Bacterial resistance has become a global concern for public health agencies. Various resistance mechanisms found in Staphylococcus aureus strains grant this bacterium resistance to a wide range of antibiotics, contributing to the rise in human mortality worldwide. Resistance mediated by efflux pumps is one of the most prevalent mechanisms in multi-resistant bacteria, which has aroused the interest of several researchers in the search for possible efflux pump inhibitors. In view of the aforementioned considerations, it is important that new strategies, such as the synthesis of chalcones, be made available as a viable strategy in antimicrobial therapy. In this study, the synthesized chalcone (2E)-1-(3'-aminophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-one was tested for its antibacterial activity, focusing on antibiotic modification and the inhibition of the MepA efflux pump present in S. aureus strain K2068. The broth microdilution method, using microdilution plates, was employed in microbiological tests to determine the minimum inhibitory concentration of the chalcone, antibiotics, and ethidium bromide. The results show that while the chalcone did not exhibit direct antibacterial activity, it synergistically enhanced the effects of ciprofloxacin and ethidium bromide, as evidenced by the reduction in MICs. In addition, computer simulations of molecular docking demonstrate that the tested chalcone acts on the same binding site as the efflux pump inhibitor chlorpromazine, interacting with essentially the same residues. These data suggest that the chalcone may act as a MepA inhibitor.
- MeSH
- Anti-Bacterial Agents * pharmacology chemistry chemical synthesis MeSH
- Bacterial Proteins * metabolism genetics chemistry antagonists & inhibitors MeSH
- Chalcone * pharmacology chemistry MeSH
- Chalcones * pharmacology chemistry MeSH
- Humans MeSH
- Membrane Transport Proteins * metabolism genetics chemistry MeSH
- Microbial Sensitivity Tests MeSH
- Multidrug Resistance-Associated Proteins * metabolism genetics chemistry MeSH
- Molecular Docking Simulation MeSH
- Staphylococcus aureus * drug effects genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Despite secondary prevention with aspirin, patients with stable cardiovascular disease (CVD) remain at elevated long-term risk of major adverse cardiovascular events. The Cardiovascular Outcomes in People Using Anticoagulant Strategies (COMPASS) double-blind, randomized clinical trial demonstrated that aspirin plus low-dose rivaroxaban (COMPASS regime) significantly decreased the incidence of major adverse cardiovascular events by 24% compared with aspirin alone. However, the mechanisms underlying these potential synergistic/nonantithrombotic effects remain elusive. Extracellular vesicles (EVs) are crucial messengers regulating a myriad of biological/pathological processes and are highly implicated in CVD. OBJECTIVES: We hypothesized that circulating EV profiles reflect the cardioprotective properties of the COMPASS regime. METHODS: A cohort of stable CVD patients (N = 40) who participated in the COMPASS trial and were previously randomized to receive aspirin were prospectively recruited and assigned a revised regimen of open-label aspirin plus rivaroxaban. Blood samples were obtained at baseline (aspirin only) and 6-month follow-up. Plasma EV concentration, size, and origin were analyzed by nanoparticle tracking analysis and flow cytometry. EVs were enriched by ultracentrifugation for proteomic analysis. RESULTS: The COMPASS regime fundamentally altered small (<200 nm) and large (200-1000 nm) EV concentration and size compared with aspirin alone. Crucially, levels of platelet-derived and myeloperoxidase-positive EVs became significantly decreased at follow-up. Comparative proteomic characterization further revealed a significant decrease in highly proinflammatory protein expression at follow-up. CONCLUSION: The observed changes in EV subpopulations, together with the differential protein expression profiles, suggest amelioration of an underlying proinflammatory and prothrombotic state upon dual therapy, which may be of clinical relevance toward understanding the fundamental mechanism underlying the reported superior cardiovascular outcomes associated with this antithrombotic regimen.
- MeSH
- Aspirin * administration & dosage therapeutic use adverse effects MeSH
- Double-Blind Method MeSH
- Extracellular Vesicles * metabolism drug effects MeSH
- Platelet Aggregation Inhibitors * administration & dosage adverse effects therapeutic use MeSH
- Factor Xa Inhibitors * administration & dosage adverse effects therapeutic use MeSH
- Cardiovascular Diseases * blood prevention & control drug therapy MeSH
- Drug Therapy, Combination * MeSH
- Middle Aged MeSH
- Humans MeSH
- Inflammation Mediators blood MeSH
- Prospective Studies MeSH
- Proteomics methods MeSH
- Rivaroxaban * administration & dosage MeSH
- Aged MeSH
- Thrombosis blood prevention & control drug therapy MeSH
- Treatment Outcome MeSH
- Inflammation blood MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Randomized Controlled Trial MeSH
Medical research is at the forefront of addressing pressing global challenges, including preventing and treating cardiovascular, autoimmune, and oncological diseases, neurodegenerative disorders, and the growing resistance of pathogens to antibiotics. Understanding the molecular mechanisms underlying these diseases, using advanced medical approaches and cutting-edge technologies, structure-based drug design, and personalized medicine, is critical for developing effective therapies, specifically anticancer treatments. Background/Objectives: One of the key drivers of cancer at the cellular level is the abnormal activity of protein enzymes, specifically serine, threonine, or tyrosine residues, through a process known as phosphorylation. While tyrosine kinase-mediated phosphorylation constitutes a minor fraction of total cellular phosphorylation, its dysregulation is critically linked to carcinogenesis and tumor progression. Methods: Small-molecule inhibitors, such as imatinib or erlotinib, are designed to halt this process, restoring cellular equilibrium and offering targeted therapeutic approaches. However, challenges persist, including frequent drug resistance and severe side effects associated with these therapies. Nanomedicine offers a transformative potential to overcome these limitations. Results: By leveraging the unique properties of nanomaterials, it is possible to achieve precise drug delivery, enhance accumulation at target sites, and improve therapeutic efficacy. Examples include nanoparticle-based delivery systems for TKIs and the combination of nanomaterials with photothermal or photodynamic therapies to enhance treatment effectiveness. Combining nanomedicine with traditional treatments holds promise and perspective for synergistic and more effective cancer management. Conclusions: This review delves into recent advances in understanding tyrosine kinase activity, the mechanisms of their inhibition, and the innovative integration of nanomedicine to revolutionize cancer treatment strategies.
- Publication type
- Journal Article MeSH
- Review MeSH
Lactic acid bacteria (LABs) have emerged as a significant area of study within the field of probiotics due to their diverse health benefits and wide application. This review examines the various methods used to evaluate the antioxidant activity of LABs, including in vitro chemical evaluation methods, cell model evaluation methods, and in vivo evaluation methods. Comprehensive overview of the various assessment techniques employed to elucidate the multifaceted roles of LABs in enhancing the body's natural defenses against oxidative damage. Moreover, this review emphasizes several pivotal aspects of the antioxidant effects of LABs, including the activation of the antioxidant signal pathway, the induction of antioxidative enzymes, the formation of a ROS-binding system, the production of metabolites, the enhancement of intestinal barrier integrity, the activation of the oxidative damage repair system, and the assurance of mitochondrial function. These represent the key antioxidant effects of LABs. The synthesis of this information advances our understanding of the dynamic and diverse antioxidant effects of LABs, providing a foundation for further research into their therapeutic applications in combating oxidative stress-related disorders. Future research should employ multi-omics technologies, genetic engineering, studies on synergistic effects, and large-scale clinical trials to further elucidate the molecular mechanisms underlying the antioxidant effects of LABs. This will promote their application in functional foods, pharmaceuticals, and cosmetics, providing a scientific basis for the development of more efficient antioxidant products.
- MeSH
- Antioxidants * metabolism pharmacology MeSH
- Lactobacillales * metabolism chemistry MeSH
- Humans MeSH
- Oxidative Stress MeSH
- Probiotics * MeSH
- Reactive Oxygen Species metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
BACKGROUND: Cancer remains a major global health challenge, necessitating innovative prevention and treatment approaches. Certain plants, adapted to specific environments, may exhibit bioactive properties with potential anticancer applications. HYPOTHESIS: Seaberry (Hippophae rhamnoides L.) fruit peels may exert anticancer effects in breast carcinoma (BC) models through the additive or synergistic actions of their unique secondary metabolites. METHODS: H. rhamnoides fruit peel extracts were analyzed using the LC-DAD-MS and LC-DAD techniques to profile the content of carotenoids and flavonoids, respectively. The preclinical study evaluated seaberry fruit peel extracts in BC models: (1) a syngeneic 4T1 mouse breast adenocarcinoma model (triple-negative), (2) a rat model of chemically induced mammary carcinogenesis, and (3) in vitro studies with MCF-7 (hormone receptor-positive) and MDA-MB-231 (triple-negative) BC cell lines. RESULTS: LC-DAD-MS and LC-DAD analyses identified dominant metabolites, including isorhamnetin, quercetin glycosides, kaempferol glycosides, catechin, zeaxanthin, and lutein. In the 4T1 mouse model, seaberry treatment resulted in a significant, dose-dependent reduction in tumor volume (43% and 48% compared to controls) and a decrease in the mitotic activity index. Serum cytokine analysis showed dose-dependent reductions in IL-6, IL-10, and TNF-α. In the rat chemopreventive model, high-dose seaberry improved cancer prognosis by reducing the ratio of poorly differentiated tumors and increasing caspase-3 and Bax expression while decreasing Ki-67 and malondialdehyde levels. Both treatment doses elevated the Bax/Bcl-2 ratio and reduced the expression of cancer stem cell markers CD44, EpCam, and VEGF compared to controls. Epigenetic analyses revealed histone modifications (H4K16ac, H4K20me3) and altered methylation of tumor-suppressor genes (PITX2, RASSF1, PTEN, TIMP3). Microarray analysis (758 miRNAs) identified beneficial changes in nine oncogenic/tumor-suppressive miRNAs, including miR-10a-5p, miR-322-5p, miR-450a-5p, miR-142-5p, miR-148b-3p, miR-1839-3p, miR-18a-5p, miR-1949, and miR-347. In vitro, ethanolic seaberry extract conferred partial resistance to cisplatin-induced cytotoxicity in MCF-7 and MDA-MB-231 cells at IC50 concentrations. CONCLUSION: This study of H. rhamnoides in rodent BC models shows promising data but requires rigorous, long-term validation. Integrating plant-based nutraceuticals into oncology necessitates precise cancer-type profiling and patient stratification for effective personalized treatments.
- Publication type
- Journal Article MeSH
Myofascial pain syndrome (MPS) is a common musculoskeletal disorder that significantly affects quality of life. Conventional treatment approaches include pharmacological interventions, physical therapy, and procedures such as dry needling. Among these, ultrasound-guided injections (USGIs) have gained recognition for their precision and therapeutic benefits. Additionally, repetitive peripheral magnetic stimulation (rPMS) has emerged as a non-invasive neuromodulatory technique for pain management. This perspective article examines the physiological mechanisms and clinical applications of USGIs and rPMS, particularly in the lumbar multifidus muscle, and explores their potential synergistic effects. MPS is often associated with chronic muscle dysfunction due to energy depletion, leading to persistent pain and motor impairment. USGIs play a crucial role in restoring muscle perfusion, disrupting pain cycles, and providing diagnostic insights in real time. In parallel, rPMS modulates neuromuscular activation, enhances endogenous pain control, and promotes functional recovery. Ultrasound guidance enhances the precision and effectiveness of interventions, such as dry needling, interfascial plane blocks, and fascial hydrodissection, while rPMS complements these strategies by facilitating neuromuscular reconditioning and reducing pain via central and peripheral mechanisms. The preliminary findings suggest that combining multifidus USGIs with rPMS results in significant pain relief and functional improvements in patients with chronic low back pain. Integrating USGIs with rPMS represents a promising multimodal strategy for managing MPS. By combining targeted injections with non-invasive neuromodulation, clinicians may optimize therapeutic outcomes and provide sustained relief for patients with chronic musculoskeletal pain. Further research is needed to refine treatment protocols and assess the long-term efficacy.
- Publication type
- Journal Article MeSH
Východiská: Na význam stresu pri nádorových chorobách poukazovali lekári už od čias Galéna. Avšak až v posledných dvoch desaťročiach umožnil kombinovaný onkologický a neurovedný výskum exaktne preskúmať tento vzťah a popísať dráhy a mechanizmy, ktoré sprostredkúvajú stimulačný vplyv stresu na nádorový proces. Tento nepriaznivý účinok stresu je sprostredkovaný hlavne mediátormi sympatikoadrenálneho systému, noradrenalínom a adrenalínom. Tieto katecholamíny aktiváciou adrenergických receptorov v nádorovom mikro- a makroprostredí stimulujú proliferáciu nádorových buniek a neoangiogenézu a inhibujú protinádorovú imunitu a znižujú účinnosť štandardnej protinádorovej liečby. Zistilo sa tiež, že intervencie obmedzujúce pôsobenie stresu na organizmus nie len že zlepšujú kvalitu života onkologických pacientov, ale môžu zlepšovať aj ich prežívanie. Vzhľadom na komplexnosť vplyvu stresu na organizmus sa experimentálne a klinické štúdie v prevažnej väčšine zameriavajú na skúmanie účinku jednej intervencie obmedzujúcej stimulačný vplyv sympatikoadrenálneho systému na nádorový proces. Cieľ: Zámerom tohto názorového článku je poukázať na možnosť synergického účinku kombinácie viacerých intervencií obmedzujúcich aktiváciu sympatikoadrenálneho systému a na základe dostupných údajov navrhnúť takú kombináciu týchto intervencií, ktorá je aplikovateľná v podpornej liečbe onkologických pacientov už aj v súčasnosti. Záver: Protokol Synergy, ktorý zahŕňa nefarmakologické intervencie zamerané na obmedzenie pôsobenia stresu, má potenciál zlepšiť kvalitu života a u určitých pacientov aj prognózu ich choroby. Zavedenie tohto protokolu do bežnej klinickej praxe síce bude vyžadovať vyriešenie personálnych a finančných aspektov, ktoré s jeho implikáciou súvisia, výsledkom ale môže byť významné zvýšenie úrovne starostlivosti o onkologických pacientov.
Background: The importance of stress in cancer has been noted by physicians since the time of Galen. However, it is only in the last two decades that combined oncological and neuroscientific research has allowed to explore this relationship in an exact way and to describe the pathways and mechanisms that mediate the stimulatory effect of stress on cancer. This adverse effect of stress is mediated mainly by the mediators of the sympathoadrenal system, norepinephrine and epinephrine, which, by activating adrenergic receptors in the tumor micro- and macro-environment, stimulate tumor cell proliferation and neoangiogenesis and inhibit antitumor immunity, reducing the efficacy of standard anticancer therapies. It has also been found that interventions reducing the effects of stress on the body not only improve the quality of life of cancer patients but may also improve their survival. Given the complexity of the impact of stress on the organism, experimental and clinical studies have overwhelmingly focused on investigating the effect of a single intervention reducing the stimulatory influence of the sympathoadrenal system on the cancer process. Purpose: The aim of this opinion article is to highlight the possibility of a synergistic effect of a combination of several interventions limiting the activation of the sympathoadrenal system and, based on the available data, to propose a combination of these interventions that is applicable in the supportive treatment of cancer patients even nowadays. Conclusion: The Protocol Synergy, which includes non-pharmacological interventions aimed at reducing the effects of stress on the cancer patient, has the potential to improve the quality and, in certain patients, the prognosis of their disease. Although the introduction of this protocol into routine clinical practice will require addressing the personnel and financial aspects associated with its implementation, it has the potential to significantly improve the level of care for cancer patients.
- MeSH
- Adrenergic beta-Antagonists therapeutic use MeSH
- Exercise MeSH
- Clinical Protocols * MeSH
- Quality of Life psychology MeSH
- Humans MeSH
- Neoplasms * etiology psychology MeSH
- Cold Temperature adverse effects MeSH
- Stress, Psychological * MeSH
- Psychotherapy methods MeSH
- Relaxation Therapy MeSH
- Heart Rate MeSH
- Self-Help Groups MeSH
- Sympathoadrenal System MeSH
- Check Tag
- Humans MeSH
The transcription factor p53 is the most frequently impaired tumor suppressor in human cancers. In response to various stress stimuli, p53 activates transcription of genes that mediate its tumor-suppressive functions. Distinctive characteristics of p53 outlined here enable a well-defined program of genes involved in cell cycle arrest, apoptosis, senescence, differentiation, metabolism, autophagy, DNA repair, anti-viral response, and anti-metastatic functions, as well as facilitating autoregulation within the p53 network. This versatile, anti-cancer network governed chiefly by a single protein represents an immense opportunity for targeted cancer treatment, since about half of human tumors retain unmutated p53. During the last two decades, numerous compounds have been developed to block the interaction of p53 with the main negative regulator MDM2. However, small molecule inhibitors of MDM2 only induce a therapeutically desirable apoptotic response in a limited number of cancer types. Moreover, clinical trials of the MDM2 inhibitors as monotherapies have not met expectations and have revealed hematological toxicity as a characteristic adverse effect across this drug class. Currently, combination treatments are the leading strategy for enhancing efficacy and reducing adverse effects of MDM2 inhibitors. This review summarizes efforts to identify and test therapeutics that work synergistically with MDM2 inhibitors. Two main types of drugs have emerged among compounds used in the following combination treatments: first, modulators of the p53-regulated transcriptome (including chromatin modifiers), translatome, and proteome, and second, drugs targeting the downstream pathways such as apoptosis, cell cycle arrest, DNA repair, metabolic stress response, immune response, ferroptosis, and growth factor signaling. Here, we review the current literature in this field, while also highlighting overarching principles that could guide target selection in future combination treatments.
- MeSH
- Molecular Targeted Therapy * MeSH
- Humans MeSH
- Tumor Suppressor Protein p53 * metabolism genetics antagonists & inhibitors MeSH
- Neoplasms * drug therapy metabolism genetics MeSH
- Antineoplastic Agents * therapeutic use pharmacology MeSH
- Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
The literature documenting the value of drug-like molecules found in natural products is vast. Although many dietary and herbal remedies have been found to be effective for treating intestinal inflammation, the identification of their active components has lagged behind. In this study, we find that a major ginger component, furanodienone (FDN), is a selective pregnane X receptor (PXR) ligand with agonistic transcriptional outcomes. We show that FDN binds within a sub-pocket of the PXR ligand binding domain (LBD), with subsequent alterations in LBD structure. Using male mice, we show that orally provided FDN has potent PXR-dependant anti-inflammatory outcomes that are colon-specific. Increased affinity and target gene activation in the presence of synergistically acting agonists indicates further opportunities for augmenting FDN activity, efficacy and safety. Collectively, these results support the translational potential of FDN as a therapeutic agent for the treatment and prevention of colonic diseases.
- MeSH
- Anti-Inflammatory Agents pharmacology chemistry MeSH
- Furans pharmacology MeSH
- Colitis drug therapy chemically induced metabolism pathology MeSH
- Colon drug effects pathology metabolism MeSH
- Humans MeSH
- Ligands MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Pregnane X Receptor * metabolism genetics MeSH
- Inflammation drug therapy metabolism MeSH
- Zingiber officinale * chemistry MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
In recent years, deep eutectic solvents (DESs) with their outstanding solubilization properties have emerged as strong candidates for oral enabling formulations of poorly soluble drugs. This study explores the use of drug-based therapeutic DESs (THEDESs) to solubilize a poorly soluble compound with the aim of providing a fixed-dose combination of two complementary therapeutic agents. Specifically, potential anticancer effects of ibuprofen (IBU) are harnessed in a novel type of THEDES to dissolve higher amounts of abiraterone acetate (AbAc), an antitumor agent. Four IBU-based combinations were studied: 1:4 M ratio with octanoic acid (OctA), 1:5 with nonanoic acid (NonA), 1:3 with decanoic acid (DeA) or 1:2 with dodecanoic acid (DoA). Fatty acids of different chain lengths were analyzed and discussed considering surface charge densities obtained via quantum chemistry. The THEDESs listed could apparently dissolve AbAc amounts up to 1311.0 ± 125.4 mg/g in IBU:OctA THEDES, 1151.7 ± 22.2 mg/g in IBU:NonA, 1160.4 ± 33.5 mg/g in IBU:DeA, and 231.3 ± 10.7 mg/g in IBU:DoA. In vitro dissolution of the simultaneously released drugs reached 37.8 ± 9.0 % to 64.2 ± 1.0 % for IBU and 5.0 ± 3.3 % to 19.4 ± 0.1 % for AbAc. This increased to between 60.4 ± 2.8 % and 79.4 ± 5.0 % of released IBU, and 23.6 ± 1.0 % to 57.3 ± 5.8 % of released AbAc, with 20 % (w/w) Tween 80 added to the formulations. This showed the significant potential of drug-containing THEDESs as solubilizing agents for poorly soluble drugs, in the form of fixed-dose combinations of synergistic APIs.
- MeSH
- Abiraterone Acetate * chemistry administration & dosage MeSH
- Chemistry, Pharmaceutical methods MeSH
- Drug Combinations MeSH
- Ibuprofen * chemistry administration & dosage MeSH
- Fatty Acids chemistry MeSH
- Drug Compounding methods MeSH
- Antineoplastic Agents chemistry administration & dosage MeSH
- Solvents * chemistry MeSH
- Solubility * MeSH
- Drug Liberation MeSH
- Publication type
- Journal Article MeSH
