Biological evaluation of levofloxacin and its thionated derivatives: antioxidant activity, aldehyde dehydrogenase enzyme inhibition, and cytotoxicity on A549 cell line.

Levofloxacin (LVX) is among the fluoroquinolones antibiotics that has also been studied in vitro and in vivo for its anticancer effects. In this study, we used LVX and novel LVX thionated derivatives; compounds 2 and 3, to evaluate their antioxidant activity, aldehyde dehydrogenase (ALDH) enzymes activity inhibition, and anticancer activity. Combination treatments with doxorubicin (DOX) were investigated as well. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to determine the antioxidant activity. The NADH fluorescence spectrophotometric activity assay was used to determine the ALDH inhibitory effects. Resazurin dye method was applied for cell viability assays. Molecular Operating Environment software was used for the molecular docking experiments. Compared to ascorbic acid, DPPH assay showed that compound 3 had the highest antioxidant activity among the tested compounds with approximately 35% scavenging activity. On ALDH enzymes, compound 3 showed a significant ALDH activity inhibition compared to compound 2 at 200 µM. The IC50 values for the tested compounds were approximately 100 µM on A549 cell line, a non-small cell lung cancer (NSCLC) cell line. However, significant enhancement of cytotoxicity and reduction of IC50 values were observed by combining DOX and synergism was achieved with LVX with a combination index value of 0.4. The molecular docking test showed a minimum binding energy with a good affinity for compound 3 towards ALDH enzymes. Thionated LVX derivatives, may be repurposed for NSCLC therapy in combination with DOX, taking into account the antioxidant activity, ALDH activity inhibition, and the molecular docking results of compound 3.

Investigating Carvedilol's Repurposing for the Treatment of Non-Small Cell Lung Cancer via Aldehyde Dehydrogenase Activity Modulation in the Presence of ß-Adrenergic Agonists.

Repurposing existing drugs appears to be a potential solution for addressing the challenges in the treatment of non-small cell lung cancer (NSCLC). ß-adrenoceptor antagonist drugs (ß-blockers) have tumor-inhibiting effects, making them promising candidates for potential NSCLC treatment. This study investigates the anticancer potential of a subset of ß-blockers in NSCLC cell lines; A549 and H1299. Additionally, it investigates the underlying mechanism behind ß-blockers' anticancer effect by influencing a potential novel target named aldehyde dehydrogenase (ALDH). The MTT assay assessed ß-blockers' cytotoxicity on both cell lines, while Western blot and NADH fluorescence assays evaluated their influence on ALDH protein expression and activity. Carvedilol (CAR) was the most effective blocker in reducing cell survival of A549 and H1299 with IC50 of 18 µM and 13.7 µM, respectively. Significantly, CAR led to a 50% reduction in ALDH expression and 80% decrease in ALDH activity in A549 cells, especially when combined with ß-agonists, in comparison to the control. This effect might be attributed to ß-agonist blockade or an alternative pathway. This novel finding adds to our understanding of CAR's multifaceted anticancer properties, implying that combining CAR with ß-agonists could be a useful strategy for lung cancer treatment.

Identifying synergistic combinations of Doxorubicin-Loaded polyquercetin nanoparticles and natural Products: Implications for breast cancer therapy.

Combining chemotherapeutic agents with bioactive natural products is an attractive cancer treatment modality to reduce the dose and side effects of chemotherapy. Combination treatments with drugs having different mechanisms of action can also be beneficial in combatting the development of drug resistance by cancer cells. Nanoparticle (NP)-mediated drug delivery can further improve the therapeutic index of cytotoxic agents by enabling passive and/or active targeting to tumor tissues in vivo. Using doxorubicin (DOX) as a model chemotherapeutic agent, we developed three NP formulations based on polyquercetin (pQCT), an emerging nanocarrier platform. The NPs were co-assembled with DOX, pQCT, and either Pluronic P123, methoxy poly(ethylene glycol)-amine, or D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS). Physicochemical characterization of the NPs revealed them to have a spherical morphology with high monodispersity, excellent drug loading capacity, and sustained drug release. Then, the NPs were evaluated in vitro to determine their potential synergism when combined with the bioactive natural products curcumin (CUR), tannic acid (TA), and thymoquinone (TQ) against breast cancer cells (MCF-7 and MDA-MB-231). Surprisingly, most of the combinations were found to be antagonistic. However, combinations containing CUR exhibited greater pro-apoptotic effects compared to the single agents, with polymer-modified pQCT NPs presenting as a promising nanoplatform for enhancing DOX's ability to promote cancer cell apoptosis. Our findings provide insights into the potential application of pQCT in nanomedicine, as well as the use of bioactive natural products in combination with DOX as a free agent and as an NP formulation in the treatment of breast cancer.

Cost-efficiency analysis and expanded treatment access modeling of conversion to rituximab biosimilars from reference rituximab in Jordan.

AIM: To assess the cost-efficiency and expanded access of three rituximab biosimilars versus the reference rituximab from the perspective of the Jordanian national health payer. METHODS: A 1-year cost-efficiency and expanded access model of conversion from reference rituximab (Mabthera) to the approved biosimilars (Truxima, Rixathon, and Tromax) to assess five metrics: total annual cost to treat a hypothetical patient; head-to-head cost comparison; changes in patients' access to rituximab; number-needed-to-convert (NNC) to provide an additional 10 patients access to a rituximab treatment; and relative amount of Jordanian Dinar (JOD) spent on rituximab options. The model included rituximab doses at 100 mg/10 ml and 500 mg/50 ml and considered both cost-saving and cost-wastage scenarios. Costs of treatments were based on the fiscal year 2022 tender prices received by the Joint Procurement Department (JPD). RESULTS: Rixathon was associated with the lowest average annual cost per patient (JOD2,860) across all six indications among all rituximab comparators, followed by Truxima (JOD4,240), Tromax (JOD4,365) and reference Mabthera (JOD11,431). The highest percentage of patient access to rituximab treatment (321%) was achieved when switching patients from Mabthera to Rixathon in the RA and PV indications. At four patients, Rixathon was associated with the lowest NNC to provide an additional 10 patients access to rituximab treatment. For each JOD1 spent on Rixathon, an additional JOD3.21 must be spent on Mabthera, an additional JOD0.55 on Tromax, and an additional JOD0.53 on Truxima. CONCLUSION: Rituximab biosimilars were associated with cost savings in all approved indications in Jordan compared to reference rituximab. Rixathon was associated with the lowest annual cost, the highest percentage of expanded patient access for all six indications, and the lowest NNC providing 10 additional patients with access.

CRHR1 polymorphism at rs242941, rs242940, and rs72834580: association of symptoms improvement with intranasal corticosteroids in allergic rhinitis Jordanian patients.

OBJECTIVES: Rhinitis is classified into several types with allergic rhinitis (AR) being the most common. AR is among the inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), in which corticosteroids are administered to overcome the decrease in cortisol production. The treatment options available for AR vary with 1st line treatment being intranasal corticosteroids (INCS). The responsiveness to corticosteroids is due to their binding to corticotropin-releasing hormone receptor-1 (CRHR1). Various studies have studied the responsiveness to corticosteroids treatment in patients with asthma and COPD in association with CRHR1 gene single nucleotide polymorphisms (SNPs). METHODS: In our study, we investigated the association of three SNPs of CRHR1 gene (rs242941, rs242940, and rs72834580) with symptoms improvement post-treatment in AR patients. Blood samples were collected from 103 patients for DNA extraction and gene sequencing. Those patients started to receive INCS for 8 weeks and their symptoms were assessed, through a questionnaire, before treatment and post-treatment to check for symptoms improvement. RESULTS: Our data showed that improvement of eye redness is significantly less following INCS treatment in patients with allele (C) (AOR=0.289, p-value-0.028, 95 % CI=0.096-0.873) and genotype (CC) (AOR=0.048, p-value-0.037, 95 % CI=0.003-0.832) of rs242941 SNP. There was no correlation with other genotypes, alleles, or haplotypes of the investigated SNPs. CONCLUSIONS: Our findings show that there is no correlation between CRHR1 gene polymorphism and symptoms improvement following INCS treatment. Further studies are required to evaluate the association of INCS and symptoms improvement post-treatment with larger sample size.

In Vitro Evaluation of ALDH1A3-Affinic Compounds on Breast and Prostate Cancer Cell Lines as Single Treatments and in Combination with Doxorubicin.

Aldehyde dehydrogenase (ALDH) enzymes are involved in the growth and development of several tissues, including cancer cells. It has been reported that targeting the ALDH family, including the ALDH1A subfamily, enhances cancer treatment outcomes. Therefore, we aimed to investigate the cytotoxicity of ALDH1A3-affinic compounds that have been recently discovered by our group, on breast (MCF7 and MDA-MB-231) and prostate (PC-3) cancer cell lines. These compounds were investigated on the selected cell lines as single treatments and in combination with doxorubicin (DOX). Results showed that the combination treatment experiments of the selective ALDH1A3 inhibitors (compounds 15 and 16) at variable concentrations with DOX resulted in significant increases in the cytotoxic effect on the MCF7 cell line for compound 15, and to a lesser extent for compound 16 on the PC-3 cell line, compared to DOX alone. The activity of compounds 15 and 16 as single treatments on all cell lines was found to be non-cytotoxic. Therefore, our findings showed that the investigated compounds have a promising potential to target cancer cells, possibly via an ALDH-related pathway, and sensitize them to DOX treatment.

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases.

Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.

A Review of the Recent Advances in Alzheimer's Disease Research and the Utilization of Network Biology Approaches for Prioritizing Diagnostics and Therapeutics.

Alzheimer's disease (AD) is a polygenic multifactorial neurodegenerative disease that, after decades of research and development, is still without a cure. There are some symptomatic treatments to manage the psychological symptoms but none of these drugs can halt disease progression. Additionally, over the last few years, many anti-AD drugs failed in late stages of clinical trials and many hypotheses surfaced to explain these failures, including the lack of clear understanding of disease pathways and processes. Recently, different epigenetic factors have been implicated in AD pathogenesis; thus, they could serve as promising AD diagnostic biomarkers. Additionally, network biology approaches have been suggested as effective tools to study AD on the systems level and discover multi-target-directed ligands as novel treatments for AD. Herein, we provide a comprehensive review on Alzheimer's disease pathophysiology to provide a better understanding of disease pathogenesis hypotheses and decipher the role of genetic and epigenetic factors in disease development and progression. We also provide an overview of disease biomarkers and drug targets and suggest network biology approaches as new tools for identifying novel biomarkers and drugs. We also posit that the application of machine learning and artificial intelligence to mining Alzheimer's disease multi-omics data will facilitate drug and biomarker discovery efforts and lead to effective individualized anti-Alzheimer treatments.

Microemulsions as Lipid Nanosystems Loaded into Thermoresponsive In Situ Microgels for Local Ocular Delivery of Prednisolone.

This study aimed to develop and evaluate thermoresponsive in situ microgels for the local ocular delivery of prednisolone (PRD) (PRD microgels) to improve drug bioavailability and prolong ocular drug residence time. Lipid nanosystems of PRD microemulsions (PRD-MEs) were prepared and evaluated at a drug concentration of 0.25-0.75%. PRD microgels were prepared by incorporating PRD-MEs into 10 and 12% Pluronic® F127 (F127) or combinations of 12% F127 and 1-10% Kolliphor®P188 (F68). PRD microgels were characterized for physicochemical, rheological, and mucoadhesive properties, eye irritation, and stability. Results showed that PRD-MEs were clear, miscible, thermodynamically stable, and spherical with droplet size (16.4 ± 2.2 nm), polydispersity index (0.24 ± 0.01), and zeta potential (-21.03 ± 1.24 mV). The PRD microgels were clear with pH (5.37-5.81), surface tension (30.96-38.90 mN/m), size, and zeta potential of mixed polymeric micelles (20.1-23.9 nm and -1.34 to -10.25 mV, respectively), phase transition temperature (25.3-36 °C), and gelation time (1.44-2.47 min). The FTIR spectra revealed chemical compatibility between PRD and microgel components. PRD microgels showed pseudoplastic flow, viscoelastic and mucoadhesive properties, absence of eye irritation, and drug content (99.3 to 106.3%) with a sustained drug release for 16-24 h. Microgels were physicochemically and rheologically stable for three to six months. Therefore, PRD microgels possess potential vehicles for local ocular delivery.

Conducting COVID-19-Related Research in Jordan: Are We Ready?

The coronavirus disease-2019 (COVID-19) pandemic is a public health emergency of international concern. This pandemic poses a challenge to research and scientific community. In this study, we developed and tested content reliability and content validity of a questionnaire designed for evaluating the readiness and willingness of researchers to participate in virology research in Jordan. The survey was hosted on an online platform, and the link was emailed. A total of 332 participants from universities across Jordan completed the survey. For factor analysis, Kaiser-Meyer-Olkin value (KMO) and Bartlett's Test of Sphericity were conducted. Furthermore, exploratory factor analysis (EFA) with parallel analysis and scree plots were conducted to evaluate the most suitable model for the data. The result of the EFA suggested a 5-factor model would fit the survey. Data showed that the lowest means were for researchers' readiness to conduct virology research and readiness for virology research with means of 2.07 and 2.95, respectively. Moreover, years of experience and speciality had a significant effect on the readiness and willingness of virology research in Jordan. In conclusion, readiness for research and researchers should be addressed and authorities should pay attention to these shortcomings in virology research.

N-tert-Prenylation of the indole ring improves the cytotoxicity of a short antagonist G analogue against small cell lung cancer.

Natural prenylated indoles have been proposed as potential anticancer agents. To exploit this discovery for developing new peptide therapeutics, we report the first studies whereby incorporation of prenylated indoles into primary sequences has been achieved. We developed a route to synthesise Nα-Fmoc-protected tryptophan derivatives in which the prenyl group is linked to the N-indole core, using Pd(ii)-mediated C-H functionalisation of 2-methyl-2-butene. Based on the Substance P antagonist G (SPG), a well-known Small Cell Lung Cancer (SCLC) anticancer agent, we designed a new penta-peptide sequence to include a prenyl moiety on one of the tryptophan residues. The N-tert-prenylated tryptophan analogue was assembled into the pentameric peptide using standard solid phase peptide synthesis or liquid phase synthesis by fragment coupling. In vitro screening showed that the N-tert-prenylation of the indole ring on the tryptophan residue located near the C-terminal of the penta-peptide enhanced the cytotoxicity against H69 (IC50 = 2.84 ± 0.14 µM) and DMS79 (IC50 = 4.37 ± 0.44 µM) SCLC cell lines when compared with the unmodified penta-peptide (H69, IC50 = 30.74 ± 0.30 µM and DMS79, IC50 = 23.00 ± 2.07 µM) or the parent SPG sequence (IC50 > 30 µM, both cell lines). SCLC almost invariably relapses with therapy-resistant disease. The DMS79 cell line was established from a patient following treatment with a number of chemotherapeutics (cytoxan, vincristine and methotrexate) and radiation therapy. Treating DMS79 tumour-bearing nude mice provided a human xenograft model of drug resistance to test the efficacy of the prenylated peptide. A low dose (1.5 mg kg-1) of the prenylated peptide was found to reduce tumour growth by ∼30% (P < 0.05) at day 7, relative to the control group receiving vehicle only. We conclude that the availability of the Fmoc-Trp(N-tert-prenyl)-OH amino acid facilitates the synthesis of prenylated-tryptophan-containing peptides to explore their therapeutic potential.