Molecules. 2024 Feb 29;29(5):1082. doi: 10.3390/molecules29051082.

ABSTRACT

Enhalus arcoides is a highly beneficial type of seagrass. Prior studies have presented proof of the bioactivity of E. acoroides, suggesting its potential to combat cancer. Therefore, this study aims to delve deeper into E. acoroides bioactive molecule profiles and their direct biological anticancer activities potentials through the combination of in-silico and in-vitro studies. This study conducted metabolite profile analysis on E. acoroides utilizing HPLC-ESI-HRMS/MS analysis. Two extraction techniques, ethanol and hexane, were employed for the extraction process. Furthermore, the in-silico study was conducted using molecular docking simulations on the HER2, EGFR tyrosine kinase and HIF-1α protein receptor. Afterward, the antioxidant activity of E. acoroides metabolites was examined to ABTS, and the antiproliferative activity was tested using an MTT assay. An in-silico study revealed its ability to combat breast cancer by inhibiting the HER2/EGFR/HIF-1α pathway through molecular docking. In addition, the MTT assay demonstrated that higher dosages of metabolites from E. acoroides increased the effectiveness of toxicity against cancer cell lines. Additionally, the study demonstrated that the metabolites possess the ability to function as potent antioxidants, effectively inhibiting a series of carcinogenic mechanisms. Ultimately, this study showed a new approach to unveiling the E. acoroides metabolites' anticancer activity through inhibiting HER2/EGFR/HIF-1α receptors, with great cytotoxicity and a potent antioxidant property to prevent a carcinogenic cascade.

PMID:38474594 | DOI:10.3390/molecules29051082

Int J Mol Sci. 2024 Feb 26;25(5):2682. doi: 10.3390/ijms25052682.

ABSTRACT

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by swelling in at least one joint. Owing to an overactive immune response, extra-articular manifestations are observed in certain cases, with interstitial lung disease (ILD) being the most common. Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is characterized by chronic inflammation of the interstitial space, which causes fibrosis and the scarring of lung tissue. Controlling inflammation and pulmonary fibrosis in RA-ILD is important because they are associated with high morbidity and mortality. Pirfenidone and nintedanib are specific drugs against idiopathic pulmonary fibrosis and showed efficacy against RA-ILD in several clinical trials. Immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) with anti-fibrotic effects have also been used to treat RA-ILD. Immunosuppressants moderate the overexpression of cytokines and immune cells to reduce pulmonary damage and slow the progression of fibrosis. DMARDs with mild anti-fibrotic effects target specific fibrotic pathways to regulate fibrogenic cellular activity, extracellular matrix homeostasis, and oxidative stress levels. Therefore, specific medications are required to effectively treat RA-ILD. In this review, the commonly used RA-ILD treatments are discussed based on their molecular mechanisms and clinical trial results. In addition, a computational approach is proposed to develop specific drugs for RA-ILD.

PMID:38473928 | DOI:10.3390/ijms25052682

Cancers (Basel). 2024 Feb 27;16(5):963. doi: 10.3390/cancers16050963.

ABSTRACT

SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is a significant need to understand the roles of kinases in regulating therapeutic responses, acknowledge the existing knowledge gaps, and discuss future directions for improved therapeutics for recalcitrant SCLC. Here, we extensively review the effect of dysregulated kinases in SCLC. We further discuss the pharmacological inhibitors of kinases used in targeted therapies for recalcitrant SCLC. We also describe the role of kinases in the ICI-mediated activation of antitumor immune responses. Finally, we summarize the clinical trials evaluating the potential of kinase inhibitors and ICIs. This review overviews dysregulated kinases in SCLC and summarizes their potential as targeted therapeutic agents. We also discuss their clinical efficacy in enhancing anticancer responses mediated by ICIs.

PMID:38473324 | DOI:10.3390/cancers16050963

Cancers (Basel). 2024 Feb 22;16(5):885. doi: 10.3390/cancers16050885.

ABSTRACT

The strategy of drug repurposing has gained traction in the field of cancer therapy as a means of discovering novel therapeutic uses for established pharmaceuticals. Paroxetine (PX), a selective serotonin reuptake inhibitor typically utilized in the treatment of depression, has demonstrated promise as an agent for combating cancer. Nevertheless, the specific functions and mechanisms by which PX operates in the context of triple-negative breast cancer (TNBC) remain ambiguous. This study aimed to examine the impact of PX on TNBC cells in vitro as both a standalone treatment and in conjunction with other pharmaceutical agents. Cell viability was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, apoptosis was assessed through flow cytometry, and the effects on signaling pathways were analyzed using RNA sequencing and Western blot techniques. Furthermore, a subcutaneous tumor model was utilized to assess the in vivo efficacy of combination therapy on tumor growth. The results of our study suggest that PX may activate the Ca2+-dependent mitochondria-mediated intrinsic apoptosis pathway in TNBC by potentially influencing the PI3K/AKT/mTOR pathway as well as by inducing cytoprotective autophagy. Additionally, the combination of PX and chemotherapeutic agents demonstrated moderate inhibitory effects on 4T1 tumor growth in an in vivo model. These findings indicate that PX may exert its effects on TNBC through modulation of critical molecular pathways, offering important implications for improving chemosensitivity and identifying potential therapeutic combinations for clinical use.

PMID:38473249 | DOI:10.3390/cancers16050885

Cancers (Basel). 2024 Feb 22;16(5):872. doi: 10.3390/cancers16050872.

ABSTRACT

Breast cancer, ranking as the second leading cause of female cancer-related deaths in the U.S., demands the exploration of innovative treatments. Repurposing FDA-approved drugs emerges as an expedited and cost-effective strategy. Our study centered on proguanil, an antimalarial drug, reveals notable anti-proliferative effects on diverse breast cancer cell lines, including those derived from patients. Proguanil-induced apoptosis was associated with a substantial increase in reactive oxygen species (ROS) production, leading to reduced mitochondrial membrane potential, respiration, and ATP production. Proguanil treatment upregulated apoptotic markers (Bax, p-H2AX, cleaved-caspase 3, 9, cleaved PARP) and downregulated anti-apoptotic proteins (bcl-2, survivin) in breast cancer cell lines. In female Balb/c mice implanted with 4T1 breast tumors, daily oral administration of 20 mg/kg proguanil suppressed tumor enlargement by 55%. Western blot analyses of proguanil-treated tumors supported the in vitro findings, demonstrating increased levels of p-H2AX, Bax, c-PARP, and c-caspase3 as compared to controls. Our results collectively highlight proguanil's anticancer efficacy in vitro and in vivo in breast cancer, prompting further consideration for clinical investigations.

PMID:38473234 | DOI:10.3390/cancers16050872

Comput Biol Chem. 2024 Mar 2;110:108048. doi: 10.1016/j.compbiolchem.2024.108048. Online ahead of print.

ABSTRACT

The rise of drug resistance in Plasmodium falciparum, rendering current treatments ineffective, has hindered efforts to eliminate malaria. To address this issue, the study employed a combination of Systems Biology approach and a structure-based pharmacophore method to identify a target against P. falciparum. Through text mining, 448 genes were extracted, and it was discovered that plasmepsins, found in the Plasmodium genus, play a crucial role in the parasite's survival. The metabolic pathways of these proteins were determined using the PlasmoDB genomic database and recreated using CellDesigner 4.4.2. To identify a potent target, Plasmepsin V (PF13_0133) was selected and examined for protein-protein interactions (PPIs) using the STRING Database. Topological analysis and global-based methods identified PF13_0133 as having the highest centrality. Moreover, the static protein knockout PPIs demonstrated the essentiality of PF13_0133 in the modeled network. Due to the unavailability of the protein's crystal structure, it was modeled and subjected to a molecular dynamics simulation study. The structure-based pharmacophore modeling utilized the modeled PF13_0133 (PfPMV), generating 10 pharmacophore hypotheses with a library of active and inactive compounds against PfPMV. Through virtual screening, two potential candidates, hesperidin and rutin, were identified as potential drugs which may be repurposed as potential anti-malarial agents.

PMID:38471353 | DOI:10.1016/j.compbiolchem.2024.108048

Comput Biol Chem. 2024 Feb 29;110:108039. doi: 10.1016/j.compbiolchem.2024.108039. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) persists to be one of the most devastating and deadliest malignancies globally. Recent research into the molecular signaling networks entailed in many malignancies has given some prominent insights that can be leveraged to create molecular therapeutics for combating HCC. Therefore, in the current communication, an in-silico drug repurposing approach has been employed to target the function of PTP4A3/PRL-3 protein in HCC using antidepressants: Fluoxetine hydrochloride, Citalopram, Amitriptyline, Imipramine, and Escitalopram oxalate as the desired ligands. The density function theory (DFT) and chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) parameters for the chosen ligands were evaluated to comprehend the pharmacokinetics, drug-likeness properties, and bioreactivity of the ligands. The precise interaction mechanism was explored using computational methods such as molecular docking and molecular dynamics (MD) simulation studies to assess the inhibitory effect and the stability of the interactions against the protein of interest. Escitalopram oxalate exhibited a comparatively significant docking score (-7.4 kcal/mol) compared to the control JMS-053 (-6.8 kcal/mol) against the PRL-3 protein. The 2D interaction plots exhibited an array of hydrophobic and hydrogen bond interactions. The findings of the ADMET forecast confirmed that it adheres to Lipinski's rule of five with no violations, and DFT analysis revealed a HOMO-LUMO energy gap of -0.26778 ev, demonstrating better reactivity than the control molecule. The docked complexes were subjected to MD studies (100 ns) showing stable interactions. Considering all the findings, it can be concluded that Escitalopram oxalate and related therapeutics can act as potential pharmacological candidates for targeting the activity of PTP4A3/PRL-3 in HCC.

PMID:38471352 | DOI:10.1016/j.compbiolchem.2024.108039

Glob Public Health. 2024 Jan;19(1):2323028. doi: 10.1080/17441692.2024.2323028. Epub 2024 Mar 12.

ABSTRACT

ABSTRACTScientific evidence on the safety and efficacy of pharmaceutical drugs, substances and herbal medicines is important in medical advertising and promotion. Following guidelines for conducting a scoping review, we systematically searched PubMed, SCOPUS and Web of Science to identify in peer reviewed articles medications that were promoted and used widely in Africa during the COVID-19 pandemic. We also searched for information about how safety concerns about untested/or not properly tested drugs were communicated to the public during the pandemic. Of the 2043 articles identified, 41 papers were eligible for inclusion. Most studies were clinical trials (n = 11), systematic reviews (n = 9), quantitative studies (n = 9) the rest were qualitative studies, reviews and reports. We found that following global trends, several drugs, traditional and herbal treatments were used and repurposed for the treatment of respiratory symptoms of COVID-19 in Africa. The results highlighted the value of some herbal medicines for treatment during the COVID-19 pandemic, as well as the risks posed by the unregulated sharing of advice and recommendations on treatments in Africa, and globally.

PMID:38471036 | DOI:10.1080/17441692.2024.2323028

FASEB J. 2024 Mar 15;38(5):e23536. doi: 10.1096/fj.202302259RR.

ABSTRACT

Rituximab, the first monoclonal antibody approved for the treatment of lymphoma, eventually became one of the most popular and versatile drugs ever in terms of clinical application and revenue. Since its patent expiration, and consequently, the loss of exclusivity of the original biologic, its repurposing as an off-label drug has increased dramatically, propelled by the development and commercialization of its many biosimilars. Currently, rituximab is prescribed worldwide to treat a vast range of autoimmune diseases mediated by B cells. Here, we present a comprehensive overview of rituximab repurposing in 115 autoimmune diseases across 17 medical specialties, sourced from over 1530 publications. Our work highlights the extent of its off-label use and clinical benefits, underlining the success of rituximab repurposing for both common and orphan immune-related diseases. We discuss the scientific mechanism associated with its clinical efficacy and provide additional indications for which rituximab could be investigated. Our study presents rituximab as a flagship example of drug repurposing owing to its central role in targeting cluster of differentiate 20 positive (CD20) B cells in 115 autoimmune diseases.

PMID:38470360 | DOI:10.1096/fj.202302259RR

Antimicrob Agents Chemother. 2024 Mar 12:e0101523. doi: 10.1128/aac.01015-23. Online ahead of print.

ABSTRACT

Existing pharmacodynamic (PD) mathematical models for drug combinations discriminate antagonistic, additive, multiplicative, and synergistic effects, but fail to consider how concentration-dependent drug interaction effects may vary across an entire dose-response matrix. We developed a two-way pharmacodynamic (TWPD) model to capture the PD of two-drug combinations. TWPD captures interactions between upstream and downstream drugs that act on different stages of viral replication, by quantifying upstream drug efficacy and concentration-dependent effects on downstream drug pharmacodynamic parameters. We applied TWPD to previously published in vitro drug matrixes for repurposed potential anti-Ebola and anti-SARS-CoV-2 drug pairs. Depending on the drug pairing, the model recapitulated combined efficacies as or more accurately than existing models and can be used to infer efficacy at untested drug concentrations. TWPD fits the data slightly better in one direction for all drug pairs, meaning that we can tentatively infer the upstream drug. Based on its high accuracy, TWPD could be used in concert with PK models to estimate the therapeutic effects of drug pairs in vivo.

PMID:38470112 | DOI:10.1128/aac.01015-23

Front Oncol. 2024 Feb 26;14:1367237. doi: 10.3389/fonc.2024.1367237. eCollection 2024.

ABSTRACT

BACKGROUND: Epithelioid hemangioendothelioma (EHE) is an ultra-rare, vascular sarcoma with clinical presentation ranging from an indolent to an aggressive form. Over 50% of patients present with metastatic disease, requiring systemic therapy, although no systemic therapies are specifically approved for EHE. Retrospective evidence supports the activity of mTOR inhibitors (e.g. sirolimus), although available only off-label. EHE patients and advocates are therefore working to support approval of effective treatments by collecting data on patient perspectives and experiences.

MATERIALS AND METHODS: In February 2023, the EHE Rare Cancer Charity (UK) and The EHE Foundation (US), with other advocates, conducted a survey of perspectives and experiences of EHE patients regarding the use and accessibility of sirolimus. The survey consisted of 20 questions designed for individuals undergoing treatment, those who had been treated, or had never been treated with the drug. Widely promoted within the patient community, the online survey categorized patients into three cohorts for the analysis: liver transplant patients, non-transplant patients who had ever taken sirolimus and sirolimus-naïve non-transplant patients.

RESULTS: The survey evaluated data from 129 patient responses from 21 countries, mostly from USA, UK, Australia, and Canada (70%). The liver transplant, sirolimus and non-sirolimus cohorts were 16%, 25% and 59%, respectively. In the sirolimus group 66% reported treatment durations exceeding one year, with 16% exceeding five years, indicating the drug's efficacy. In the non-sirolimus group, the drug was not available for 42% and for 11% sirolimus was available but not selected for treatment because of its off-label status. Overall, 87% of all patients across all cohorts expressed the importance of the drug's availability as hugely or very important.

CONCLUSION: The survey responses highlight the activity of sirolimus for EHE and the importance of securing a label extension for the drug delivering equitable access to this treatment for patients.

PMID:38469238 | PMC:PMC10925709 | DOI:10.3389/fonc.2024.1367237

Heliyon. 2024 Feb 23;10(5):e26345. doi: 10.1016/j.heliyon.2024.e26345. eCollection 2024 Mar 15.

ABSTRACT

Ubiquitin-specific protease7 (USP7) regulates the stability of the p53 tumor suppressor protein and several other proteins critical for tumor cell survival. Aberrant expression of USP7 facilitates human malignancies by altering the activity of proto-oncogenes/proteins, and tumor suppressor genes. Therefore, USP7 is a validated anti-cancer drug target. In this study, a drug repurposing approach was used to identify new hits against the USP7 enzyme. It is one of the most strategic approaches to find new uses for drugs in a cost- and time-effective way. Nuclear Magnetic Resonance-based screening of 172 drugs identified 11 compounds that bind to the catalytic domain of USP7 with dissociation constant (Kd) values in the range of 0.6-1.49 mM. These 11 compounds could thermally destabilize the USP7 enzyme by decreasing its melting temperature up to 9 °C. Molecular docking and simulation studies provided structural insights into the ligand-protein complexes, suggesting that these compounds bind to the putative substrate binding pocket of USP7, and interact with its catalytically important residues. Among the identified 11 hits, compound 6 (oxybutynin), 7 (ketotifen), 10 (pantoprazole sodium), and 11 (escitalopram) also showed anti-cancer activity with an effect on the expression of proto-oncogenes and tumor-suppressor gene at mRNA level in HCT116 cells. The compounds identified in this study can serve as potential leads for further studies.

PMID:38468948 | PMC:PMC10925992 | DOI:10.1016/j.heliyon.2024.e26345

Neurol Res. 2024 Mar 11:1-11. doi: 10.1080/01616412.2024.2328481. Online ahead of print.

ABSTRACT

OBJECTIVES: The search for drugs that can protect the brain tissue and reduce nerve damage in acute ischemic stroke has emerged as a research hotspot. We investigated the potential protective effects and mechanisms of action of dihydroergotamine against ischemic stroke.

METHODS: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO), and dihydroergotamine at a dose of 10 mg/kg/day was intraperitoneally injected for 14 days. Adhesive removal and beam walking tests were conducted 1, 3, 5, 7, 10, and 14 days after MCAO surgery. Thereafter, the mechanism by which dihydroergotamine regulates microglia/macrophage polarization and inflammation and imparts ischemic stroke protection was studied using enzyme-linked immunosorbent assay, immunofluorescence staining, and western blotting.

RESULTS: From the perspective of a drug repurposing strategy, dihydroergotamine was found to inhibit oxygen-glucose deprivation damage to neurons, significantly improve cell survival rate, and likely exert a protective effect on ischemic brain injury. Dihydroergotamine significantly improved neural function scores and survival rates and reduced brain injury severity in mice. Furthermore, dihydroergotamine manifests its protective effect on ischemic brain injury by reducing the expression of TNF-α and IL-1β in mouse ischemic brain tissue, inhibiting the polarization of microglia/macrophage toward the M1 phenotype and promoting polarization toward the M2 phenotype.

CONCLUSION: This study is the first to demonstrate the protective effect of dihydroergotamine, a first-line treatment for migraine, against ischemic nerve injury in vitro and in vivo.

PMID:38468466 | DOI:10.1080/01616412.2024.2328481

Braz J Microbiol. 2024 Mar 11. doi: 10.1007/s42770-024-01301-5. Online ahead of print.

ABSTRACT

The drugs available to treat sporotrichosis, an important yet neglected fungal infection, are limited. Some Sporothrix spp. strains present reduced susceptibility to these antifungals. Furthermore, some patients may not be indicated to use these drugs, while others may not respond to the therapy. The anthelmintic drug niclosamide is fungicidal against the Sporothrix brasiliensis type strain. This study aimed to evaluate whether niclosamide also has antifungal activity against Sporothrix globosa, Sporothrix schenckii and other S. brasiliensis strains with distinct genotypes and antifungal susceptibility status. Minimal inhibitory and fungicidal concentrations (MIC and MFC, respectively) were determined using the microdilution method according to the CLSI protocol. The checkerboard method was employed to evaluate niclosamide synergism with drugs used in sporotrichosis treatment. Metabolic activity of the strains under niclosamide treatment was evaluated using the resazurin dye. Niclosamide was active against all S. brasiliensis strains (n = 17), but it was ineffective (MIC > 20 µM) for some strains (n = 4) of other pathogenic Sporothrix species. Niclosamide MIC values for Sporothrix spp. were similar for mycelial and yeast-like forms of the strains (P = 0.6604). Niclosamide was fungicidal (MFC/MIC ratio ≤ 2) for most strains studied (89%). Niclosamide activity against S. brasiliensis is independent of the fungal genotype or non-wild-type phenotypes for amphotericin B, itraconazole, or terbinafine. These antifungal drugs presented indifferent interactions with niclosamide. Niclosamide has demonstrated potential for repurposing as a treatment for sporotrichosis, particularly in S. brasiliensis cases, instigating in vivo studies to validate the in vitro findings.

PMID:38466550 | DOI:10.1007/s42770-024-01301-5

bioRxiv [Preprint]. 2024 Feb 29:2024.02.27.582333. doi: 10.1101/2024.02.27.582333.

ABSTRACT

Microbiome studies have revealed gut microbiota's potential impact on complex diseases. However, many studies often focus on one disease per cohort. We developed a meta-analysis workflow for gut microbiome profiles and analyzed shotgun metagenomic data covering 11 diseases. Using interpretable machine learning and differential abundance analysis, our findings reinforce the generalization of binary classifiers for Crohn's disease (CD) and colorectal cancer (CRC) to hold-out cohorts and highlight the key microbes driving these classifications. We identified high microbial similarity in disease pairs like CD vs ulcerative colitis (UC), CD vs CRC, Parkinson's disease vs type 2 diabetes (T2D), and schizophrenia vs T2D. We also found strong inverse correlations in Alzheimer's disease vs CD and UC. These findings detected by our pipeline provide valuable insights into these diseases.

IMPORTANCE: Assessing disease similarity is an essential initial step preceding disease-based approach for drug repositioning. Our study provides a modest first step in underscoring the potential of integrating microbiome insights into the disease similarity assessment. Recent microbiome research has predominantly focused on analyzing individual disease to understand its unique characteristics, which by design excludes comorbidities individuals. We analyzed shotgun metagenomic data from existing studies and identified previously unknown similarities between diseases. Our research represents a pioneering effort that utilize both interpretable machine learning and differential abundance analysis to assess microbial similarity between diseases.

PMID:38464323 | PMC:PMC10925178 | DOI:10.1101/2024.02.27.582333

bioRxiv [Preprint]. 2024 Feb 29:2024.02.28.582164. doi: 10.1101/2024.02.28.582164.

ABSTRACT

Computational modeling of perturbation biology identifies relationships between molecular elements and cellular response, and an accurate understanding of these systems will support the full realization of precision medicine. Traditional deep learning, while often accurate in predicting response, is unlikely to capture the true sequence of involved molecular interactions. Our work is motivated by two assumptions: 1) Methods that encourage mechanistic prediction logic are likely to be more trustworthy, and 2) problem-specific algorithms are likely to outperform generic algorithms. We present an alternative to Graph Neural Networks (GNNs) termed Graph Structured Neural Networks (GSNN), which uses cell signaling knowledge, encoded as a graph data structure, to add inductive biases to deep learning. We apply our method to perturbation biology using the LINCS L1000 dataset and literature-curated molecular interactions. We demonstrate that GSNNs outperform baseline algorithms in several prediction tasks, including 1) perturbed expression, 2) cell viability of drug combinations, and 3) disease-specific drug prioritization. We also present a method called GSNNExplainer to explain GSNN predictions in a biologically interpretable form. This work has broad application in basic biological research and pre-clincal drug repurposing. Further refinement of these methods may produce trustworthy models of drug response suitable for use as clinical decision aids.

PMID:38464019 | PMC:PMC10925270 | DOI:10.1101/2024.02.28.582164

EMBO Mol Med. 2024 Mar 10. doi: 10.1038/s44321-024-00048-8. Online ahead of print.

ABSTRACT

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin disease characterized by defects in type VII collagen leading to a range of fibrotic pathologies resulting from skin fragility, aberrant wound healing, and altered dermal fibroblast physiology. Using a novel in vitro model of fibrosis based on endogenously produced extracellular matrix, we screened an FDA-approved compound library and identified antivirals as a class of drug not previously associated with anti-fibrotic action. Preclinical validation of our lead hit, daclatasvir, in a mouse model of RDEB demonstrated significant improvement in fibrosis as well as overall quality of life with increased survival, weight gain and activity, and a decrease in pruritus-induced hair loss. Immunohistochemical assessment of daclatasvir-treated RDEB mouse skin showed a reduction in fibrotic markers, which was supported by in vitro data demonstrating TGFβ pathway targeting and a reduction of total collagen retained in the extracellular matrix. Our data support the clinical development of antivirals for the treatment of patients with RDEB and potentially other fibrotic diseases.

PMID:38462666 | DOI:10.1038/s44321-024-00048-8

Zhonghua Yan Ke Za Zhi. 2024 Mar 11;60(3):272-274. doi: 10.3760/cma.j.cn112142-20231025-00181.

ABSTRACT

A 61-year-old male patient presented with blurred vision in the right eye for 1 day. The patient had previously undergone phacoemulsification with intraocular lens implantation (10 years ago) and intravitreal implantation of dexamethasone (due to uveitis) in the eye. There was edema in the inferior cornea, along with Descemet membrane folds. The rod-shaped dexamethasone implant was visible in the inferior anterior chamber. Without pupil dilation, the patient was asked to keep a supine position and avoid head tilting for 1 day. The implant spontaneously relocated into the vitreous cavity, resulting in a reduction of corneal edema. This suggests that the dislocation of the intravitreal implant into the anterior chamber may be caused by a local zonular abnormality, and the dislocated implant has the potential to reposition itself spontaneously.

PMID:38462376 | DOI:10.3760/cma.j.cn112142-20231025-00181

Biomed Pharmacother. 2024 Mar 9;173:116394. doi: 10.1016/j.biopha.2024.116394. Online ahead of print.

ABSTRACT

Recently, anthelmintics have showcased versatile therapeutic potential in addressing various diseases, positioning them as promising candidates for drug repurposing. However, challenges such as low bioavailability and a lack of a solid pharmacokinetic basis impede successful repurposing. To overcome these flaws, we aimed to investigate the key pharmacokinetic factors of anthelmintics mainly focusing on the absorption, distribution, and metabolism profiles by employing niclosamide (NIC) as a model drug. The intestinal permeability of NIC is significantly influenced by solubility and doesn't function as a substrate for efflux transporters. It showed high plasma protein binding. Also, the metabolism study indicated that NIC would have low metabolic stability by extensively undergoing the intestinal glucuronidation. Additionally, we investigated the CYP-mediated drug-drug interaction potential of NIC in both direct and time-dependent ways. NIC showed strong inhibitory effects on CYP1A2 and CYP2C8 and is not likely to become a time-dependent inhibitor. Our findings could contribute to the identification of essential factors in the pharmacokinetics of anthelmintics, potentially facilitating their repositioning.

PMID:38461686 | DOI:10.1016/j.biopha.2024.116394

BMC Cancer. 2024 Mar 8;24(1):323. doi: 10.1186/s12885-024-12064-5.

ABSTRACT

BACKGROUND: Increased mitochondrial activities contributing to cancer cell proliferation, invasion, and metastasis have been reported in different cancers; however, studies on the therapeutic targeting of mitochondria in regulating cell proliferation and invasiveness are limited. Because mitochondria are believed to have evolved through bacterial invasion in mammalian cells, antibiotics could provide an alternative approach to target mitochondria, especially in cancers with increased mitochondrial activities. In this study, we investigated the therapeutic potential of bacteriostatic antibiotics in regulating the growth potential of colorectal cancer (CRC) cells, which differ in their metastatic potential and mitochondrial functions.

METHODS: A combination of viability, cell migration, and spheroid formation assays was used to measure the effect on metastatic potential. The effect on mitochondrial mechanisms was investigated by measuring mitochondrial DNA copy number by qPCR, biogenesis (by qPCR and immunoblotting), and functions by measuring reactive oxygen species, membrane potential, and ATP using standard methods. In addition, the effect on assembly and activities of respiratory chain (RC) complexes was determined using blue native gel electrophoresis and in-gel assays, respectively). Changes in metastatic and cell death signaling were measured by immunoblotting with specific marker proteins and compared between CRC cells.

RESULTS: Both tigecycline and tetracycline effectively reduced the viability, migration, and spheroid-forming capacity of highly metastatic CRC cells. This increased sensitivity was attributed to reduced mtDNA content, mitochondrial biogenesis, ATP content, membrane potential, and increased oxidative stress. Specifically, complex I assembly and activity were significantly inhibited by these antibiotics in high-metastatic cells. Significant down-regulation in the expression of mitochondrial-mediated survival pathways, such as phospho-AKT, cMYC, phospho-SRC, and phospho-FAK, and upregulation in cell death (apoptosis and autophagy) were observed, which contributed to the enhanced sensitivity of highly metastatic CRC cells toward these antibiotics. In addition, the combined treatment of the CRC chemotherapeutic agent oxaliplatin with tigecycline/tetracycline at physiological concentrations effectively sensitized these cells at early time points.

CONCLUSION: Altogether, our study reports that bacterial antibiotics, such as tigecycline and tetracycline, target mitochondrial functions specifically mitochondrial complex I architecture and activity and would be useful in combination with cancer chemotherapeutics for high metastatic conditions.

PMID:38459456 | DOI:10.1186/s12885-024-12064-5