Int J Mol Sci. 2023 Jan 15;24(2):1728. doi: 10.3390/ijms24021728.

ABSTRACT

Salicylanilides are pharmacologically active compounds with a wide spectrum of biological effects. Halogenated salicylanilides, which have been used for decades in human and veterinary medicine as anthelmintics, have recently emerged as candidates for drug repurposing in oncology. The most prominent example of salicylanilide anthelmintic, that is intensively studied for its potential anticancer properties, is niclosamide. Nevertheless, recent studies have discovered extensive anticancer potential in a number of other salicylanilides. This potential of their anticancer action is mediated most likely by diverse mechanisms of action such as uncoupling of oxidative phosphorylation, inhibition of protein tyrosine kinase epidermal growth factor receptor, modulation of different signaling pathways as Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways or induction of B-Raf V600E inhibition. Here we provide a comprehensive overview of the current knowledge about the proposed mechanisms of action of anticancer activity of salicylanilides based on preclinical in vitro and in vivo studies, or structural requirements for such an activity.

PMID:36675241 | DOI:10.3390/ijms24021728

Int J Mol Sci. 2023 Jan 13;24(2):1635. doi: 10.3390/ijms24021635.

ABSTRACT

Visceral leishmaniasis is a neglected vector-borne tropical disease caused by Leishmania donovani and Leishmania infantum that is endemic not only in East African countries, but also in Asia, regions of South America and the Mediterranean Basin. For the pharmacological control of this disease, there is a limited number of old and, in general, poorly adherent drugs, with a multitude of adverse effects and low oral bioavailability, which favor the emergence of resistant pathogens. Pentavalent antimonials are the first-line drugs, but due to their misuse, resistant Leishmania strains have emerged worldwide. Although these drugs have saved many lives, it is recommended to reduce their use as much as possible and replace them with novel and more friendly drugs. From a commercial collection of anti-infective drugs, we have recently identified nifuratel-a nitrofurantoin used against vaginal infections-as a promising repurposing drug against a mouse model of visceral leishmaniasis. In the present work, we have tested combinations of miltefosine-the only oral drug currently used against leishmaniasis-with nifuratel in different proportions, both in axenic amastigotes from bone marrow and in intracellular amastigotes from infected Balb/c mouse spleen macrophages, finding a potent synergy in both cases. In vivo evaluation of oral miltefosine/nifuratel combinations using a bioimaging platform has revealed the potential of these combinations for the treatment of this disease.

PMID:36675150 | DOI:10.3390/ijms24021635

Int J Mol Sci. 2023 Jan 10;24(2):1334. doi: 10.3390/ijms24021334.

ABSTRACT

Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical indication that may help increase the number of possible, effective anticancer drugs. The use of drugs in ways other than their original FDA-approved indications could offer novel avenues such as bypassing the chemoresistance and recurrence seen with conventional therapy and treatment; moreover, it can offer a safe and economic strategy for combination therapy. Recent works have demonstrated the anticancer properties of the FDA-approved drug Mebendazole. This synthetic benzimidazole proved effective against a broad spectrum of intestinal Helminthiasis. Mebendazole can penetrate the blood-brain barrier and has been shown to inhibit the malignant progression of glioma by targeting signaling pathways related to cell proliferation, apoptosis, or invasion/migration, or by increasing the sensitivity of glioma cells to conventional chemotherapy or radiotherapy. Moreover, several preclinical models and ongoing clinical trials explore the efficacy of Mebendazole in multiple cancers, including acute myeloid leukemia, brain cancer, oropharyngeal squamous cell carcinoma, breast cancer, gastrointestinal cancer, lung carcinoma, adrenocortical carcinoma, prostate cancer, and head and neck cancer. The present review summarizes central literature regarding the anticancer effects of MBZ in cancer cell lines, animal tumor models, and clinical trials to suggest possible strategies for safe and economical combinations of anticancer therapies in brain cancer. Mebendazole might be an excellent candidate for the treatment of brain tumors because of its efficacy both when used as monotherapy and in combination as an enhancement to standard chemotherapeutics and radiotherapy, due to its effectiveness on tumor angiogenesis inhibition, cell cycle arrest, apoptosis induction, and targeting of critical pathways involved in cancer such as Hedgehog signaling. Therefore, attention to MBZ repurposing has recently increased because of its potential therapeutic versatility and significant clinical implications, such as reducing medical care costs and optimizing existing therapies. Using new treatments is essential, particularly when current therapeutics for patients with brain cancer fail.

PMID:36674870 | DOI:10.3390/ijms24021334

Int J Mol Sci. 2023 Jan 7;24(2):1210. doi: 10.3390/ijms24021210.

ABSTRACT

The GTP cyclohydrolase 1 enzyme (GTPCH1) is the rate-limiting enzyme of the tetrahydrobiopterin (BH4) biosynthetic pathway. Physiologically, BH4 plays a crucial role as an essential cofactor for the production of catecholamine neurotransmitters, including epinephrine, norepinephrine and dopamine, as well as the gaseous signaling molecule, nitric oxide. Pathological levels of the cofactor have been reported in a number of disease states, such as inflammatory conditions, neuropathic pain and cancer. Targeting the GTPCH1 enzyme has great potential in the management of a number of disease pathologies associated with dysregulated BH4 physiology. This study is an in silico investigation of the human GTPCH1 enzyme using virtual screening and molecular dynamic simulation to identify molecules that can be repurposed to therapeutically target the enzyme. A three-tier molecular docking protocol was employed in the virtual screening of a comprehensive library of over 7000 approved medications and nutraceuticals in order to identify hit compounds capable of binding to the GTPCH1 binding pocket with the highest affinity. Hit compounds were further verified by molecular dynamic simulation studies to provide a detailed insight regarding the stability and nature of the binding interaction. In this study, we identify a number of drugs and natural compounds with recognized anti-inflammatory, analgesic and cytotoxic effects, including the aminosalicylate olsalazine, the antiepileptic phenytoin catechol, and the phlorotannins phlorofucofuroeckol and eckol. Our results suggest that the therapeutic and clinical effects of hit compounds may be partially attributed to the inhibition of the GTPCH1 enzyme. Notably, this study offers an understanding of the off-target effects of a number of compounds and advocates the potential role of aminosalicylates in the regulation of BH4 production in inflammatory disease states. It highlights an in silico drug repurposing approach to identify a potential means of safely targeting the BH4 biosynthetic pathway using established therapeutic agents.

PMID:36674724 | DOI:10.3390/ijms24021210

Int J Mol Sci. 2023 Jan 6;24(2):1095. doi: 10.3390/ijms24021095.

ABSTRACT

Fabry disease is a lysosomal storage disease caused by mutations in the GLA gene that encodes alpha-galactosidase (AGAL). The disease causes abnormal globotriaosylceramide (Gb3) storage in the lysosomes. Variants responsible for the genotypic spectrum of Fabry disease include mutations that abolish enzymatic activity and those that cause protein instability. The latter can be successfully treated with small molecules that either bind and stabilize AGAL or indirectly improve its cellular activity. This paper describes the first attempt to reposition curcumin, a nutraceutical, to treat Fabry disease. We tested the efficacy of curcumin in a cell model and found an improvement in AGAL activity for 80% of the tested mutant genotypes (four out of five tested). The fold-increase was dependent on the mutant and ranged from 1.4 to 2.2. We produced evidence that supports a co-chaperone role for curcumin when administered with AGAL pharmacological chaperones (1-deoxygalactonojirimycin and galactose). The combined treatment with curcumin and either pharmacological chaperone was beneficial for four out of five tested mutants and showed fold-increases ranging from 1.1 to 2.3 for DGJ and from 1.1 to 2.8 for galactose. Finally, we tested a long-term treatment on one mutant (L300F) and detected an improvement in Gb3 clearance and lysosomal markers (LAMP-1 and GAA). Altogether, our findings confirmed the necessity of personalized therapies for Fabry patients and paved the way to further studies and trials of treatments for Fabry disease.

PMID:36674610 | DOI:10.3390/ijms24021095

Int J Mol Sci. 2023 Jan 4;24(2):985. doi: 10.3390/ijms24020985.

ABSTRACT

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system still lacking a cure. Treatment typically focuses on slowing the progression and managing MS symptoms. Single-cell transcriptomics allows the investigation of the immune system-the key player in MS onset and development-in great detail increasing our understanding of MS mechanisms and stimulating the discovery of the targets for potential therapies. Still, de novo drug development takes decades; however, this can be reduced by drug repositioning. A promising approach is to select potential drugs based on activated or inhibited genes and pathways. In this study, we explored the public single-cell RNA data from an experiment with six patients on single-cell RNA peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid cells (CSF) of patients with MS and idiopathic intracranial hypertension. We demonstrate that AIM2 inflammasome, SMAD2/3 signaling, and complement activation pathways are activated in MS in different CSF and PBMC immune cells. Using genes from top-activated pathways, we detected several promising small molecules to reverse MS immune cells' transcriptomic signatures, including AG14361, FGIN-1-27, CA-074, ARP 101, Flunisolide, and JAK3 Inhibitor VI. Among these molecules, we also detected an FDA-approved MS drug Mitoxantrone, supporting the reliability of our approach.

PMID:36674506 | DOI:10.3390/ijms24020985

Reprod Sci. 2023 Jan 20. doi: 10.1007/s43032-023-01167-2. Online ahead of print.

ABSTRACT

Endometriosis is a common condition in women of reproductive age, but its current interventions are unsatisfactory. Recent research discovered a dysregulation of the sphingosine 1-phosphate (S1P) signaling pathway in endometriosis and showed a positive outcome by targeting it. The S1P axis participates in a series of fundamental pathophysiological processes. This narrative review is trying to expound the reported and putative (due to limited reports in this area for now) interactions between the S1P axis and endometriosis in those pathophysiological processes, to provide some perspectives for future research. In short, S1P signaling pathway is highly activated in the endometriotic lesion. The S1P concentration has a surge in the endometriotic cyst fluid and the peritoneal fluid, with the downstream dysregulation of its receptors. The S1P axis plays an essential role in the migration and activation of the immune cells, fibrosis, angiogenesis, pain-related hyperalgesia, and innervation. S1P receptor (S1PR) modulators showed an impressive therapeutic effect by targeting the different S1P receptors in the endometriosis model, and many other conditions resemble endometriosis. And several of them already got approval for clinical application in many diseases, which means a drug repurposing direction and a rapid clinical translation for endometriosis treatments.

PMID:36662421 | DOI:10.1007/s43032-023-01167-2

Curr Oncol. 2023 Jan 5;30(1):704-719. doi: 10.3390/curroncol30010055.

ABSTRACT

Lung cancer is the second most common cancer and the leading cause of cancer-related deaths in 2022. The majority (80%) of lung cancer cases belong to the non-small cell lung carcinoma (NSCLC) subtype. Despite the increased screening efforts, the median five-year survival of metastatic NSCLC remains low at approximately 3%. Common treatment approaches for NSCLC include surgery, multimodal chemotherapy, and concurrent radio and chemotherapy. NSCLC exhibits high rates of resistance to treatment, driven by its heterogeneity and the plasticity of cancer stem cells (CSCs). Drug repurposing offers a faster and cheaper way to develop new antineoplastic purposes for existing drugs, to help overcome therapy resistance. The decrease in time and funds needed stems from the availability of the pharmacokinetic and pharmacodynamic profiles of the Food and Drug Administration (FDA)-approved drugs to be repurposed. This review provides a synopsis of the drug-repurposing approaches and mechanisms of action of potential candidate drugs used in treating NSCLC, including but not limited to antihypertensives, anti-hyperlipidemics, anti-inflammatory drugs, anti-diabetics, and anti-microbials.

PMID:36661704 | DOI:10.3390/curroncol30010055

Biochemistry. 2023 Jan 19. doi: 10.1021/acs.biochem.2c00658. Online ahead of print.

ABSTRACT

Over one and a half million people die of tuberculosis (TB) each year. Multidrug-resistant TB infections are especially dangerous, and new drugs are needed to combat them. The high cost and complexity of drug development make repositioning of drugs that are already in clinical use for other indications a potentially time- and money-saving avenue. In this study, we identified among existing drugs five compounds: azelastine, venlafaxine, chloroquine, mefloquine, and proguanil as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis, a causative agent of TB. Eis upregulation is a cause of clinically relevant resistance of TB to kanamycin, which is inactivated by Eis-catalyzed acetylation. Crystal structures of these drugs as well as chlorhexidine in complexes with Eis showed that these inhibitors were bound in the aminoglycoside binding cavity, consistent with their established modes of inhibition with respect to kanamycin. Among three additionally synthesized compounds, a proguanil analogue, designed based on the crystal structure of the Eis-proguanil complex, was 3-fold more potent than proguanil. The crystal structures of these compounds in complexes with Eis explained their inhibitory potencies. These initial efforts in rational drug repositioning can serve as a starting point in further development of Eis inhibitors.

PMID:36657084 | DOI:10.1021/acs.biochem.2c00658

Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2213363120. doi: 10.1073/pnas.2213363120. Epub 2023 Jan 18.

ABSTRACT

With the emergence of antibiotic-resistant bacteria, innovative approaches are needed for the treatment of urinary tract infections. Boosting antimicrobial peptide expression may provide an alternative to antibiotics. Here, we developed reporter cell lines and performed a high-throughput screen of clinically used drugs to identify compounds that boost ribonuclease 4 and 7 expression (RNase 4 and 7), peptides that have antimicrobial activity against antibiotic-resistant uropathogens. This screen identified histone deacetylase (HDAC) inhibitors as effective RNase 4 and RNase 7 inducers. Validation studies in primary human kidney and bladder cells confirmed pan-HDAC inhibitors as well as the HDAC class I inhibitor, MS-275, induce RNase 4 and RNase 7 to protect human kidney and bladder cells from uropathogenic Escherichia coli. When we administered MS-275 to mice, RNase 4 and 7 expression increased and mice were protected from acute transurethral E. coli challenge. In support of this mechanism, MS-275 treatment increased acetylated histone H3 binding to the RNASE4 and RNASE7 promoters. Overexpression and knockdown of HDAC class I proteins identified HDAC3 as a primary regulator of RNase 4 and 7. These results demonstrate the protective effects of enhancing RNase 4 and RNase 7, opening the door to repurposing medications as antibiotic conserving therapeutics for urinary tract infection.

PMID:36652479 | DOI:10.1073/pnas.2213363120

J Biomol Struct Dyn. 2023 Jan 18:1-10. doi: 10.1080/07391102.2023.2166589. Online ahead of print.

ABSTRACT

The deaths caused by the covid-19 pandemic have recently decreased due to a worldwide effort in vaccination campaigns. However, even vaccinated people can develop a severe form of the disease that requires ICU admission. As a result, the search for antiviral drugs to treat these severe cases has become a necessity. In this context, natural products are an interesting alternative to synthetic medicines used in drug repositioning, as they have been consumed for a long time through traditional medicine. Many natural compounds found in plant extracts have already been shown to be effective in treating viral and bacterial diseases, making them possible hits to exploit against covid-19. The objective of this work was to evaluate the antiviral activity of different plant extracts available in the library of natural products of the Universidade Estadual de Maringá, by inhibiting the SARS-CoV-2 main protease (Mpro), and by preventing viral infection in a cellular model. As a result, the extract of Cytinus hypocistis, obtained by ultrasound, showed a Mpro inhibition capacity greater than 90%. In the infection model assays using Vero cells, an inhibition of 99.6% was observed, with a selectivity index of 42.7. The in silico molecular docking simulations using the extract compounds against Mpro, suggested Tellimagrandin II as the component of C. hypocistis extract most likely to inhibit the viral enzyme. These results demonstrate the potential of C. hypocistis extract as a promising source of natural compounds with antiviral activity against covid-19.Communicated by Ramaswamy H. Sarma.

PMID:36651196 | DOI:10.1080/07391102.2023.2166589

ACS Chem Neurosci. 2023 Jan 17. doi: 10.1021/acschemneuro.2c00672. Online ahead of print.

ABSTRACT

Parkinson's disease (PD) is the second most common neurodegenerative disorder that affects more than ten million people worldwide. However, the current PD treatments are still limited and alternative treatment strategies are urgently required. Leucine-rich repeat kinase 2 (LRRK2) has been recognized as a promising target for PD treatment. However, there are no approved LRRK2 inhibitors on the market. To rapidly identify potential drug repurposing candidates that inhibit LRRK2 kinase, we report a structure-based drug repurposing workflow that combines molecular docking, recursive partitioning model, molecular dynamics (MD) simulation, and molecular mechanics-generalized Born surface area (MM-GBSA) calculation. Thirteen compounds screened from our drug repurposing workflow were further evaluated through the experiment. The experimental results showed six drugs (Abivertinib, Aumolertinib, Encorafenib, Bosutinib, Rilzabrutinib, and Mobocertinib) with IC50 less than 5 μM that were identified as potential LRRK2 kinase inhibitors. The most potent compound Abivertinib showed potent inhibitions with IC50 toward G2019S mutation and wild-type LRRK2 of 410.3 nM and 177.0 nM, respectively. Our combination screening strategy had a 53% hit rate in this repurposing task. MD simulations and MM-GBSA free energy analysis further revealed the atomic binding mechanism between the identified drugs and G2019S LRRK2. In summary, the results showed that our drug repurposing workflow could be used to identify potent compounds for LRRK2. The potent inhibitors discovered in our work can be a starting point to develop more effective LRRK2 inhibitors.

PMID:36649061 | DOI:10.1021/acschemneuro.2c00672

Med Sci (Basel). 2023 Jan 14;11(1):9. doi: 10.3390/medsci11010009.

ABSTRACT

Melanoma is the most aggressive type of skin cancer, with a greater risk of metastasis and a higher prevalence and mortality rate. This cancer type has been demonstrated to develop resistance to the known treatment options such as conventional therapeutic agents and targeted therapy that are currently being used as the standard of care. Drug repurposing has been explored as a potential alternative treatment strategy against disease pathophysiologies, including melanoma. To that end, multiple studies have suggested that melatonin produced by the pineal gland possesses anti-proliferative and oncostatic effects in experimental melanoma models. The anticarcinogenic activity of melatonin is attributed to its ability to target a variety of oncogenic signaling pathways, including the MAPK pathways which are involved in regulating the behavior of cancer cells, including cell survival and proliferation. Additionally, preclinical studies have demonstrated that melatonin in combination with chemotherapeutic agents exerts synergistic effects against melanoma. The goal of this review is to highlight the mechanistic insights of melatonin as a monotherapy or combinational therapy for melanoma treatment.

PMID:36649046 | DOI:10.3390/medsci11010009

Hypertens Res. 2023 Jan 16. doi: 10.1038/s41440-023-01176-3. Online ahead of print.

ABSTRACT

The pathogenesis of hypertension is multifactorial and highly complex. Basic research plays critical roles in elucidating the complex pathogenesis of hypertension and developing its treatment. This review covers recent topics in basic research related to hypertension in the following six parts: brain/autonomic nervous system, kidney, vascular system, potential treatments, extracellular vesicles, and gut microbiota. The brain receives afferent nerve inputs from peripheral organs, including the heart, kidneys, and adipose tissue, and humoral inputs from circulating factors such as proinflammatory cytokines and leptin, which are involved in the regulation of central sympathetic outflow. In the kidneys, changes in Wnt/β-catenin signaling have been reported in several hypertensive models. New findings on the renin-angiotensin-aldosterone system in the kidneys have also been reported. Sirtuin 6, which participates in various cellular functions, including DNA repair, has been shown to have protective effects on the vascular system. Skin water conservation, mediated by skin vasoconstriction and the accumulation of osmolytes such as sodium, has been found to contribute to hypertension. Studies of rivaroxaban and sodium-glucose cotransporter-2 inhibitors as drug repositioning candidates have been performed. Extracellular vesicles have been shown to be involved in novel diagnostic approaches and treatments for hypertension as well as other diseases. In gut microbiota studies, interactions between microbiota and antihypertensive drugs and potential pathophysiology linking microbiota and COVID-19 have been reported. It can be seen that inter-organ communication has received particular attention from these recent research topics. To truly understand the pathogenesis of hypertension and to develop treatments for conquering hypertension, interresearcher communication and collaboration should be further facilitated. This mini-review focuses on recent topics on basic research in hypertension from the several points of view. The recent topics indicate that inter-organ communication has received particular attention. Interresearcher communication and collaboration should also be further facilitated to truly understand the complex pathogenesis of hypertension and to develop the treatments.

PMID:36646880 | DOI:10.1038/s41440-023-01176-3

SLAS Discov. 2023 Jan 13:S2472-5552(23)00001-1. doi: 10.1016/j.slasd.2023.01.001. Online ahead of print.

ABSTRACT

The SARS coronavirus 2 (SARS-CoV-2) pandemic remains a major problem in many parts of the world and infection rates remain at extremely high levels. This high prevalence drives the continued emergence of new variants, and possibly ones that are more vaccine-resistant and that can drive infections even in highly vaccinated populations. The high rate of variant evolution makes clear the need for new therapeutics that can be clinically applied to minimize or eliminate the effects of COVID-19. With a hurdle of 10 years, on average, for first in class small molecule therapeutics to achieve FDA approval, the fastest way to identify therapeutics is by drug repurposing. To this end, we developed a high throughput cell-based screen that incorporates the essential viral 3C-like protease and its peptide cleavage site into a luciferase complementation assay to evaluate the efficacy of known drugs encompassing approximately 15,000 clinical-stage or FDA-approved small molecules. Confirmed inhibitors were also tested to determine their cytotoxic properties. Medicinal chemistry efforts to optimize the hits identified Tranilast as a potential lead. Here, we report the rapid screening and identification of potentially relevant drugs that exhibit selective inhibition of the SARS-CoV-2 viral 3C-like protease.

PMID:36646172 | DOI:10.1016/j.slasd.2023.01.001

Cancer Med. 2023 Jan 16. doi: 10.1002/cam4.5594. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is a common gastrointestinal malignancy with high morbidity and fatality. Chemotherapy, as traditional therapy for CRC, has exerted well antitumor effect and greatly improved the survival of CRC patients. Nevertheless, chemoresistance is one of the major problems during chemotherapy for CRC and significantly limits the efficacy of the treatment and influences the prognosis of patients. To overcome chemoresistance in CRC, many strategies are being investigated. Here, we review the common and novel measures to combat the resistance, including drug repurposing (nonsteroidal anti-inflammatory drugs, metformin, dichloroacetate, enalapril, ivermectin, bazedoxifene, melatonin, and S-adenosylmethionine), gene therapy (ribozymes, RNAi, CRISPR/Cas9, epigenetic therapy, antisense oligonucleotides, and noncoding RNAs), protein inhibitor (EFGR inhibitor, S1PR2 inhibitor, and DNA methyltransferase inhibitor), natural herbal compounds (polyphenols, terpenoids, quinones, alkaloids, and sterols), new drug delivery system (nanocarriers, liposomes, exosomes, and hydrogels), and combination therapy. These common or novel strategies for the reversal of chemoresistance promise to improve the treatment of CRC.

PMID:36645225 | DOI:10.1002/cam4.5594

ACS Omega. 2022 Dec 29;8(1):56-73. doi: 10.1021/acsomega.2c05821. eCollection 2023 Jan 10.

ABSTRACT

Prostate cancer (PCA), the most common cancer in men, accounted for 1.3 million new incidences in 2018. An increase in incidences is an issue of concern that should be addressed. Of all the reported prostate cancers, 85% were detected in stages III and IV, making them difficult to treat. Conventional drugs gradually lose their efficacy due to the developed resistance against them, thus requiring newer therapeutic agents to be used as monotherapy or combination. Recent research regarding treatment options has attained remarkable speed and development. Therefore, in this context, drug repurposing comes into the picture, which is defined as the "investigation of the off-patent, approved and marketed drugs for a novel therapeutic indication" which saves at least 30% of the time and cost, reducing the cost of treatment for patients, which usually runs high in cancer patients. The anticancer property of cardiac glycosides in cancers was tested in the early 1980s. The trend then shifts toward treating prostate cancer by repurposing other cardiovascular drugs. The current review mainly emphasizes the advantageous antiprostate cancer profile of conventional CVS drugs like cardiac glycosides, RAAS inhibitors, statins, heparin, and beta-blockers with underlying mechanisms.

PMID:36643505 | PMC:PMC9835086 | DOI:10.1021/acsomega.2c05821

Free Radic Res. 2023 Jan 15:1-18. doi: 10.1080/10715762.2022.2146500. Online ahead of print.

ABSTRACT

Drug repurposing allows searching for new biological targets, especially against emerging diseases such as Covid-19. Drug colchicine (COL) presents recognized anti-inflammatory action, while the nanotechnology purpose therapies with low doses, efficacy, and decrease the drug's side-effects. This study aims to evaluate the effects of COL and colchicine nanocapsules (NCCOL) on survival, LC50, activity locomotor, and oxidative stress parameters, elucidating the toxicity profile in acute and chronic exposure in Drosophila melanogaster. Three-day-old flies were investigated into groups: Control, 0.001, 0.0025, 0.005, and 0.010 mg/mL of COL or NCCOL. The survival rate, open field test, LC50, oxidative stress markers (reactive species (RS) production, thiobarbituric acid reactive substances), antioxidant enzyme activity (catalase (CAT), superoxide dismutase (SOD), glutathione S-transferase), protein thiols, nonprotein thiols, acetylcholinesterase activity, and cell viability were measured. As a result, acute exposure to the COL decreases the number of crosses in the open field and increases CAT activity. NCCOL reduced RS levels, increased lipoperoxidation and SOD activity. Chronic exposure to the COL and NCCOL in high concentrations implied high mortality and enzymatic inhibition of the CAT and AChE, and only the COL caused locomotor damage in the open field test. Thus, NCCOL again reduced the formation of RS while COL increased. In this comparative study, NCCOL was less toxic to the antioxidant system than COL and showed notable involvement of oxidative stress as one of their toxicity mechanisms. Future studies are needed to elucidate all aspects of nanosafety related to the NCCOL.

PMID:36641780 | DOI:10.1080/10715762.2022.2146500

BMC Psychiatry. 2023 Jan 14;23(1):40. doi: 10.1186/s12888-023-04543-z.

ABSTRACT

Schizophrenia (SCZ) is a severe mental illness mainly characterized by a number of psychiatric symptoms. Obsessive-compulsive disorder (OCD) is a long-lasting and devastating mental disorder. SCZ has high co-occurrence with OCD resulting in the emergence of a concept entitled "schizo-obsessive disorder" as a new specific clinical entity with more severe psychiatric symptoms. Many studies have been done on SCZ and OCD, but the common pathogenesis between them is not clear yet. Therefore, this study aimed to identify shared genetic basis, potential biomarkers and therapeutic targets between these two disorders. Gene sets were extracted from the Geneweaver and Harmonizome databases for each disorder. Interestingly, the combination of both sets revealed 89 common genes between SCZ and OCD, the most important of which were BDNF, SLC6A4, GAD1, HTR2A, GRIN2B, DRD2, SLC6A3, COMT, TH and DLG4. Then, we conducted a comprehensive bioinformatics analysis of the common genes. Receptor activity as the molecular functions, neuron projection and synapse as the cellular components as well as serotonergic synapse, dopaminergic synapse and alcoholism as the pathways were the most significant commonalities in enrichment analyses. In addition, transcription factor (TFs) analysis predicted significant TFs such as HMGA1, MAPK14, HINFP and TEAD2. Hsa-miR-3121-3p and hsa-miR-495-3p were the most important microRNAs (miRNAs) associated with both disorders. Finally, our study predicted 19 existing drugs (importantly, Haloperidol, Fluoxetine and Melatonin) that may have a potential influence on this co-occurrence. To summarize, this study may help us to better understand and handle the co-occurrence of SCZ and OCD by identifying potential biomarkers and therapeutic targets.

PMID:36641432 | DOI:10.1186/s12888-023-04543-z

J Exp Clin Cancer Res. 2023 Jan 14;42(1):22. doi: 10.1186/s13046-022-02590-0.

ABSTRACT

BACKGROUND: Nitric oxide-releasing drugs are used for cardiovascular diseases; however, their effects on the tumor immune microenvironment are less clear. Therefore, this study explored the impact of nitric oxide donors on tumor progression in immune-competent mice.

METHODS: The effects of three different nitric oxide-releasing compounds (SNAP, SNP, and ISMN) on tumor growth were studied in tumor-bearing mouse models. Three mouse tumor models were used: B16F1 melanoma and LL2 lung carcinoma in C57BL/6 mice, CT26 colon cancer in BALB/c mice, and LL2 lung carcinoma in NOD/SCID mice. After nitric oxide treatment, splenic cytokines and lymphocytes were analyzed by cytokine array and flow cytometry, and tumor-infiltrating lymphocytes in the TME were analyzed using flow cytometry and single-cell RNA sequencing.

RESULTS: Low doses of three exogenous nitric oxide donors inhibited tumor growth in two immunocompetent mouse models but not in NOD/SCID immunodeficient mice. Low-dose nitric oxide donors increase the levels of splenic cytokines IFN-γ and TNF-α but decrease the levels of cytokines IL-6 and IL-10, suggesting an alteration in Th2 cells. Nitric oxide donors increased the number of CD8+ T cells with activation gene signatures, as indicated by single-cell RNA sequencing. Flow cytometry analysis confirmed an increase in infiltrating CD8+ T cells and dendritic cells. The antitumor effect of nitric oxide donors was abolished by depletion of CD8+ T cells, indicating the requirement for CD8+ T cells. Tumor inhibition correlated with a decrease in a subtype of protumor macrophages and an increase in a subset of Arg1-positive macrophages expressing antitumor gene signatures. The increase in this subset of macrophages was confirmed by flow cytometry analysis. Finally, the combination of low-dose nitric oxide donor and cisplatin induced an additive cancer therapeutic effect in two immunocompetent animal models. The enhanced therapeutic effect was accompanied by an increase in the cells expressing the gene signature of NK cell.

CONCLUSIONS: Low concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages. CD8+ T cells are essential for antitumor effects. In addition, low-dose nitric oxide donors may be combined with chemotherapeutic drugs in cancer therapy in the future.

PMID:36639681 | PMC:PMC9840268 | DOI:10.1186/s13046-022-02590-0