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Multiple sclerosis (MS) is a severe immune-mediated neurological disease characterized by neuroinflammation, demyelination, and axonal degeneration in the central nervous system (CNS). This is frequently linked to motor abnormalities and cognitive impairments. The pathophysiological hallmarks of MS include inflammatory demyelination, axonal injury, white matter degeneration, and the development of CNS lesions that result in severe neuronal degeneration. Several studies suggested downregulation of nuclear factor erythroid-2-related factor-2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling is a causative factor for MS pathogenesis. Acetyl-11-keto-β-boswellic acid (AKBA) is an active pentacyclictriterpenoid obtained from Boswellia serrata, possessing antioxidant and anti-inflammatory properties. The present study explores the protective potential of AKBA on behavioral, molecular, neurochemical, and gross pathological abnormalitiesandhistopathological alterations by H&E and LFB staining techniques in an experimental model of multiple sclerosis, emphasizing the increase inNrf2/HO-1 levels in the brain. Moreover, we also examine the effect of AKBA on the intensity of myelin basic protein (MBP) in CSF and rat brain homogenate. Specific apoptotic markers (Bcl-2, Bax, andcaspase-3) were also estimated in rat brain homogenate. Neuro behavioralabnormalities in rats were examined using an actophotometer, rotarod test, beam crossing task (BCT),and Morris water maze (MWM). AKBA 50 mg/kg and 100 mg/kg were given orally from day 8 to 35 to alleviate MS symptoms in the EB-injected rats. Furthermore, cellular, molecular, neurotransmitter, neuroinflammatory cytokine, and oxidative stress markers in rat whole brain homogenate, blood plasma, and cerebral spinal fluid were investigated. This study shows that AKBA upregulates the level of antioxidant proteins such as Nrf2 and HO-1 in the rat brain. AKBA restores altered neurochemical levels, potentially preventing gross pathological abnormalities during MS progression.

In this work, a novel chromatin-loaded chitosan polyvinyl alcohol composite was developed as a simple, efficient and environmentally friendly adsorbent for the efficient removal of ethidium bromide (EtBr). SEM images showed that the composites were characterized by dense porous and uniformly distributed morphology. The BET analysis showed the presence of mesopores and macropores in the composites. FTIR and XRD results showed that the chromatin was uniformly dispersed in the chitosan-polyvinyl alcohol carrier through hydrogen bonding. The fluorescence microscopy images showed the change of fluorescence effect before and after the adsorption of the material, which indicated that the chromatin was uniformly distributed in the composites and had a good adsorption effect. The optimal experimental conditions were T = 30℃, t = 120 min, pH = 7.4, m = 0.2 g when the composite with only 5% chromatin content had the ability to adsorb EtBr efficiently (minimum concentration 2 mg·L −1 : adsorption rate 99%; maximum concentration 20 mg·L −1 : adsorption rate 90%).The adsorption kinetics and thermodynamics showed that the EtBr adsorption kinetics of the composite conformed to the pseudo-second-order kinetic model (0.995 <  R 2  < 0.999) and the Freundlich isothermal model, and was a spontaneous process (Δ H  < 0). This study on the immobilization of chromatin will provide a new way and reference for the application of chromatin in the treatment of EtBr pollutants. Graphical abstracts

The study investigates the neuroprotective potential of paeoniflorin (PNN) in mitigating the multifaceted pathology of multiple sclerosis (MS) in an ethidium bromide-induced (EBRO) rat model. A comprehensive approach utilizing in silico , in-vitro , and in-vivo methodologies reveals that PNN targets key molecular pathways implicated in MS, including the GDNF/GFRA1/RET/AKT/ERK1/2/GSK3-Beta signaling cascade. PNN (50 mg/kg, 100 mg/kg, p.o .) administration, both as monotherapy and in combination with VB-12 (30 mg/kg, p.o .), demonstrated significant efficacy in reducing EBRO-induced neurodegeneration, demyelination, synaptic dysfunction, and neuroinflammation. Behavioral assessments such as the rotarod, beam crossing, and Morris water maze tests highlighted PNN capacity to restore motor coordination, spatial memory, and cognitive function. Combination therapy with VB12 (30) further enhanced these outcomes, demonstrating synergistic therapeutic benefits. Histological and molecular analyses revealed that PNN100 alleviates demyelination, reduces inflammatory cytokines TNF-α, IL-1β, and restores anti-inflammatory markers (IL-10) in brain homogenates, CSF, and blood plasma. Moreover, PNN normalized neurotransmitter imbalances, including elevated glutamate and reduced GABA, dopamine, serotonin, and acetylcholine levels, highlighting its role in restoring excitatory-inhibitory balance. ELISA studies confirmed PNN ability to modulate apoptotic markers Bax, Bcl-2, and Caspase-3 and upregulate neurotrophic factors GDNF, and GFRA1 while downregulating hyperactivated pathways like AKT, ERK1/2, and GSK3-Beta. Additionally, hematological parameters disrupted by EBRO were significantly restored by PNN, indicating its systemic anti-inflammatory and hematoprotective effects. This research provides the first evidence of PNN’s role in modulating the GDNF/GFRA1/RET/AKT/ERK1/2/GSK3β pathway in MS. Its synergistic action with VB12 underscores its potential as a combinatorial therapeutic strategy. The findings pave the way for innovative treatment approaches to improve outcomes for MS patients by addressing neurodegeneration, inflammation, and systemic immune dysregulation.

This study was focused on elucidating inhibition of antibiotic efflux mechanism of cadmium adapted (CdA) Salmonella Typhi Ty2 cells. Herein, upregulated expression of efflux genes ( acrB , tolC ) and their regulators ( soxS , marA ) was observed in CdA Ty2 cells by qRT-PCR. The pathogen further elevated the expression of these genes even in the presence of three efflux pump inhibitors (EPIs), i.e., Phe-Arg-β-naphthylamide, 1-(1-naphthyl-methyl)piperazine, and 5-hydroxy-2-methyl-1,4-naphthoquinone, perhaps by sensing the pressure of the latter in addition to cadmium stress. Interaction of different EPIs with efflux pumps of CdA Ty2 cells was confirmed using ethidium bromide (EtBr) accumulation and efflux assay. All the EPIs could cause retention of EtBr which was indicated by increased fluorescence units. Considering this potential of EPIs, retention of antibiotics was evaluated in CdA Ty2 cells wherein EPIs were used in combination with selected antibiotics (instead of EtBr). A decrease in the effective concentration of antibiotics was observed. This was further validated using the clinical isolates. The data revealed the efficiency of EPIs as they could inhibit the efflux potential of even the overexpressed efflux pumps. Thus, combination of EPI(s)-antibiotics may be exploited in future as one of the strategies for combating metal induced antibiotic resistance.

The aim of the study was investigate the occurrence of multidrug resistance efflux pumps genes in local clinical isolates of Salmonella sp and try to apply efflux inhibitor for phenotypic detection besides their possibly future therapeutic uses to retain the activity of some frequently used antibiotics. Among 114 bacterial specimens obtained from several hospitals in Baghdad city only 67 isolates were diagnosed to Salmonella typhi according to conventional and molecular methods. The disk diffusion (Kirby Bauer) method was adopted to assess the antibiotic susceptibility of S. typhi isolates, and the results revealed variable rates of resistance to various antibiotics. While Gentamicin are the most effective antibiotic in this study since 100% sensitive to it .Cartwheel method used for evaluating the efflux pumps activity by using ethidium bromide in different concentration, the outcomes appeared positive reaction for 42 isolates (62.6%) at 0.25 µg/ml, 25(37.3%) at 0.5 µg/ml , 15(22.3%) at 1 µg/ml , 9(13.4%) at 1.5 µg/ml , 4 (5.9%) at 2 µg/ml, 4(5.9%) at 4µg/ml. Four isolates which characterized highly expression level of efflux pumps activity and high resistant to antibiotic were selected to confirmed the result of cartwheel assay through determining the minimum inhibitory concentration (MIC) level though applied different concentration (500, 250, 125, 62.5, 31.25, 15.62, 7.8, 3.9, and 1.9) µg/ml of fluphenazine decanoate as efflux pump inhibitor (EPIs) and appeared at 15.62 µg/ml of EPIs the positive activity efflux pumps became negative and Etbr appeared fluorescent.

Carvotacetones (1–7) isolated from Sphaeranthus africanus were screened for their antimycobacterial and efflux pump (EP) inhibitory potential against the mycobacterial model strains Mycobacterium smegmatis mc2 155, Mycobacterium aurum ATCC 23366, and Mycobacterium bovis BCG ATCC 35734. The minimum inhibitory concentrations (MICs) of the carvotacetones were detected through high-throughput spot culture growth inhibition (HT-SPOTi) and microbroth dilution assays. In order to assess the potential of the compounds 1 and 6 to accumulate ethidium bromide (EtBr) in M. smegmatis and M. aurum, a microtiter plate-based fluorometric assay was used to determine efflux activity. Compounds 1 and 6 were analyzed for their modulating effects on the MIC of EtBr and the antibiotic rifampicin (RIF) against M. smegmatis. Carvotacetones 1 and 6 had potent antibacterial effects on M. aurum and M. bovis BCG (MIC ≤ 31.25 mg/L) and could successfully enhance EtBr activity against M. smegmatis. Compound 1 appeared as the most efficient agent for impairing the efflux mechanism in M. smegmatis. Both compounds 1 and 6 were highly effective against M. aurum and M. bovis BCG. In particular, compound 1 was identified as a valuable candidate for inhibiting mycobacterial efflux mechanisms and as a promising adjuvant in the therapy of tuberculosis or other non-tubercular mycobacterial infections.

Antibiotic resistance is a growing problem and may become the next major global health crisis if no timely actions are taken. Mycobacterial infections are widespread and, due to antibiotic resistance, also hard to treat and a major cause of mortality. Natural compounds have the potential to increase antibiotic effectiveness due to their resistance modulatory and antimicrobial effects. In this study, Peucedanum ostruthium extracts, fractions, and isolated compounds were investigated regarding their antimicrobial and resistance-modulatory effects as well as efflux pump inhibition in Mycobacterium smegmatis. P. ostruthium extracts were found to have anti-mycobacterial potential and resistance modulating effects on ethidium bromide activity. The major antibacterial effect was attributed to ostruthin, and we found that the more lipophilic the substrate, the greater the antimicrobial effect. Imperatorin caused potent modulatory effects by interfering with the action of the major LfrA efflux pump in M. smegmatis. The plant P. ostruthuim has a complex effect on M. smegmatis, including antibacterial, efflux pump inhibition, resistance modulation, and membrane permeabilization, and its major constituents, ostruthin and imperatorin, have a distinct role in these effects. This makes P. ostruthium and its coumarins promising therapeutics to consider in the fight against drug-resistant mycobacteria.

Background: Vanillin is responsible for the flavor and smell of vanilla, a widely used flavoring agent. Previous studies showed that vanillin could enhance the repair of mutations and thus function as an anti-mutagen. However, its role in cancer, a disease that is closely related to mutation has not yet been fully elucidated. Methods: Hence, this study investigated the cytolytic and cytostatic properties of vanillin against HT-29, a human colorectal cancer cell line. Methods used including cell viability assay, acridine orange (AO)–ethidium bromide (EB) double staining cell morphological analysis, Cell cycle analysis, annexin V–propidium iodide apoptosis test and 5-bromo-2-deoxyuridine (BrdU)-labeling cell proliferation assay. Results: Results showed that apoptosis was induced by vanillin and the IC 50 for HT-29 and NIH/3T3 normal cell lines were 400 μg/ml and 1000 μg/ml, respectively. Different concentrations of vanillin arrest cell cycle at different checkpoints. 5-Bromo-2-deoxyuridine-labeling cell proliferation assay showed that G0/G1 arrest was achieved at lower concentration of vanillin (200 μg/ml) while cell cycle analysis by flow cytometer showed that G2/M arrest occurs at higher concentration of vanillin (1000 μg/ml). Conclusion: Cytolytic and cytostatic effects shown by vanillin showed that it could be a useful colorectal cancer preventive agent. Further in vivo study should be carried out to confirm that similar effects could happen in animals.

Various parts of Mimusops elengi Linn. (Sapotaceae) have been used widely in traditional Indian medicine for the treatment of pain, inflammation and wounds. The study was conducted to explore the use of stem bark of M. elengi on pharmacological grounds and to evaluate the scientific basis of cytotoxic and anti-tumor activity. Extract/fractions were prepared and in vitro cytotoxicity was assessed using SRB assay. Most effective fractions were subjected to fluorescence microscopy based acridine orange/ethidium bromide (AO/EB) and Hoechst 33342 staining to determine apoptosis induction and DNA fragmentation assay. Comet and micronuclei assay were performed to assess genotoxicity. Cell cycle analysis was also performed. In vivo anti-tumor potential was evaluated by Ehrlich ascites carcinoma (EAC) model in mice. The alcoholic stem bark extract of M. elengi along with four fractions showed potential in vitro cytotoxicity in SRB assay. Of these, dichloromethane and ethyl acetate fractions were selected for further studies. The fractions revealed apoptosis inducing potential in AO/EB and Hoechst 33342 staining, which was further confirmed by DNA fragmentation assay. Genotoxic potential was revealed by comet and micronuclei assay. Fractions also exhibited specific cell cycle inhibition in G 0 /G 1 phase. In EAC model, ethyl acetate fraction along with the standard (cisplatin) effectively reduced the increase in body weight compared to control and improved mean survival time. Both fractions were able to restore the altered hematological and biochemical parameters. Hence, M. elengi stem bark may be a possible therapeutic candidate having cytotoxic and anti-tumor potential.

Pozol is a handcrafted nonalcoholic Mayan beverage produced by the spontaneous fermentation of maize dough by lactic acid bacteria. Lactic acid bacteria (LAB) are carriers of chromosomal encoded multidrug‐resistant efflux pumps genes that can be transferred to pathogens and/or confer resistance to compounds released during the fermentation process causing food spoiling. The aim of this study was to evaluate the antibiotic sensibility and the transcriptional expression of ABC‐type efflux pumps in LAB isolated from pozol that contributes to multidrug resistance. Analysis of LAB and Staphylococcus (S.) aureus ATCC 29213 and ATCC 6538 control strains to antibiotic susceptibility, minimal inhibitory concentration (MIC), and minimal bactericidal concentration (MBC) to ethidium bromide were based in “standard methods” whereas the ethidium bromide efflux assay was done by fluorometric assay. Transcriptional expression of efflux pumps was analyzed by RT‐PCR. LAB showed antibiotic multiresistance profiles, moreover, Lactococcus (L.) lactis and Lactobacillus (L.) plantarum displayed higher ethidium bromide efflux phenotype than S. aureus control strains. Ethidium bromide resistance and ethidium bromide efflux phenotypes were unrelated with the overexpression of lmrD in L. lactics, or the underexpression of lmrA in L. plantarum and norA in S. aureus. These findings suggest that, moreover, the analyzed efflux pumps genes, other unknown redundant mechanisms may underlie the antibiotic resistance and the ethidium bromide efflux phenotype in L. lactis and L. plantarum. Phenotypic and molecular drug multiresistance assessment in LAB may improve a better selection of the fermentation starter cultures used in pozol, and to control the antibiotic resistance widespread and food spoiling for health safety. Antibiotic sensibility and transcriptional expression of ABC‐type efflux pumps in lactic acid bacteria isolated from pozol, a nonalcoholic Mayan beverage highly consumed in southeastern Mexico, showed antibiotic multiresistance profiles, and Lactococcus lactis and Lactobacillus plantarum displayed the higher ethidium bromide efflux phenotype. These findings will improve a better selection of the fermentation starter cultures used in pozol and to control the antibiotic resistance widespread and food spoiling for health safety.