hypertrophy, acute kidney injury (AKI), and chronic kidney disease (CKD). Here, we review Sig-1R signaling pathways and the evidence of Sig-1R modulation in preclinical cardiac and renal injury models to support the potential therapeutic use of Sig-1R agonists and antagonists in these diseases.

PMID:36768323 | DOI:10.3390/ijms24031997

Int J Mol Sci. 2023 Jan 19;24(3):1955. doi: 10.3390/ijms24031955.

ABSTRACT

Finding an effective drug to prevent or treat COVID-19 is of utmost importance in tcurrent pandemic. Since developing a new treatment takes a significant amount of time, drug repurposing can be an effective option for achieving a rapid response. This study used a combined in silico virtual screening protocol for candidate SARS-CoV-2 PLpro inhibitors. The Drugbank database was searched first, using the Informational Spectrum Method for Small Molecules, followed by molecular docking. Gramicidin D was selected as a peptide drug, showing the best in silico interaction profile with PLpro. After the expression and purification of PLpro, gramicidin D was screened for protease inhibition in vitro and was found to be active against PLpro. The current study's findings are significant because it is critical to identify COVID-19 therapies that are efficient, affordable, and have a favorable safety profile.

PMID:36768280 | DOI:10.3390/ijms24031955